Brain Injury

Research & Studies

Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury

 

“Oxidative stress is the principal factor in traumatic brain injury (TBI) that initiates events that result in protracted neuronal dysfunction and remodeling. Importantly, antioxidants can protect the brain against oxidative damage and modulate the capacity of the brain to cope with synaptic dysfunction and cognitive impairment. However, no studies have investigated the effects of hydrogen-rich saline on cognitive deficits after TBI. In the present study, rats with fluid percussion injury (FPI) were used to investigate the protective effects of hydrogen-rich saline. The results showed that hydrogen-rich saline reduced the level of malondialdehyde (MDA) and elevated the level of silent information regulator 2 (Sir2). In addition, treatment with hydrogen-rich saline, which elevated the levels of molecules associated with brain-derived neurotropic factor (BDNF)-mediated synaptic plasticity, improved cognitive performance in the Morris water maze after mild TBI. These results suggest that hydrogen-rich saline can protect the brain against the deleterious effects of mild TBI on synaptic plasticity and cognition and that hydrogen-rich saline could be an effective therapeutic strategy for patients with cognitive deficits after TBI.”

 

Hou, Z., Luo, W., Sun, X., Hao, S., Zhang, Y., Xu, F., . . . Liu, B. (2012). Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Research Bulletin, 88(6), 560-565. doi: 10.1016/j.brainresbull.2012.06.006

 

Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury

 

“Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI.”

 

Dohi, K., Kraemer, B. C., Erickson, M. A., Mcmillan, P. J., Kovac, A., Flachbartova, Z., . . . Banks, W. A. (2014). Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLOS ONE, 9(9), 1-16. doi: 10.1371/journal.pone.0108034 

 

 

Treatment with hydrogen-rich saline delays disease progression in a mouse model of amyotrophic lateral sclerosis

 

“Treatment of mutant SOD1 G93A mice with hydrogen-rich saline (HRS, i.p.) significantly delayed disease onset and prolonged survival, and attenuated loss of motor neurons and suppressed microglial and glial activation. Treatment of mutant SOD1 G93A mice with HRS inhibited the release of mitochondrial apoptogenic factors and the subsequent activation of downstream caspase-3. Furthermore, treatment of mutant SOD1 G93A mice with HRS reduced levels of protein carbonyl and 3-nitrotyrosine, and suppressed formation of reactive oxygen species (ROS), peroxynitrite, and malondialdehyde. Treatment of mutant SOD1 G93A mice with HRS preserved mitochondrial function, marked by restored activities of Complex I and IV, reduced mitochondrial ROS formation and enhanced mitochondrial adenosine triphosphate synthesis. In conclusion, hydrogen molecule may be neuroprotective against ALS, possibly through abating oxidative and nitrosative stress and preserving mitochondrial function.”

 

Zhang, Y., Li, H., Yang, C., Fan, D., Guo, D., Hu, H., . . . Pan, S. (2015). Treatment with hydrogen-rich saline delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurochemical Research, 41(4), 770-778. doi: 10.1007/s11064-015-1750-7

Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats

 

“HRW treatment improved neurological function and tended to improve overall survival but without significant difference. The numbers of bleeds and infarcts were lower in the cortex and hippocampus in the HRW group. The HRW group exhibited a significantly lower number of 8-hydroxy-2'-deoxyguanosine-positive cells and vessels of extravasated albumin in the hippocampus compared with the control group. MMP-9 activity was reduced in the hippocampus in the HRW group compared with the control group. CONCLUSION: The present study suggests that ingestion of HRW can improve neurological function outcome in the SHRSP model. This beneficial effect may be due to attenuation of BBB disruption via reduction in reactive oxygen species and suppression of MMP-9 activity in the hippocampus.”

 

Takeuchi, S., Nagatani, K., Otani, N., Nawashiro, H., Sugawara, T., Wada, K., & Mori, K. (2015). Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats. BioMed Central Neuroscience, 16(1), 1-13. doi: 10.1186/s12868-015-0165-3

 

Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice

 

“Molecular hydrogen has been shown to have neuroprotective effects in mouse models of acute neurodegeneration. The effect was suggested to be mediated by its free-radical scavenger properties. However, it has been shown recently that molecular hydrogen alters gene expression and protein phosphorylation. The aim of this study was to test whether chronic ad libitum consumption of molecular hydrogen-enriched electrochemically reduced water (H-ERW) improves the outcome of lipopolysaccharide (LPS)-induced neuroinflammation. Seven days after the initiation of H-ERW treatment, C57Bl/6 mice received a single injection of LPS (0.33 mg/kg i.p.) or an equivalent volume of vehicle. The LPS-induced sickness behaviour was assessed 2 h after the injection, and recovery was assessed by monitoring the spontaneous locomotor activity in the homecage for 72 h after the administration of LPS. The mice were killed in the acute or recovery phase, and the expression of pro- and antiinflammatory cytokines in the hippocampus was assessed by real-time PCR. We found that molecular hydrogen reduces the LPS-induced sickness behaviour and promotes recovery. These effects are associated with a shift towards anti-inflammatory gene expression profile at baseline (downregulation of TNF- α and upregulation of IL-10). In addition, molecular hydrogen increases the amplitude, but shortens the duration and promotes the extinction of neuroinflammation. Consistently, molecular hydrogen modulates the activation and gene expression in a similar fashion in immortalized murine microglia (BV-2 cell line), suggesting that the effects observed in vivo may involve the modulation of microglial activation. Taken together, our data point to the regulation of cytokine expression being an additional critical mechanism underlying the beneficial effects of molecular hydrogen.”

 

Spulber, S., Edoff, K., Hong, L., Morisawa, S., Shirahata, S., & Ceccatelli, S. (2012). Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice. PLOS ONE, 7(7), 1-12. doi: 10.1371/journal.pone.0042078

 

Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice

 

“We have reported that hydrogen (H(2)) acts as an efficient antioxidant by gaseous rapid diffusion. When water saturated with hydrogen (hydrogen water) was placed into the stomach of a rat, hydrogen was detected at several microM level in blood. Because hydrogen gas is unsuitable for continuous consumption, we investigated using mice whether drinking hydrogen water ad libitum, instead of inhaling hydrogen gas, prevents cognitive impairment by reducing oxidative stress. Chronic physical restraint stress to mice enhanced levels of oxidative stress markers, malondialdehyde and 4-hydroxy-2-nonenal, in the brain, and impaired learning and memory, as judged by three different methods: passive avoidance learning, object recognition task, and the Morris water maze. Consumption of hydrogen water ad libitum throughout the whole period suppressed the increase in the oxidative stress markers and prevented cognitive impairment, as judged by all three methods, whereas hydrogen water did not improve cognitive ability when no stress was provided. Neural proliferation in the dentate gyrus of the hippocampus was suppressed by restraint stress, as observed by 5-bromo-2'-deoxyuridine incorporation and Ki-67 immunostaining, proliferation markers. The consumption of hydrogen water ameliorated the reduced proliferation although the mechanistic link between the hydrogen-dependent changes in neurogenesis and cognitive impairments remains unclear. Thus, continuous consumption of hydrogen water reduces oxidative stress in the brain, and prevents the stress-induced decline in learning and memory caused by chronic physical restraint. Hydrogen water may be applicable for preventive use in cognitive or other neuronal disorders.”

 

Nagata, K., Nakashima-Kamimura, N., Mikami, T., Ohsawa, I., & Ohta, S. (2008). Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology, 34(2), 501-508. doi: 10.1038/npp.2008.95

 

Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer's disease

 

“This study is to examine if hydrogen-rich saline reduced amyloid-beta (Aβ) induced neural inflammation and oxidative stress in a rat model by attenuation of activation of JNK and NF-κB. Sprague-Dawley male rats (n=18, 280-330 g) were divided into three groups, sham operated, Aβ1-42 injected and Aβ1-42 plus hydrogen-rich saline treated animals. Hydrogen-rich saline (5 ml/kg, i.p., daily) was injected for 10 days after intraventricular injection of Aβ1-42. The levels of IL-1β were assessed by ELISA analysis, 8-OH-dG by immunohistochemistry in the brain slides, and JNK and NF-κB by immunohistochemistry and western blotting. After Aβ1-42 injection, the level of IL-1β, 8-OH-dG, JNK and NF-κB all increased in brain tissues, while hydrogen-rich saline treatment decreased the level of IL-1β, 8-OH-dG and the activation of JNK and NF-κB. In conclusion, hydrogen-rich saline prevented Aβ-induced neuroinflammation and oxidative stress, possibly by attenuation of activation of c-Jun NH₂-terminal kinase (JNK) and nuclear factor-κB (NF-κB) in this rat model.”

 

Wang, C., Li, J., Liu, Q., Yang, R., Zhang, J. H., Cao, Y., & Sun, X. (2011). Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer's disease. Neuroscience Letters, 491(2), 127-132. doi: 10.1016/j.neulet.2011.01.022

 

Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats

 

“Measurements and main results: hydrogen gas significantly alleviated brain edema and blood-brain barrier disruption, reduced apoptosis, and improved neurologic function at 24 hrs but not 72 hrs after subarachnoid hemorrhage. These effects were associated with the amelioration of oxidative injury of lipid, protein, and DNA. Conclusions: hydrogen gas could exert its neuroprotective effect against early brain injury after subarachnoid hemorrhage by its antioxidative activity.”

 

Zhan, Y., Chen, C., Suzuki, H., Hu, Q., Zhi, X., & Zhang, J. H. (2012). Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Critical Care Medicine, 40(4), 1291-1296. doi: 10.1097/ccm.0b013e31823da96d

 

Hydrogen-rich saline reverses oxidative stress, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and puncture

 

“Cecal ligation and puncture resulted in a poor survival rate, evidence of brain injury, and cognitive dysfunciton. The hippocampal reactive oxygen species and malondialdehyde levels increased significantly, and superoxide dismutase activity decreased significantly. HRS reversed these changes in a dose-dependend manner. CONCLUSION These findings indicate that HRS could attenuate the consequences of sepsis induced by cecal ligation and puncture in rats, at least in part, by the inhibition of oxidative stress.”

 

Zhou, J., Chen, Y., Huang, G., Li, J., Wu, G., Liu, L., . . . Wang, J. (2012). Hydrogen-rich saline reverses oxidative stress, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and puncture. Journal of Surgical Research, 178(1), 390-400. doi: 10.1016/j.jss.2012.01.041

 

Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits

 

“The level of MDA, caspase-12/3 and brain water content increased significantly at 72 hours after experimental SAH. Correspondingly, obvious brain injury was found in the SAH group by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) and Nissl staining. Similar results were found in the SAH+saline group. In contrast, the upregulated level of MDA, caspase-12/3 and brain edema was attenuated and the brain injury was substantially alleviated in the hydrogen treated rabbits, but the improvement of neurology outcome was not obvious. The results suggest that treatment with hydrogen in experimental SAH rabbits could alleviate brain injury via decreasing the oxidative stress injury and brain edema. Hence, we conclude that hydrogen possesses the potential to be a novel therapeutic agent for EBI after SAH.”

 

Zhuang, Z., Zhou, M., You, W., Zhu, L., Ma, C., Sun, X., & Shi, J. (2012). Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neuroscience, 13(1), 1-10. doi: 10.1186/1471-2202-13-47

 

Hydrogen is neuroprotective against surgically induced brain injury

 

“SBI resulted in localized brain edema (p = < 0.001). Hydrogen (2.9%) administered concurrently with surgery significantly decreased the formation of cerebral edema (p = 0.028) and improved neurobehavioral score (p = 0.022). However, hydrogen treatment failed to reduce oxidative stress (LPO assay) or inflammation (MPO assay) in brain tissues.
Hydrogen appears to be promising as an effective, yet inexpensive way to reduce cerebral edema caused by surgical procedures. Hydrogen has the potential to improve clinical outcome, decrease hospital stay, and reduce overall cost to patients and the health care system.”

 

Eckermann, J. M., Chen, W., Jadhav, V., Hsu, F. P., Colohan, A. R., Tang, J., & Zhang, J. H. (2011). Hydrogen is neuroprotective against surgically induced brain injury. Medical Gas Research, 1(1), 1-7. doi: 10.1186/2045-9912-1-7

 

Hydrogen-rich saline prevents early neurovascular dysfunction resulting from inhibition of oxidative stress in STZ-diabetic rats

 

“STZ-diabetic rats were marked by clearly reduced b-wave amplitudes and oscillatory potentials, DM-related BRB breakdown and histological changes in the inner retina, all of which were suppressed following treatment with hydrogen-rich saline. Furthermore, hydrogen-rich saline reduced oxidative stress, increased antioxidant enzyme activities and preserved synaptophysin and BDNF levels in the diabetic rat retina. Based on its inhibition of oxidative stress and up-regulation of anti-oxidative enzymes, we conclude that hydrogen-rich saline is a potentially valuable therapeutic modality for the treatment of DR.”

 

Feng, Y., Wang, R., Xu, J., Sun, J., Xu, T., Gu, Q., & Wu, X. (2012). Hydrogen-rich saline prevents early neurovascular dysfunction resulting from inhibition of oxidative stress in STZ-diabetic rats. Current Eye Research, 38(3), 396-404. doi: 10.3109/02713683.2012.748919

 

Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease

 

“Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinson's disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of approximately 50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinson's disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinson's disease.”

 

Fu, Y., Ito, M., Fujita, Y., Ito, M., Ichihara, M., Masuda, A., . . . Ohno, K. (2009). Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. Neuroscience Letters, 453(2), 81-85. doi: 10.1016/j.neulet.2009.02.016

 

Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

 

“It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration.”

 

Fujita, K., Seike, T., Yutsudo, N., Ohno, M., Yamada, H., Yamaguchi, H., . . . Noda, M. (2009). Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. PLOS ONE, 4(9), 1-10. doi: 10.1371/journal.pone.0007247

 

Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice

 

“Hydrogen has been reported to have neuron protective effects due to its antioxidant properties, but the effects of hydrogen on cognitive impairment due to senescence-related brain alterations and the underlying mechanisms have not been characterized. In this study, we investigated the efficacies of drinking hydrogen water for prevention of spatial memory decline and age-related brain alterations using senescence-accelerated prone mouse 8 (SAMP8), which exhibits early aging syndromes including declining learning ability and memory. However, treatment with hydrogen water for 30 days prevented age-related declines in cognitive ability seen in SAMP8 as assessed by a water maze test and was associated with increased brain serotonin levels and elevated serum antioxidant activity. In addition, drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control, aged brains of mice receiving regular water. On the basis of our results, hydrogen water merits further investigation for possible therapeutic/preventative use for age-related cognitive disorders.”

 

Gu, Y., Huang, C., Inoue, T., Yamashita, T., Ishida, T., Kang, K., & Nakao, A. (2010). Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. Journal of Clinical Biochemistry and Nutrition, 46(3), 269-276. doi: 10.3164/jcbn.10-19

 

Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins

 

“Hydrogen-rich water (HRW) has anti-oxidant activities, and it exerts neuroprotective effects during ischemia-reperfusion brain injury. Parvalbumin and hippocalcin are two calcium buffering proteins, which are involved in neuronal differentiation, maturation and apoptosis. The aim of this study was to investigate whether HRW could moderate parvalbumin and hippocalcin expression during ischemic brain injury and glutamate toxicity-induced neuronal cell death. Focal brain ischemia was induced in male Sprague-Dawley rats by middle cerebral artery occlusion (MCAO). Rats were treated with H2O or HRW (6 ml/kg per rat) before and after MCAO, and cerebral cortical tissues were collected 1, 7 and 14 days after MCAO. Based on our results, HRW treatment was able to reduce brain infarct volume and improve neurological function following ischemic brain injury. In addition, HRW prevented the ischemia-induced reduction of parvalbumin and hippocalcin levels in vivo and also reduced the glutamate toxicity-induced death of neurons, including the dose-dependent reduction of glutamate toxicity-associated proteins in vitro. Moreover, HRW attenuated the glutamate toxicity-induced elevate in intracellular Ca(2+) levels. All these results suggest that HRW could protect against ischemic brain injury and that the maintenance of parvalbumin and hippocalcin levels by HRW during ischemic brain injury might contribute to the neuroprotective effects against neuron damage.”

 

Han, L., Tian, R., Yan, H., Pei, L., Hou, Z., Hao, S., . . . Zhang, Q. (2015). Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins. Brain Research, 1615, 129-138. doi: 10.1016/j.brainres.2015.04.038

  

Hydrogen supplemented air inhalation reduces changes of prooxidant enzyme and gap junction protein levels after transient global cerebral ischemia in the rat hippocampus

 

“Transient global cerebral ischemia (TGCI) occurs during acute severe hypotension depriving the brain of oxygen and glucose for a short period of time. During reperfusion, several mechanisms can induce secondary neuronal damage, including the increased production of reactive oxygen species (ROS). Hydrogen gas-enriched air inhalation is a neuroprotective approach with proven antioxidant potential, which has not yet been examined in TGCI. Accordingly, we set out to describe the effect of inhalation of 2.1% hydrogen supplemented room air (H(2)-RA) in comparison with a well studied neuroprotective agent, rosiglitazone (RSG) in a TGCI rat model. Male Wistar rats were exposed to TGCI (n=26) or sham operation (n=26), while a third group served as intact control (naive, n=5). The operated groups were further divided into non-treated, H(2)-RA, RSG (6 mg/kg i.v.) and vehicle treated animals. Tissue samples from the hippocampus and frontal cortex were taken 3 days following surgery. Western blot analysis was applied to determine the expressions of cyclooxygenase-2 (COX-2), neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively), manganese superoxide dismutase (MnSOD) and glial connexin proteins: connexin 30 and connexin 43. The expressions of COX-2, and connexin proteins were upregulated, while nNOS was downregulated 3 days after TGCI. Both RSG and H(2)-RA prevented the changes of enzyme and connexin levels. Considering the lack of harmful side effects, inhalation of H(2)-RA can be a promising approach to reduce neuronal damage after TGCI.”

 

Hugyecz, M., Mracskó, É, Hertelendy, P., Farkas, E., Domoki, F., & Bari, F. (2011). Hydrogen supplemented air inhalation reduces changes of prooxidant enzyme and gap junction protein levels after transient global cerebral ischemia in the rat hippocampus. Brain Research, 1404, 31-38. doi: 10.1016/j.brainres.2011.05.068

 

Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson's disease in rats

 

“Hydrogen water increased breath hydrogen concentrations from 8.6 ± 2.1 to 32.6 ± 3.3 ppm (mean and SEM, n = 8) in 10 min in healthy subjects. Lactulose increased breath hydrogen concentrations in 86% of healthy subjects and 59% of PD patients. Compared to monophasic hydrogen increases in 71% of healthy subjects, 32% and 41% of PD patients showed biphasic and no increases, respectively. Lactulose also increased breath hydrogen levels monophasically in 9 rats. Lactulose, however, marginally ameliorated 6-OHDA-induced PD in rats. Continuous administration of 2% hydrogen gas similarly had marginal effects. On the other hand, intermittent administration of 2% hydrogen gas prevented PD in 4 of 6 rats. Lack of dose responses of hydrogen and the presence of favorable effects with hydrogen water and intermittent hydrogen gas suggest that signal modulating activities of hydrogen are likely to be instrumental in exerting a protective effect against PD.”

 

Ito, M., Hirayama, M., Yamai, K., Goto, S., Ito, M., Ichihara, M., & Ohno, K. (2012). Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Medical Gas Research, 2(1), 1-7. doi: 10.1186/2045-9912-2-15

 

 

Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?

 

“It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).”

 

Faden, A. I., & Loane, D. J. (2014). Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurotherapeutics, 12(1), 143-150. doi: 10.1007/s13311-014-0319-5

 

Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment

 

“Free radicals and other so-called 'reactive species' are constantly produced in the brain in vivo. Some arise by 'accidents of chemistry', an example of which may be the leakage of electrons from the mitochondrial electron transport chain to generate superoxide radical (O2*-). Others are generated for useful purposes, such as the role of nitric oxide in neurotransmission and the production of O2*- by activated microglia. Because of its high ATP demand, the brain consumes O2 rapidly, and is thus susceptible to interference with mitochondrial function, which can in turn lead to increased O2*- formation. The brain contains multiple antioxidant defences, of which the mitochondrial manganese-containing superoxide dismutase and reduced glutathione seem especially important. Iron is a powerful promoter of free radical damage, able to catalyse generation of highly reactive hydroxyl, alkoxyl and peroxyl radicals from hydrogen peroxide and lipid peroxides, respectively. Although most iron in the brain is stored in ferritin, 'catalytic' iron is readily mobilised from injured brain tissue. Increased levels of oxidative damage to DNA, lipids and proteins have been detected by a range of assays in post-mortem tissues from patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and at least some of these changes may occur early in disease progression. The accumulation and precipitation of proteins that occur in these diseases may be aggravated by oxidative damage, and may in turn cause more oxidative damage by interfering with the function of the proteasome. Indeed, it has been shown that proteasomal inhibition increases levels of oxidative damage not only to proteins but also to other biomolecules. Hence, there are many attempts to develop antioxidants that can cross the blood-brain barrier and decrease oxidative damage. Natural antioxidants such as vitamin E (tocopherol), carotenoids and flavonoids do not readily enter the brain in the adult, and the lazaroid antioxidant tirilazad (U-74006F) appears to localise in the blood-brain barrier. Other antioxidants under development include modified spin traps and low molecular mass scavengers of O2*-. One possible source of lead compounds is the use of traditional remedies claimed to improve brain function. Little is known about the impact of dietary antioxidants upon the development and progression of neurodegenerative diseases, especially Alzheimer's disease. Several agents already in therapeutic use might exert some of their effects by antioxidant action, including selegiline (deprenyl), apomorphine and nitecapone.”

 

Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs & Aging, 18(9), 685-716. doi: 10.2165/00002512-200118090-00004

 

The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis

 

“Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motoneurons and degradation of the neuromuscular junctions (NMJ). Consistent with the dying-back hypothesis of motoneuron degeneration the decline in synaptic function initiates from the presynaptic terminals in ALS. Oxidative stress is a major contributory factor to ALS pathology and affects the presynaptic transmitter releasing machinery. Indeed, in ALS mouse models nerve terminals are sensitive to reactive oxygen species (ROS) suggesting that oxidative stress, along with compromised mitochondria and increased intracellular Ca(2+) amplifies the presynaptic decline in NMJ. This initial dysfunction is followed by a neurodegeneration induced by inflammatory agents and loss of trophic support. To develop effective therapeutic approaches against ALS, it is important to identify the mechanisms underlying the initial pathological events. Given the role of oxidative stress in ALS, targeted antioxidant treatments could be a promising therapeutic approach. However, the complex nature of ALS and failure of monotherapies suggest that an antioxidant therapy should be accompanied by anti-inflammatory interventions to enhance the restoration of the redox balance.”

 

Pollari, E., Goldsteins, G., Bart, G., Koistinaho, J., & Giniatullin, R. (2014). The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis. Frontiers in Cellular Neuroscience, 13, 1-8. doi: 10.3389/fncel.2014.00131

 

Recent advances in the treatment of neurodegenerative diseases based on GSH delivery systems

 

“Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD.”

 

Cacciatore, I., Baldassarre, L., Fornasari, E., Mollica, A., & Pinnen, F. (2012). Recent advances in the treatment of neurodegenerative diseases based on GSH delivery systems. Oxidative Medicine and Cellular Longevity, 2012, 1-12. doi: 10.1155/2012/240146

 

Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET.

 

“Increasing evidence suggests that neuroinflammation is an active process in Parkinson's disease (PD) that contributes to ongoing neurodegeneration. PD brains and experimental PD models show elevated cytokine levels and up-regulation of inflammatory-associated factors as cyclo-oxygenase-2 and inducible nitric oxide oxidase. Antiinflammatory treatment reduced neuronal degeneration in experimental models. In this review, we summarize the place of neuroinflammation in the pathophysiology of PD. In vivo PET studies are discussed. These methods provide a means to monitor in vivo potential clinical relevance of antiinflammatory treatment strategies in PD.”

 

Bartels, A. L., & Leenders, K. L. (2007). Neuroinflammation in the pathophysiology of Parkinson's disease: Evidence from animal models to human in vivo studies with [11 C]-PK11195 PET. Movement Disorders, 22(13), 1852-1856. doi: 10.1002/mds.21552

 

The role of oxidative stress in Parkinson's disease.

 

“Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.”

 

Dias, V., Junn, E., & Mouradian, M. M. (2013). The role of oxidative stress in Parkinson's disease. Journal of Parkinson's Disease, 3(4), 461-491. doi: 10.3233/JPD-130230. 

Lipid-Mediated Oxidative Stress and Inflammation in the Pathogenesis of Parkinson's Disease

 

“Parkinson's disease (PD) is a neurodegenerative movement disorder of unknown etiology. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, depletion of dopamine in the striatum, abnormal mitochondrial and proteasomal functions, and accumulation of α-synuclein that may be closely associated with pathological and clinical abnormalities. Increasing evidence indicates that both oxidative stress and inflammation may play a fundamental role in the pathogenesis of PD. Oxidative stress is characterized by increase in reactive oxygen species (ROS) and depletion of glutathione. Lipid mediators for oxidative stress include 4-hydroxynonenal, isoprostanes, isofurans, isoketals, neuroprostanes, and neurofurans. Neuroinflammation is characterized by activated microglial cells that generate proinflammatory cytokines, such as TNF-α and IL-1β. Proinflammatory lipid mediators include prostaglandins and platelet activating factor, together with cytokines may play a prominent role in mediating the progressive neurodegeneration in PD.”

 

Farooqui, T., & Farooqui, A. A. (2011). Lipid-mediated oxidative stress and inflammation in the pathogenesis of Parkinson's disease. Parkinson's Disease, 2011, 1-9. doi: 10.4061/2011/247467

 

Neuronal and vascular oxidative stress in Alzheimer's disease.

 

“The brain is a highly metabolically active organ producing large amounts of reactive oxygen species (ROS). These ROS are kept in check by an elaborate network of antioxidants. Although ROS are necessary for signaling and synaptic plasticity, their uncontrolled levels cause oxidation of essential macromolecules such as membrane lipids, nucleic acids, enzymes and cytoskeletal proteins. Indeed, overproduction of ROS and/or failure of the antioxidant network lead to neuronal oxidative stress, a condition associated with not only aging but also Alzheimer's disease (AD). However, the specific source of excessive ROS production has not yet been identified. On one hand, amyloid beta (Aβ) has been extensively shown to act as an oxidant molecule. On the other hand, oxidative stress has been shown to precede and exacerbate Aβ pathology. This review will address the involvement of oxidative stress in the context of neuronal as well as vascular dysfunction associated with AD.”

 

Massaad, C. A. (2011). Neuronal and vascular oxidative stress in Alzheimers disease. Current Neuropharmacology, 9(4), 662-673. doi: 10.2174/157015911798376244

 

Amyloid-beta peptide, oxidative stress and inflammation in Alzheimer's disease: Potential neuroprotective effects of omega-3 polyunsaturated fatty acids

 

“Alzheimer's disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterized by a decline in cognitive function and also profound alterations in mood and behavior. The pathology of the disease is characterized by the presence of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles in the brain. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidative stress appear key to be features contributing to the pathology. The omega-3 polyunsaturated fats, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have well-characterized effects on inflammation and may have neuroprotective effects in a number of neurodegenerative conditions including Alzheimer's disease. The aims of this paper are to review the neuroprotective effects of EPA and DHA in Alzheimer's disease, with special emphasis on their role in modulating oxidative stress and inflammation and also examine their potential as therapeutic agents.”

 

Dyall, S. C. (2010). Amyloid-beta peptide, oxidative stress and inflammation in Alzheimer's disease: potential neuroprotective effects of omega-3 polyunsaturated fatty acids. International Journal of Alzheimer's Disease, 2010(274128), 1-10. doi: 10.4061/2010/274128

Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes

 

“Hydrogen exerts beneficial effects in disease animal models of ischemia-reperfusion injury as well as inflammatory and neurological disease. Additionally, molecular hydrogen is useful for various novel medical and therapeutic applications in the clinical setting. In the present study, the hydrogen concentration in rat blood and tissue was estimated. Wistar rats were orally administered hydrogen super-rich water (HSRW), intraperitoneal and intravenous administration of hydrogen super-rich saline (HSRS), and inhalation of hydrogen gas. A new method for determining the hydrogen concentration was then applied using high-quality sensor gas chromatography, after which the specimen was prepared via tissue homogenization in airtight tubes. This method allowed for the sensitive and stable determination of the hydrogen concentration. The hydrogen concentration reached a peak at 5 minutes after oral and intraperitoneal administration, compared to 1 minute after intravenous administration. Following inhalation of hydrogen gas, the hydrogen concentration was found to be significantly increased at 30 minutes and maintained the same level thereafter. These results demonstrate that accurately determining the hydrogen concentration in rat blood and organ tissue is very useful and important for the application of various novel medical and therapeutic therapies using molecular hydrogen. The hydrogen concentration was measured at five minutes after the oral and intraperitoneal administration of hydrogen at different concentrations (1.25, 2.5 and 5.0 ppm). The hydrogen concentrations in the blood and tissues of the liver, spleen, pancreas and brain exhibited a dose-dependent increase in association with an increase in the concentration of orally administered Hydrogen Super Rich Water. The intraperitoneal injection of Hydrogen Super Rich Saline also resulted in a dose-dependent increase in the tissue hydrogen concentration.”

 

Liu, C., Kurokawa, R., Fujino, M., Hirano, S., Sato, B., & Li, X. (2014). Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Scientific Reports, 4(5485), 1-11. doi: 10.1038/srep05485

 

Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury

 

“Inhalation of hydrogen (H(2)) gas has been demonstrated to limit the infarct volume of brain and liver by reducing ischemia-reperfusion injury in rodents. When translated into clinical practice, this therapy must be most frequently applied in the treatment of patients with acute myocardial infarction, since angioplastic recanalization of infarct-related occluded coronary artery is routinely performed. Therefore, we investigate whether H(2) gas confers cardioprotection against ischemia-reperfusion injury in rats. In isolated perfused hearts, H(2) gas enhances the recovery of left ventricular function following anoxia-reoxygenation. Inhaled H(2) gas is rapidly transported and can reach 'at risk' ischemic myocardium before coronary blood flow of the occluded infarct-related artery is reestablished. Inhalation of H(2) gas at incombustible levels during ischemia and reperfusion reduces infarct size without altering hemodynamic parameters, thereby preventing deleterious left ventricular remodeling. Thus, inhalation of H(2) gas is promising strategy to alleviate ischemia-reperfusion injury coincident with recanalization of coronary artery.”

 

Hayashida, K., Sano, M., Ohsawa, I., Shinmura, K., Tamaki, K., Kimura, K., . . . Ogawa, S. (2008). Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochemical and Biophysical Research Communications, 373(1), 30-35. doi: 10.1016/j.cardfail.2008.07.178

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A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level

 

“The HC gradually reached a plateau level in 20 min after H2 inhalation in the blood, which was equivalent to the level reported by animal experiments. The HC rapidly decreased to 10% of the plateau level in about 6 min and 18 min in arterial and venous blood, respectively after H2 inhalation was discontinued. Physiological parameters on these 3 patients were essentially unchanged by use of hydrogen. The consistency study of 10 patients showed the HC at the end of 30-min inhalation treatment was quite variable but the inconsistency improved with more attention and encouragement. CONCLUSION: H2 inhalation of at least 3% concentration for 30 min delivered enough HC, equivalent to the animal experiment levels, in the blood without compromising the safety. However, the consistency of H2 delivery by inhalation needs to be improved.”

 

Ono, H., Nishijima, Y., Adachi, N., Sakamoto, M., Kudo, Y., Kaneko, K., . . . Imaoka, T. (2012). A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Medical Gas Research, 2(1), 1-7. doi: 10.1186/2045-9912-2-21

 

Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management

 

“Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O2 and normothermia (control); mechanically ventilated with 26% O2, 1.3% H2, and normothermia (H2); mechanically ventilated with 26% O2 and TTM (TTM); and mechanically ventilated with 26% O2, 1.3% H2, and TTM (TTM+H2). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H2 and TTM groups, and 85.7% in the TTM+H2 group. Combined therapy of TTM and H2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H2 inhalation alone, with the combined therapy of TTM and H2 inhalation being most effective. CONCLUSIONS: H2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia. Combined TTM and H2 inhalation was more effective than TTM alone.”

 

Hayashida, K., Sano, M., Kamimura, N., Yokota, T., Suzuki, M., Ohta, S., . . . Hori, S. (2014). Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation, 130(24), 2173-2180. doi: 10.1161/circulationaha.114.011848  

Hydrogen inhalation decreases lung graft injury in brain-dead donor rats

 

“Hydrogen improved PaO (2)/FIO(2) and PVO (2)/FIO(2) from the arterial and pulmonary venous blood in recipients and decreased the lung injury score in grafts from brain-dead donors. Hydrogen decreased the amount of IL-8 and TNF-α in serum, inhibited the activity of malondialdehyde and myeloperoxidase, and increased the activity of superoxide dismutase in the lung grafts from brain-dead donors. Furthermore, hydrogen decreased the apoptotic index of the cells and inhibited the protein expression of intercellular adhesion molecule-1 and caspase-3 in lung grafts from brain-dead donors.
Hydrogen can exert protective effects on lung grafts from brain-dead donors through anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms.”

 

Zhou, H., Fu, Z., Wei, Y., Liu, J., Cui, X., Yang, W., . . . Li, W. (2013). Hydrogen inhalation decreases lung graft injury in brain-dead donor rats. The Journal of Heart and Lung Transplantation, 32(2), 251-258. doi: 10.1016/j.healun.2012.11.007 

 

Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis

 

“During the development of sepsis, the complication in central nervous system (CNS), appearing early and frequently relative to other systems, can obviously increase the mortality of sepsis. Moreover, sepsis survivors also accompany long-term cognitive dysfunction, while the ultimate causes and effective therapeutic strategies of brain injury in sepsis are still not fully clear. We designed this study to investigate the effects of 2% hydrogen gas (H2) on brain injury in a mouse model of sepsis. Male ICR mice were underwent cecal ligation and puncture (CLP) or sham operation. 2% H2 was inhaled for 60min beginning at both 1 and 6h after sham or CLP operation, respectively. H2 concentration in arterial blood, venous blood and brain tissue was detected after H2 inhalation separately. The survival rate was observed and recorded within 7 days after sham or CLP operation. The histopathologic changes and neuronal apoptosis were observed in hippocampus by Nissl staining and TUNEL assay. The permeability of brain-blood barrier (BBB), brain water content, inflammatory cytokines, activities of antioxidant enzymes (SOD and CAT) and oxidative products (MDA and 8-iso-PGF2α) in serum and hippocampus were detected at 24h after sham or CLP operation. The expressions of nucleus and total nuclear factor erythroid 2-related factor 2 (Nrf2) and cytoplasmic heme oxygenase-1(HO-1) in hippocampus were measured at 24h after sham or CLP operation. We assessed their cognitive function via Y-maze and Fear Conditioning test on day 3, 5, 7 and 14 after operation. H2 treatment markedly improved the survival rate and cognitive dysfunction of septic mice. CLP mice showed obvious brain injury characterized by aggravated pathological damage, BBB disruption and brain edema at 24h after CLP operation, which was markedly alleviated by 2% H2 treatment. Furthermore, we found that the beneficial effects of H2 on brain injury in septic mice were linked to the decreased levels of inflammatory cytokines and oxidative products and the increased activities of antioxidant enzymes in serum and hippocampus. In addition, 2% H2 inhalation promoted the expression and transposition of Nrf2 and the expression of HO-1 to mitigate brain injury in sepsis. Thus, the inhalation of hydrogen gas may be a promising therapeutic strategy to relieve brain injury in sepsis.”

 

Liu, L., Xie, K., Chen, H., Dong, X., Li, Y., Yu, Y., . . . Yu, Y. (2014). Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Research, 1589, 78-92. doi: 10.1016/j.brainres.2014.09.030

 

Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress

 

“Inhalation of hydrogen gas decreased significantly the average latency of the ischemic rats in finding hidden platform and elongated markedly their retention in the target quadrant. The neuronal density 3·3±2·1 cells/mm in CA1 region of the ischemic rats increased to 21·7±2·6 cells/mm after they were treated with hydrogen gas. Moreover, hydrogen gas made higher levels of MDA and 8-iso-PGF2α in the ischemic rats attenuate to 3·2±0·2, 3·5±0·5, 3·4±0·3 and 26·4±2·3, 28·2±2·6, 26·8±2·1 at reperfusion 4, 24, and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time). By contrast, the activities of superoxide dismutase and catalase damaged by ischemia/reperfusion recovered to 129·7±14·8, 100·5±12·2 and 11·4±0·8, 9·6±1·1 at reperfusion 24 and 72 hours, respectively (P<0·01 versus ischemia group at each indicated time). Inhalation of hydrogen gas could attenuate cognitive impairment in the ischemic rats. This protection is associated with decreased neuronal death in CA1 region and inhibition of oxidative stress.”

 

Ge, P., Zhao, J., Li, S., Ding, Y., Yang, G., & Luo, Y. (2012). Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress. Neurological Research, 34(2), 187-194. doi: 10.1179/1743132812y.0000000002

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Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress

 

“Traumatic brain injury (TBI) is a leading cause of mortality and disability among the young population. It has been shown that hydrogen gas (H(2)) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical (OH, the most cytotoxic ROS). Recently, we have found that H(2) inhalation significantly improved the survival rate and organ damage of septic mice. In the present study, we investigated the effectiveness of H(2) therapy on brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in TBI-challenged rats. In addition, we investigated the effects of H(2) treatment on the changes of oxidative products and antioxidant enzymes in brain tissue of TBI-challenged rats. Hydrogen treatment was given by exposure to 2% H(2) from 5 min to 5h after sham or TBI operation, respectively. Here, we found that TBI-challenged rats showed significant brain injuries characterized by the increase of BBB permeability, brain edema and lesion volume as well as neurological dysfunction, which was significantly attenuated by 2% H(2) treatment. In addition, we found that the decrease of oxidative products and the increase of endogenous antioxidant enzymatic activities in the brain tissue may be associated with the protective effects of H(2) treatment in TBI-challenged rats. The present study supports that H(2) inhalation may be a more effective therapeutic strategy for patients with TBI.”

 

Ji, X., Liu, W., Xie, K., Liu, W., Qu, Y., Chao, X., . . . Fei, Z. (2010). Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress. Brain Research, 1354, 196-205. doi: 10.1016/j.brainres.2010.07.038

 

Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress

 

“This study is to examine if hydrogen-rich saline reduced amyloid beta (Abeta) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n=84, 280-330g) were divided into three groups, sham-operated, Abeta1-42 injected and Abeta1-42 plus hydrogen-rich saline-treated animals. Hydrogen-rich saline (5ml/kg, i.p., daily) was injected for 14days after intracerebroventricular injection of Abeta1-42. The levels of MDA, IL-6 and TNF-alpha were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Abeta1-42 injection, the levels of MDA, IL-6, and TNF-alpha were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-alpha concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Abeta1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Abeta1-42. In conclusion, hydrogen-rich saline prevented Abeta-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.”

 

Li, J., Wang, C., Zhang, J. H., Cai, J., Cao, Y., & Sun, X. (2010). Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress. Brain Research, 1328, 152-161. doi: 10.1016/j.brainres.2010.02.046

 

Pilot study of H2 therapy in Parkinson's disease: A randomized double-blind placebo-controlled trial

 

“Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H2) functions as a highly effective antioxidant in cultured cells and animal models. Drinking H2-dissolved water (H2-water) reduced oxidative stress and improved Parkinson's features in model animals. In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H2-water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H2-water or pseudo water for 48 weeks. Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H2-water group (n=9) improved (median, −1.0; mean±standard deviation, −5.7±8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean±standard deviation, 4.1±9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P<0.05). The results indicated that drinking H2-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H2-water group was demonstrated.”

 

Yoritaka, A., Takanashi, M., Hirayama, M., Nakahara, T., Ohta, S., & Hattori, N. (2013). Pilot study of H2 therapy in Parkinson's disease: A randomized double-blind placebo-controlled trial. Movement Disorders, 28(6), 836-839. doi: 10.1002/mds.25375

 

Hydrogen-rich saline attenuates neuronal ischemia--reperfusion injury by protecting mitochondrial function in rats

 

“We used a four-vessel occlusion model of global cerebral ischemia and reperfusion, with Sprague-Dawley rats. The rats were divided randomly into six groups (n = 90): sham (group S), I/R (group I/R), normal saline (group NS), atractyloside (group A), hydrogen-rich saline (group H), and hydrogen-rich saline + atractyloside (group HA). In groups H and HA, intraperitoneal hydrogen-rich saline (5 mL/kg) was injected immediately after reperfusion, whereas the equal volume of NS was injected in the other four groups. In groups A and HA, atractyloside (15 μL) was intracerebroventricularly injected 10 min before reperfusion, whereas groups NS and H received equal NS. The mitochondrial permeability transition pore opening and mitochondrial membrane potential were measured by spectrophotometry. Cytochrome c protein expression in the mitochondria and cytoplasm was detected by western blot. The hippocampus mitochondria ultrastructure was examined with transmission electron microscope. The histologic damage in hippocampus was assessed by hematoxylin and eosin staining. Hydrogen-rich saline treatment significantly improved the amount of surviving cells (P < 0.05). Furthermore, hydrogen-rich saline not only reduced tissue damage, the degree of mitochondrial swelling, and the loss of mitochondrial membrane potential but also preserved the mitochondrial cytochrome c content (P < 0.05). Our study showed that hydrogen-rich saline was able to attenuate neuronal I/R injury, probably by protecting mitochondrial function in rats.”

 

Cui, Y., Zhang, H., Ji, M., Jia, M., Chen, H., Yang, J., & Duan, M. (2014). Hydrogen-rich saline attenuates neuronal ischemia–reperfusion injury by protecting mitochondrial function in rats. Journal of Surgical Research, 192(2), 564-572. doi: 10.1016/j.jss.2014.05.060

 

A review of experimental studies of hydrogen as a new therapeutic agent in emergency and critical care medicine

 

“Hydrogen is the most abundant chemical element in the Universe, but is seldom regarded as a therapeutic agent. Recent evidence has shown that hydrogen is a potent antioxidative, antiapoptotic and anti-inflammatory agent and so may have potential medical applications in cells, tissues and organs. There are several methods to administer hydrogen, such as inhalation of hydrogen gas, aerosol inhalation of a hydrogen-rich solution, drinking hydrogen dissolved in water, injecting hydrogen-rich saline (HRS) and taking a hydrogen bath. Drinking hydrogen solution (saline/pure water/other solutions saturated with hydrogen) may be more practical in daily life and more suitable for daily consumption. This review summarizes the findings of recent studies on the use of hydrogen in emergency and critical care medicine using different disease models”

 

Shen, M., Zhang, H., Yu, C., Wang, F., & Sun, X. (2014). A review of experimental studies of hydrogen as a new therapeutic agent in emergency and critical care medicine. Medical Gas Research, 4(1), 1-8. doi: 10.1186/2045-9912-4-17

 

Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs

 

“Hydrogen (H2) has been reported to neutralize toxic reactive oxygen species. Oxidative stress is an important mechanism of neuronal damage after perinatal asphyxia. We examined whether 2.1% H2-supplemented room air (H2-RA) ventilation would preserve cerebrovascular reactivity (CR) and brain morphology after asphyxia/reventilation (A/R) in newborn pigs. Anesthetized, ventilated piglets were assigned to one of the following groups: A/R with RA or H2-RA ventilation (A/R-RA and A/R-H2-RA; n = 8 and 7, respectively) and respective time control groups (n = 9 and 7). Asphyxia was induced by suspending ventilation for 10 min, followed by reventilation with the respective gases for 4 h. After euthanasia, the brains were processed for neuropathological examination. Pial arteriolar diameter changes to graded hypercapnia (5-10% CO2 inhalation), and NMDA (10(-4) M) were determined using the closed cranial window/intravital microscopy before and 1 h after asphyxia. Neuropathology revealed that H2-RA ventilation significantly reduced neuronal injury induced by A/R in virtually all examined brain regions including the cerebral cortex, the hippocampus, basal ganglia, cerebellum, and the brainstem. Furthermore, H2-RA ventilation significantly increased CR to hypercapnia after A/R (% vasodilation was 23 ± 4% versus 41 ± 9%, p < 0.05). H2-RA ventilation did not affect reactive oxygen species-dependent CR to NMDA. In summary, H2-RA could be a promising approach to reduce the neurologic deficits after perinatal asphyxia.”

 

Domoki, F., Oláh, O., Zimmermann, A., Németh, I., Tóth-Szűki, V., Hugyecz, M., . . . Bari, F. (2010). Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs. Pediatric Research, 68(5), 387-392. doi: 10.1203/pdr.0b013e3181f2e81c

 

Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats

 

“Cerebral vasospasm (CV) remains a common and devastating complication in patients with subarachnoid hemorrhage (SAH). Despite its clinical significance and extensive research, the underlying pathogenesis and therapeutic perspectives of CV remain incompletely understood. Recently, it has been suggested that molecular hydrogen (H(2)) can selectively reduce levels of hydroxyl radicals (·OH) and ameliorate oxidative and inflammatory injuries to organs in many models. However, whether H(2) can ameliorate CV after SAH is still unknown. This study was designed to evaluate the efficacy of H(2) in preventing SAH-induced CV. Experimental SAH was induced in Sprague-Dawley rats using cisterna magna blood injection. Hydrogen-rich saline (HS) was injected intraperitoneally (5 ml/kg) immediately and at 24 hr after injury. All rats were sacrificed 48 hr after the neurological examination scores had been recorded following SAH. Levels of oxidative stress and inflammation were evaluated. Basilar artery vasospasm was assessed by histological examination using light and transmission electron microscopy. HS treatment significantly improved neurological outcomes and attenuated morphological vasospasm of the basilar artery after SAH. In addition, we found that the beneficial effects of HS treatment on SAH-induced CV were associated with decreased levels of lipid peroxidation, increased activity of antioxidant enzymes, and reduced levels of proinflammatory cytokines in the basilar artery. These results indicate that H(2) has the potential to be a novel therapeutic strategy for the treatment of CV after SAH, and its neuroprotective effect might be partially mediated via limitation of vascular inflammation and oxidative stress.”

 

Hong, Y., Guo, S., Chen, S., Sun, C., Zhang, J., & Sun, X. (2012). Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats. Journal of Neuroscience Research, 90(8), 1670-1680. doi: 10.1002/jnr.22739

 

Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain Injury following subarachnoid hemorrhage: Possible role of the Akt/GSK3β signaling pathway

 

“Sprague-Dawley rats (n = 85) were randomly divided into the following groups: sham group (n = 17), SAH group (n = 17), SAH + saline group (n = 17), SAH + hydrogen-rich saline (HS) group (n = 17) and SAH + HS + Ly294002 (n = 17) group. HS or an equal volume of physiological saline was administered immediately after surgery and repeated 8 hours later. The PI3K inhibitor, Ly294002, was applied to manipulate the proposed pathway. Neurological score and SAH grade were assessed at 24 hours after SAH. Western blot was used for the quantification of Akt, pAkt, GSK3β, pGSK3β, Bcl-2, Bax and cleaved caspase-3 proteins. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining and NeuN, and quantified by apoptosis index. Immunohistochemistry and immunofluorescent double-labeling staining was performed to clarify the relationships between neuronal apoptosis and pAkt or pGSK3β. HS significantly reduced neuronal apoptosis and improved neurological function at 24 hours after SAH. The levels of pAkt and pGSK3β, mainly expressed in neurons, were markedly up-regulated. Additionally, Bcl-2 was significantly increased while Bax and cleaved caspase-3 was decreased by HS treatment. Double staining of pAkt and TUNEL showed few colocalization of pAkt-positive cells and TUNEL-positive cells. The inhibitor of PI3K, Ly294002, suppressed the beneficial effects of HS. HS could attenuate neuronal apoptosis in EBI and improve the neurofunctional outcome after SAH, partially via the Akt/GSK3β pathway.”

 

Hong, Y., Shao, A., Wang, J., Chen, S., Wu, H., Mcbride, D. W., . . . Zhang, J. (2014). Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: Possible role of the Akt/GSK3β signaling pathway. PLOS ONE, 9(4), 1-10. doi: 10.1371/journal.pone.0096212

 

The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest

 

“Intraperitoneal injection of H2 improved the 72-h survival rate and neurological scores, reduced neuronal injury and inhibited neuronal apoptosis. Intraperitoneal injection of A rabbit model of CA was established by the delivery of alternating current between the esophagus and chest wall to induce ventricular fibrillation. Before CA, the animals were randomly divided into four groups: a sham group (no CA), a CA group, a CA + low dose (10 ml/kg) H2 group (CA + H2 group 1), and a CA + high dose (20 ml/kg) H2 group (CA + H2 group 2). In the first experiment, animals were observed for 72 h after the restoration of spontaneous circulation (ROSC). The neurological scores were assessed at 24, 48 and 72 h after ROSC. The rabbits that survived until 72 h were sacrificed using an overdose of anesthetic, and the brain tissues were collected and Nissl-stained to observe nerve cell damage in the hippocampal CA1 area. In addition, TUNEL assay was performed to detect apoptosis. In the second experiment, animals were observed for 6h after ROSC. Blood samples and brain hippocampal tissues were collected, and differences in oxidative stress indicators were compared among the four groups. H2 reduced oxidative stress indicators in the plasma and hippocampal tissues and enhanced antioxidant enzyme activity. No significant difference was observed between the two CA groups treated with different doses of H2. Intraperitoneal injection of H2 is a novel hydrogen administration method and can reduce cerebral ischemia-reperfusion injury and improve the prognosis of cardiopulmonary cerebral resuscitation in a rabbit model of CA.”

 

Huang, G., Zhou, J., Zhan, W., Xiong, Y., Hu, C., Li, X., . . . Liao, X. (2013). The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest. Resuscitation, 84(5), 690-695. doi: 10.1016/j.resuscitation.2012.10.018

 

Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress

 

“Hydrogen gas (H(2)) has been considered as a novel antioxidant to selectively reduce the toxic reactive oxygen species (ROS) such as hydroxyl radical (•OH) without affecting the other signal ROS. Our recent study shows that H(2) inhalation is beneficial to traumatic brain injury (TBI) via reducing oxidative stress. In contrast to H(2), hydrogen-rich saline (HS) may be more suitable for clinical application. The present study was designed to investigate whether HS has a protective effect against TBI via reducing oxidative stress in rats. TBI-challenged rats exhibited significant brain injuries characterized by the increase of BBB permeability, brain edema, and lesion volume as well as neurological dysfunction, which were dose-dependently ameliorated by HS treatment. Moreover, we found that TBI model was induced by controlled cortical impact injury. Different dosages of HS were intraperitoneally administered at 5 min after TBI operation. We then measured the brain edema, blood-brain barrier (BBB) breakdown, neurological dysfunction and injury volume in all animals. In addition, the oxidative products and antioxidant enzymes in brain tissues were detected.
HS treatment increased the endogenous antioxidant enzymatic activities and decreased the oxidative product levels in brain tissues of TBI-challenged rats.
Hydrogen-rich saline can exert a protective effect against TBI via reducing oxidative stress. Molecular hydrogen may be a more effective therapeutic strategy for TBI “

 

Ji, X., Tian, Y., Xie, K., Liu, W., Qu, Y., & Fei, Z. (2012). Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress. Journal of Surgical Research, 178(1), 9-16. doi: 10.1016/j.jss.2011.12.038

 

 

Electrochemically reduced water protects neural cells from oxidative damage

 

“Aging-related neurodegenerative disorders are closely associated with mitochondrial dysfunction and oxidative stresses and their incidence tends to increase with aging. Brain is the most vulnerable to reactive species generated by a higher rate of oxygen consumption and glucose utilization compared to other organs. Electrochemically reduced water (ERW) was demonstrated to scavenge reactive oxygen species (ROS) in several cell types. In the present study, the protective effect of ERW against hydrogen peroxide (H2O2) and nitric oxide (NO) was investigated in several rodent neuronal cell lines and primary cells. ERW was found to significantly suppress H2O2 (50-200 μM) induced PC12 and SFME cell deaths. ERW scavenged intracellular ROS and exhibited a protective effect against neuronal network damage caused by 200 μM H2O2 in N1E-115 cells. ERW significantly suppressed NO-induced cytotoxicity in PC12 cells despite the fact that it did not have the ability to scavenge intracellular NO. ERW significantly suppressed both glutamate induced Ca(2+) influx and the resulting cytotoxicity in primary cells. These results collectively demonstrated for the first time that ERW protects several types of neuronal cells by scavenging ROS because of the presence of hydrogen and platinum nanoparticles dissolved in ERW.”

 

Kashiwagi, T., Yan, H., Hamasaki, T., Kinjo, T., Nakamichi, N., Teruya, K., . . . Shirahata, S. (2014). Electrochemically reduced water protects neural cells from oxidative damage. Oxidative Medicine and Cellular Longevity, 2014, 1-18. doi: 10.1155/2014/869121

 

 

Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventive and therapeutic applications

 

“Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H2) has potential as a “novel” antioxidant in preventive and therapeutic applications. H2 has a number of advantages as a potential antioxidant: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H2. There are several methods to ingest or consume H2, including inhaling hydrogen gas, drinking H2-dissolved water (hydrogen water), taking a hydrogen bath, injecting H2-dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H2 by bacteria. Since the publication of the first H2 paper in Nature Medicine in 2007, the biological effects of H2 have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H2 shows not only effects against oxidative stress, but also various anti-inflammatory and anti-allergic effects. H2 regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H2 remain elusive.”

 

Ohta, S. (2011). Recent progress toward hydrogen medicine: Potential of molecular hydrogen for preventive and therapeutic applications. Current Pharmaceutical Design, 17(22), 2241-2252. doi: 10.2174/138161211797052664

 

Molecular hydrogen suppresses reactive astrogliosis related to oxidative injury during spinal cord injury in rats

 

“Hydrogen-rich saline (HS, 8 mL/kg, i.p.) was injected every 12 h after SCI in rats. The expression of STAT3, p-STAT3, and glial fibrillary acidic protein (GFAP); the release of IL-1β, IL-6, and TNF-α; and astrogliosis, along with the BBB score, were evaluated. Culturing astrocytes with hydrogen-rich medium, the intracellular reactive oxygen species (ROS), astrogliosis, and the release of proinflammatory cytokines were assessed after H2O2-induced injury. In the HS group, the expression of STAT3, p-STAT3, and GFAP and the proinflammatory cytokines were decreased in local spinal cord on postoperation day (POD) 3; on PODs 7 and 14, reactive astrogliosis was suppressed, and the locomotor function was also improved. Furthermore, hydrogen-rich medium attenuated the intracellular production of ROS (especially HO•), astrogliosis, and the secretion of proinflammatory cytokines in astrocytes 12 h after H2O2-induced injury.
Molecular hydrogen could suppress reactive astrogliosis after contusive SCI and reduce the release of proinflammatory cytokines produced by active astrocytes related to oxidative injury. Thus, molecular hydrogen is potential to be a neuroprotective agent.”

 

Liu, F., Xu, S., Xiang, Z., Li, X., Li, J., Yuan, H., & Sun, X. (2014). Molecular hydrogen suppresses reactive astrogliosis related to oxidative injury during spinal cord injury in rats. CNS Neuroscience & Therapeutics, 20(8), 778-786. doi: 10.1111/cns.12258

 

Protective effects of hydrogen on fetal brain injury during maternal hypoxia

 

“This study aimed to investigate the effects of hydrogen on fetal brain injury during maternal hypoxia. Pregnant rats (n=12, at gestational day 17) were randomly assigned into three groups; air, hypoxia, and hypoxia plus hydrogen groups were put into a chamber and flushed with room air (21% O2 and 79% N2), hypoxia (8% O2 and 92% N2), and hypoxia with hydrogen mixture (2% H2, 8% O2 and 90% N2), respectively, for 4 consecutive hours. After birth, body and brain weights, body-righting reflex, and negative geotropism of neonates were measured, and then pups were killed at days 1 and 7. Oligodendrocytes were studied at post-natal day 1 by immunohistochemistry. We found significant decreases in body weight in the hypoxia group (P<0.05 vs. room air group), but not in the hypoxia plus hydrogen group (P>0.05 vs. room air group). Even though brain weight was not different among groups, the brain weight to body weight ratio in the room air group was significantly (P<0.05) lower than that in the hypoxia alone or hypoxia plus hydrogen groups. Body-righting reflex at day 1 and negative geotropism at days 3-4 showed deficiency in hypoxia animals when compared with the room air group (P<0.05). Hydrogen treatment improved the body-righting reflex and negative geotropism (P<0.05 vs. room air group). The above-mentioned functional changes caused by hypoxia were not associated with morphology and cell death of oligodendrocytes. Therefore, the maternal hypoxia-induced body weight loss, and functional abnormalities and hydrogen treatment during hypoxia offered a protective effect and improved functions in neonates.”

 

Liu, W., Chen, O., Chen, C., Wu, B., Tang, J., & Zhang, J. H. (2011). Protective effects of hydrogen on fetal brain injury during maternal hypoxia. Acta Neurochirurgica Supplementum, 2011, 307-311. doi: 10.1007/978-3-7091-0693-8_51

 

Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage

 

“CD1 male mice (weight 30-35 g) were divided into the following groups: sham, ICH+vehicle (room air), ICH+1-h hydrogen treatment, and ICH+2-h hydrogen treatment. ICH was induced by injection of bacterial collagenase into the right basal ganglia. The evaluation of outcomes was done at two time points: 24 and 72 h post-ICH. Brain water content was measured for assessment of brain edema (wet/dry weight method), and three neurological tests were performed pre- and postoperatively. Collagenase injection was found to induce brain edema and impair functional performance of rats. The hydrogen inhalation reduced these effects acutely (24 h); however it exhibited only a tendency to improvement in the delayed study (72 h). Our results suggest that hydrogen inhalation exerts an acute brain-protective effect in the mouse ICH model. However, the acute hydrogen therapy alone is not sufficient to improve delayed ICH outcomes in this model.”

 

Manaenko, A., Lekic, T., Ma, Q., Ostrowski, R. P., Zhang, J. H., & Tang, J. (2011). Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. Acta Neurochirurgica Supplementum, 111, 179-183. doi: 10.1007/978-3-7091-0693-8_30

 

Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice

 

“At 24 and 72 hours post intracerebral hemorrhage, animals showed blood-brain barrier disruption, brain edema, and neurologic deficits, accompanied with phosphorylation of Lyn kinase and release of tryptase, indicating mast cell activation. Hydrogen treatment diminished phosphorylation of Lyn kinase and release of tryptase, decreased accumulation and degranulation of mast cells, attenuated blood-brain barrier disruption, and improved neurobehavioral function. Activation of mast cells following intracerebral hemorrhage contributed to increase of blood-brain barrier permeability and brain edema. Hydrogen inhalation preserved blood-brain barrier disruption by prevention of mast cell activation after intracerebral hemorrhage.”

 

Manaenko, A., Lekic, T., Ma, Q., Zhang, J. H., & Tang, J. (2013). Hydrogen inhalation ameliorated mast cell–mediated brain injury after intracerebral hemorrhage in mice. Critical Care Medicine, 41(5), 1266-1275. doi: 10.1097/ccm.0b013e31827711c9

 

 

Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion

 

“Molecular hydrogen (H2) scavenges hydroxyl radicals. Recently, H2 has been reported to prevent a variety of diseases associated with oxidative stress in model systems and in humans. Here, we studied the effects of H2 on rat fetal hippocampal damage caused by ischemia and reperfusion (IR) on day 16 of pregnancy with the transient occlusion of the bilateral utero-ovarian arteries. Starting 2 days before the operation, we provided the mothers with hydrogen-saturated water ad libitum until vaginal delivery. We observed a significant increase in the concentration of H2 in the placenta after the oral administration of hydrogen-saturated water to the mothers, with less placental oxidative damage after IR in the presence of H2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H2 administration. We analyzed the neuronal cell damage in the CA1 and CA3 areas of the hippocampus at day 7 after birth by immunohistochemical analysis of the 8-oxo-7,8-dihydro-2׳-deoxyguanosine- and 4-hydroxy-2-nonenal-modified proteins. Both oxidative stress markers were significantly increased in the IR group, which was again ameliorated by the H2 intake. Last, 8-week-old rats were subjected to a Morris water maze test. Maternal H2 administration improved the reference memory of the offspring to the sham level after IR injury during pregnancy. Overall, the present results support the idea that maternal H2 intake helps prevent the hippocampal impairment of offspring induced by IR during pregnancy.”

 

Mano, Y., Kotani, T., Ito, M., Nagai, T., Ichinohashi, Y., Yamada, K., . . . Toyokuni, S. (2014). Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia–reperfusion. Free Radical Biology and Medicine, 69, 324-330. doi: 10.1016/j.freeradbiomed.2014.01.037

 

Oral 'hydrogen water' induces neuroprotective ghrelin secretion in mice

 

“The therapeutic potential of molecular hydrogen (H₂) is emerging in a number of human diseases and in their animal models, including in particular Parkinson's disease (PD). H₂ supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H₂ supplementation does not result in detectable changes in striatal H₂ levels, indicating an indirect effect. Here we show that H₂ supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the β1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H₂ water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys(3) GHRP-6, or atenolol. Thus, the neuroprotective effect of H₂ in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H₂ supplementation has been demonstrated.”

 

Matsumoto, A., Yamafuji, M., Tachibana, T., Nakabeppu, Y., Noda, M., & Nakaya, H. (2013). Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice. Scientific Reports, 3(3273), 1-5. doi: 10.1038/srep03273

 

 

Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs

 

“Anesthetized, ventilated piglets were assigned to three groups of 9 animals: time control, asphyxia/reventilation with air, and asphyxia/reventilation with air +2.1% H2 for 4 h. Asphyxia was induced by suspending ventilation for 8 min. Cerebrovascular reactivity (CR) of pial arterioles was determined using closed cranial window/intravital microscopy 24 h after asphyxia to the endothelium-dependent cerebrovascular stimulus hypercapnia, the neuronal function-dependent stimulus N-methyl-D-aspartate (NMDA), norepinephrine, and sodium nitroprusside. The brains were subjected to histopathology.
Hemodynamic parameters, blood gases, and core temperature did not differ significantly among the experimental groups. In the early reventilation period, the recovery of electroencephalographic activity was significantly better in H2-treated animals. Asphyxia/reventilation severely attenuated CR to hypercapnia and NMDA; however, reactivity to norepinephrine and sodium nitroprusside were unaltered. H2 fully or partially preserved CR to hypercapnia or NMDA, respectively. Histopathology revealed modest neuroprotection afforded by H2. Severe stimulus-selective delayed neurovascular dysfunction develops and persists even after mild H/I stress. H2 alleviates this delayed neurovascular dysfunction that can contribute to its neuroprotective effect.”

 

Oláh, O., Tóth-Szuki, V., Temesvári, P., Bari, F., & Domoki, F. (2013). Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs. Neonatology, 104(2), 79-86. doi: 10.1159/000348445

 

Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study

 

“The patients were divided in Edaravone only group (E group. 26 patients) and combined treatment group with Edaravone and hydrogen enriched saline (EH group. 8 patients). The extent of the initial hump of rDWI, the initial dip of rADC and pseudo-normalization time were determined in each patient serially and averages of these data were compared in these two groups and also with the natural course in the literatures. The initial hump of rDWI reached 2.0 in the E group which was better than 2.5 of the natural course but was not as good as 1.5 of the EH group. The initial dip of rADC was 0.6 in the E group which was close to the natural course but worse than 0.8 of the EH group. Pseudonormalization time of rDWI and rADC was 9 days only in EH group but longer in other groups. Addition of hydrogen caused no side effects. Administration of hydroxyl radical scavengers in acute stage of brainstem infarction improved MRI indices against the natural course. The effects were more obvious and significant in the EH group. These findings may imply the need for more frequent daily administration of hydroxyl scavenger, or possible additional hydrogen effects on scavenger mechanisms.”

 

Ono, H., Nishijima, Y., Adachi, N., Tachibana, S., Chitoku, S., Mukaihara, S., . . . Nawashiro, H. (2011). Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study. Medical Gas Research, 1(1), 1-9. doi: 10.1186/2045-9912-1-12

Targeting molecular hydrogen to mitochondria: Barriers and gateways

 

“Although the administration of molecular hydrogen (H2, dihydrogen) has been recognized as an effective innovative therapeutic procedure in biomedicine, H2 cellular kinetics and utilization seems to be less understood. In particular, mitochondrial barriers might impact on H2 use in mitochondria-related diseases and conditions. Double-membrane organization of mitochondria and large membrane potential are important elements of mitochondrial stability that control the transport of the molecule into and out of the organelle. In this perspective paper, we advanced possible obstacles and advantages for H2 delivery to mitochondria.”

 

Ostojic, S. M. (2015). Targeting molecular hydrogen to mitochondria: Barriers and gateways. Pharmacological Research, 94, 51-53. doi: 10.1016/j.phrs.2015.02.004

 

Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice

 

“Hydrogen is an established anti-oxidant that prevents acute oxidative stress. To clarify the mechanism of hydrogen's effect in the brain, we administered hydrogen-rich pure water (H(2)) to senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize vitamin C (VC), also a well-known anti-oxidant. These KO mice were divided into three groups; recipients of H(2), VC, or pure water (H(2)O), administered for 33 days. VC levels in H(2) and H(2)O groups were <6% of those in the VC group. Subsequently, superoxide formation during hypoxia-reoxygenation treatment of brain slices from these groups was estimated by a real-time biography imaging system, which models living brain tissues, with Lucigenin used as chemiluminescence probe for superoxide. A significant 27.2% less superoxide formed in the H(2) group subjected to ischemia-reperfusion than in the H(2)O group. Thus hydrogen-rich pure water acts as an anti-oxidant in the brain slices and prevents superoxide formation.”

 

Sato, Y., Kajiyama, S., Amano, A., Kondo, Y., Sasaki, T., Handa, S., . . . Ishigami, A. (2008). Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochemical and Biophysical Research Communications, 375(3), 346-350. doi: 10.1016/j.bbrc.2008.08.020

 

Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest

 

“Deep hypothermic circulatory arrest (DHCA) has been widely used in the operations involving the aortic arch and brain aneurysm since 1950s; but prolonged DHCA contributes significantly to neurological deficit which remains a major cause of postoperative morbidity and mortality. It has been reported that hydrogen exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical. In this study, DHCA treated rats developed a significant oxidative stress, inflammatory reaction and apoptosis. The administration of HRS resulted in a significant decrease in the brain injury, together with lower production of IL-1β, TNF-α, 8-OHdG and MDA as well as decreased activity of NOS while increased activity of SOD. The apoptotic index as well as the expressions of caspase-3 in brain tissue was significantly decreased after treatment. HRS administration significantly attenuated the severity of DHCA induced brain injury by mechanisms involving amelioration of oxidative stress, down-regulation of inflammatory factors and reduction of apoptosis.”

 

Shen, L., Wang, J., Liu, K., Wang, C., Wang, C., Wu, H., . . . Jing, H. (2011). Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest. Neurochemical Research, 36(8), 1501-1511. doi: 10.1007/s11064-011-0476-4

 

Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity

 

“The rats were exposed to 1000 ppm CO in air for 40 min and then to 3000 ppm for another 20 min until they lost consciousness. Rats were intraperitoneal injected with hydrogen-rich saline or normal saline (10 mL/kg) for six times after resuscitation at 0, 12, 24, 36, 48, and 60 hrs, respectively. The rats without CO poisoning were used as normal controls.
Brain tissue inflammation, cell death, and cognitive dysfunction were observed at one week after CO poisoning. Hydrogen-rich saline treatment significantly reduced the level of degraded myelin basic protein, decreased the expression of ionized calcium-binding adapter molecule 1, Iba1, a microglial marker, reduced DNA oxidation, and suppressed proinflammatory cytokine interleukin-1β, interleukin-6, and tumor necrosis factor-α in the cortex and hippocampal tissues when compared with those in normal saline-treated rats. These histologic and biological improvements were accompanied with an improvement in the Morris water maze test.
This observation demonstrated that hydrogen-rich saline peritoneal injection improves histologic and functional assessment in a rat model of CO encephalopathy. Hydrogen saline has potentials as a novel and alternative therapy for severely CO-poisoned patients with delayed neurologic sequelae. The therapeutic effects of hydrogen-rich saline may be related to antioxidant and anti-inflammatory actions.”

 

Sun, Q., Cai, J., Zhou, J., Tao, H., Zhang, J. H., Zhang, W., & Sun, X. (2011). Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Critical Care Medicine, 39(4), 765-769. doi: 10.1097/ccm.0b013e318206bf44

 

Hydrogen-related enhancement of in vivo antioxidant ability in the brain of rats fed coral calcium hydride

 

“This study explored the effect of coral calcium hydride (CCH) on rat intrahippocampal antioxidant ability by measuring the PCAM nitroxide radical decay ratio when CCH was (a) co-perfused into the hippocampus and (b) fed orally to the rats for 4 weeks under a freely moving state. Estimation of the in vivo antioxidant effect was obtained by administration of the blood-brain barrier-permeable PCAM nitroxide radical and the measured PCAM radical decay ratio then correlated to the amount of antioxidant in the brain using electron spin resonance (ESR) spectroscopy combined with microdialysis. The half-life periods of PCAM in rats treated with CCH in both the co-perfusion and orally fed groups were significantly shorter compared to the control group. These results clarify the mechanism that CCH may exert antioxidant activity by significantly enhancing the basal endogenous antioxidant ability in the hippocampus through a synergistic effect with α-tocopherol and ascorbic acid.”

 

Ueda, Y., Nakajima, A., & Oikawa, T. (2010). Hydrogen-related enhancement of In vivo antioxidant ability in the brain of rats fed coral calcium hydride. Neurochemical Research, 35(10), 1510-1515. doi: 10.1007/s11064-010-0204-5

 

Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats

 

“Chronic exposure to low-levels of organophosphate (OP) compounds, such as chlorpyrifos (CPF), induces oxidative stress and could be related to neurological disorders. Hydrogen has been identified as a novel antioxidant which could selectively scavenge hydroxyl radicals. We explore whether intake of hydrogen-rich water (HRW) can protect Wistar rats from CPF-induced neurotoxicity. Rats were gavaged daily with 6.75mg/kg body weight (1/20 LD50) of CPF and given HRW by oral intake. Nissl staining and electron microscopy results indicated that HRW intake had protective effects on the CPF-induced damage of hippocampal neurons and neuronal mitochondria. Immunostaining results showed that the increased glial fibrillary acidic protein (GFAP) expression in astrocytes induced by CPF exposure can be ameliorated by HRW intake. Moreover, HRW intake also attenuated CPF-induced oxidative stress as evidenced by enhanced level of MDA, accompanied by an increase in GSH level and SOD and CAT activity. Acetylcholinesterase (AChE) activity tests showed significant decrease in brain AChE activity after CPF exposure, and this effect can be ameliorated by HRW intake. An in vitro study demonstrated that AChE activity was more intense in HRW than in normal water with or without chlorpyrifos-oxon (CPO), the metabolically-activated form of CPF. These observations suggest that HRW intake can protect rats from CPF-induced neurotoxicity, and the protective effects of hydrogen may be mediated by regulating the oxidant and antioxidant status of rats. Furthermore, this work defines a novel mechanism of biological activity of hydrogen by directly increasing the AChE activity.”

 

Wang, T., Zhao, L., Liu, M., Xie, F., Ma, X., Zhao, P., . . . Zhang, Y. (2014). Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats. Toxicology and Applied Pharmacology, 280(1), 169-176. doi: 10.1016/j.taap.2014.06.011

 

Hydrogen rich saline reduces immune-mediated brain injury in rats with acute carbon monoxide poisoning

 

“Sprague-Dawley male rats were used for CO poisoning and H(2) rich saline treatment. Changes in neurons, microglias, and myelin sheath were observed by electron microscope. Neuron loss was assessed by Nissl staining. Antioxidant capacities were evaluated by studying superoxide dismutase activities and malondialdehyde concentration in the brain and serum. Infiltration of macrophages, expression of immune-associated cytokines (MIP-1-alpha and ICAM-1), and changes in myelin basic protein (MBP) were monitored by immunohistochemical staining and western blotting.
CO-exposed rats showed the increase in neuron loss and the decrease in antioxidant capacities. And H(2) rich saline given after CO poisoning can prevent the alterations mentioned above. CO-mediated oxidative stress caused alterations in MBP, which initiated an adaptive immunological response that led to brain injury. MBP from H(2) rich saline-treated, CO-exposed rats was recognized normally by immunohistochemical staining and western blotting. Electron microscope observation from CO-exposed rats showed an apparent aggregation of microglias. Macrophages from CO-exposed rats were significantly more than those from H(2) rich saline-treated and control rats, and the immunofluorescence observation showed that macrophages were similar to microglias in type. Expression levels of MIP-1-alpha and ICAM-1 increased in the brains of CO-poisoned rats and H(2) rich saline treatment decreased the levels.
The results indicate that H(2) rich saline prevents immune-mediated brain injury after CO poisoning.”

 

Wang, W., Li, Y., Ren, J., Xia, F., Li, J., & Zhang, Z. (2012). Hydrogen rich saline reduces immune-mediated brain injury in rats with acute carbon monoxide poisoning. Neurological Research, 34(10), 1007-1015. doi: 10.1179/1743132812y.0000000106

 

Molecular hydrogen and its potential application in therapy of brain disorders

 

“Although the protective effects of molecular hydrogen have been reported in many kinds of brain disorders, the mechanism to explain the neuroprotective effects of hydrogen is limited to its antioxidant property [6,8,10]. A possible cause for the neuroprotective effect of hydrogen may be related to its high diffusibility. Hydrogen molecules can readily cross the blood-brain barrier and penetrate biomembranes smoothly to diffuse into the cytosol, nucleus and mitochondria. This is particularly important, as mitochondria is the major source of ROS and notoriously difficult to target. The protective effect of molecular hydrogen on the mitochondria have also been found in our study. However, the detailed mechanism underlying the protective effect of molecular hydrogen on the mitochondria remains unknown. Several reports have demonstrated an effect on the regulation of gene expression and protein-phosphorylation, however, the transcriptional factors and kinases involved in the effects of molecuar hydrogen have not been identified. Recently, our study defines a novel mechanism of biological activity of hydrogen by directly increase the AChE activity, which indicates the possibility of the direct interaction between hydrogen and other enzyme molecules [9]. We believed that once more targets interacting directly with molecular hydrogen be found, the mechanisms underlying the marked effects of the molecular hydrogen will be elucidated.”

 

Ma, F. X. (2015). Molecular hydrogen and its potential application in therapy of brain disorders. Brain Disorders & Therapy, 4(1), 1-2. doi: 10.4172/2168-975x.1000154

 

The neuroprotective effects of electrolyzed reduced water and its model water containing molecular hydrogen and Pt nanoparticles

 

“In this research, we used TI-200S ERW derived from 2 mM NaOH solution produced by a batch type electrolysis device and model waters containing molecular hydrogen and synthetic Pt NPs of 2-3 nm sizes as research models of ERW to examine the anti-oxidant capabilities of ERW on several kinds of neural cells such as PC12, N1E115, and serum free mouse embryo (SFME) cells. We pretreated the ERW and 200 μM H2O2 and examined the neuroprotective effects of ERW on PC12, N1E115 and SFME cells, using WST-8 method. We also examined the intracellular ROS scavenging effects of ERW on N1E115 cells after pretreated cells with ERW and H2O2 using DCFH-DA. We checked the protective effects of ERW on mitochondria and cytoplasm by Rh123 and Fuo-3 AM stain. We also examined the ATP production of SFME cells after pretreated with ERW and H2O2 by Bioluminescence Assay Kit. Finally, we used dissolved hydrogen (DH) and Pt NPs as research models to examine their neuroprotective effects.
ERW significantly reduced the cell death induced by H2O2 pretreatment. ERW also scavenged the intracellular ROS and prevented the decrease of mitochondrial membrane potential and ATP production induced by ROS. We also examined the neuroprotective effects of molecular hydrogen and Pt NPs and showed that both molecular hydrogen and Pt NPs contributed to the neuroprotective effects of ERW. The results suggest that ERW is beneficial for the prevention and alleviation of oxidative stress-induced human neurodegenerative diseases.”

 

Yan, H., Kashiwaki, T., Hamasaki, T., Kinjo, T., Teruya, K., Kabayama, S., & Shirahata, S. (2011). The neuroprotective effects of electrolyzed reduced water and its model water containing molecular hydrogen and Pt nanoparticles. BioMed Central Proceedings, 5(8), 1-2. doi: 10.1186/1753-6561-5-s8-p69

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Nuclear factor-κB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits

 

“Early brain injury (EBI), a significant contributor to poor outcome after subarachnoid hemorrhage (SAH), is intimately associated with neuronal apoptosis. Recently, the protective role of hydrogen (H2 ) in the brain has been widely studied, but the underlying mechanism remains elusive. Numerous studies have shown nuclear factor-κB (NF-κB) as a crucial survival pathway in neurons. Here we investigated the role of H2 in EBI following SAH, focusing on the NF-κB pathway. A double blood injection model was used to produce experimental SAH, and H2 -rich saline was injected intraperitoneally. NF-κB activity within the occipital cortex was measured. Immunofluorescence was performed to demonstrate the activation of NF-κB; Bcl-xL and cleaved caspase-3 were determined via Western blot. Gene expression of Bcl-xL was detected by real-time PCR, and TUNEL and Nissl staining were performed to illustrate brain injury in the occipital cortex. SAH induced a significant increase of cleaved caspase-3. Correspondingly, TUNEL staining demonstrated obvious neuronal apoptosis following SAH. In contrast, H2 treatment markedly increased NF-κB activity and the expression of Bcl-xL and decreased the level of cleaved caspase-3. Additionally, H2 treatment significantly reduced post-SAH neuronal apoptosis. The current study shows that H2 treatment alleviates EBI in the rabbits following SAH and that NF-κB/Bcl-xL pathway is involved in the protective role of H2.”

 

Zhuang, Z., Sun, X., Zhang, X., Liu, H., You, W., Ma, C., . . . Shi, J. (2013). Nuclear factor-κB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. Journal of Neuroscience Research, 91(12), 1599-1608. doi: 10.1002/jnr.23281

 

Hydrogen-rich water attenuates amyloid β-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMP-activated protein kinase in SK-N-MC cells

 

“Amyloid β (Aβ) peptides are identified in cause of neurodegenerative diseases such as Alzheimer's disease (AD). Previous evidence suggests Aβ-induced neurotoxicity is linked to the stimulation of reactive oxygen species (ROS) production. The accumulation of Aβ-induced ROS leads to increased mitochondrial dysfunction and triggers apoptotic cell death. This suggests antioxidant therapies may be beneficial for preventing ROS-related diseases such as AD. Recently, hydrogen-rich water (HRW) has been proven effective in treating oxidative stress-induced disorders because of its ROS-scavenging abilities. However, the precise molecular mechanisms whereby HRW prevents neuronal death are still unclear. In the present study, we evaluated the putative pathways by which HRW protects against Aβ-induced cytotoxicity. Our results indicated that HRW directly counteracts oxidative damage by neutralizing excessive ROS, leading to the alleviation of Aβ-induced cell death. In addition, HRW also stimulated AMP-activated protein kinase (AMPK) in a sirtuin 1 (Sirt1)-dependent pathway, which upregulates forkhead box protein O3a (FoxO3a) downstream antioxidant response and diminishes Aβ-induced mitochondrial potential loss and oxidative stress. Taken together, our findings suggest that HRW may have potential therapeutic value to inhibit Aβ-induced neurotoxicity.”

 

Lin, C., Huang, W., Li, H., Huang, C., Hsieh, S., Lai, C., & Lu, F. (2015). Hydrogen-rich water attenuates amyloid β-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMP-activated protein kinase in SK-N-MC cells. Chemico-Biological Interactions, 240, 12-21. doi: 10.1016/j.cbi.2015.07.013

 

Role of transcription factor FOXO3a in alleviating global cerebral ischemia-reperfusion injury in rats by hydrogen-rich solution 

 

“72 male SD rats, weighing 280 ~ 320 g, using a random number table, randomly divided into six groups ( N = 12): sham operation group (Ⅰ), global cerebral ischemia-reperfusion group (Ⅱ group) hydrogen rich solution group (ⅲ group), dimethyl sulfoxide (DMSO) solvent group (ⅳ group), c-jun N-terminal kinase (JNK) inhibitor group (ⅴ group), JNK inhibitor + hydrogen-rich solution group (ⅵ group). Using transesophageal cardiac pacing-induced cardiac arrest and cardiopulmonary resuscitation rat global cerebral ischemia and reperfusion injury model. Ⅰ group were not given electrical stimulation and cardiopulmonary resuscitation; Ⅱ ~ Ⅵ group of electrical stimulation 4 min establish global cerebral ischemia-reperfusion model; Ⅲ group and Ⅵ group immediately and 6 h intraperitoneal injection of hydrogen-rich liquid 5 ml / kg of reperfusion, and the rest group were injected with normal saline; ⅴ and ⅵ group group 30 min before ischemia lateral ventricle give 10 μl JNK inhibitor SP600125, ⅳ group 30 min before ischemia in the left ventricle given the same volume DMSO solvent. 24 h after reperfusion neurologic impairment score line; then each group were sacrificed 6 rats sections of brain tissue, HE staining, light microscope pathological changes in the hippocampal CA1 region, and vertebral cell count; another 6 just take in hippocampus, hippocampal neurons detect phosphorylation of c-jun N-terminal kinase (p-JNK) by Western blotting, JNK and nuclear and cytoplasmic FOXO3a expression.
24 h after reperfusion, group Ⅰ normal hippocampal CA1 pyramidal cells, nerve injury does not appear; and Ⅰ group, Ⅱ and Ⅳ severe vertebral cell damage, severe neurological damage, increased expression of p-JNK, FOXO3a increased expression in the nucleus; compared with group ⅱ, ⅲ group, ⅴ and ⅵ group hippocampal area CA1 pyramidal cells less damage, neurological damage mitigation, p-JNK decreased expression, FOXO3a expression in the nucleus significantly reduced. Hydrogen-rich liquid mitigate global cerebral reperfusion injury may be related to inhibition of JNK activity, reduce FOXO3a translocation to the nucleus, inhibiting its activity.”

 

Lin, Z., Xingdong, C., Qiongyan, D., Lu, Z., Gao, Y., Lin, W., . . . Jianguo, X. (2015). Role of transcription factor FOXO3a in alleviating global cerebral ischemia-reperfusion injury in rats by hydrogen-rich solution. Chinese Medical Journal, 95(6), 457-461. doi: 10.3760/cma.j.issn.0376-2491.2015.06.014

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