|Year : 2023 | Volume
| Issue : 3 | Page : 94-98
Molecular hydrogen therapy for neurological diseases: a review of current evidence
Dinesh Ramanathan1, Lei Huang2, Taylor Wilson1, Warren Boling1
1 Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA
2 Department of Neurosurgery, Loma Linda University; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA
|Date of Submission||25-Apr-2021|
|Date of Decision||16-May-2021|
|Date of Acceptance||23-Jul-2021|
|Date of Web Publication||22-Dec-2022|
Department of Neurosurgery, Loma Linda University, Loma Linda, CA
Source of Support: None, Conflict of Interest: None
Reactive oxygen species and other free radicals cause oxidative stress which is the underlying pathogenesis of cellular injury in various neurological diseases. Molecular hydrogen therapy with its unique biological property of selectively scavenging pathological free radicals has demonstrated therapeutic potential in innumerable animal studies and some clinical trials. These studies have implicated several cellular pathways affected by hydrogen therapy in explaining its anti-inflammatory and antioxidative effects. This article reviews relevant animal and clinical studies that demonstrate neuroprotective effects of hydrogen therapy in stroke, neurodegenerative diseases, neurotrauma, and global brain injury.
Keywords: animal; antioxidant; brain injury; clinical study; hydrogen therapy; molecular hydrogen; neurodegenation; neuroinflammation; oxidative stress; stroke
|How to cite this article:|
Ramanathan D, Huang L, Wilson T, Boling W. Molecular hydrogen therapy for neurological diseases: a review of current evidence. Med Gas Res 2023;13:94-8
|How to cite this URL:|
Ramanathan D, Huang L, Wilson T, Boling W. Molecular hydrogen therapy for neurological diseases: a review of current evidence. Med Gas Res [serial online] 2023 [cited 2023 Jan 28];13:94-8. Available from: https://www.medgasres.com/text.asp?2023/13/3/94/359677
| Introduction|| |
Molecular hydrogen scavenges reactive oxygen species and acts as a therapeutic antioxidant. Since the initial demonstration of benefit of molecular hydrogen on the rat model of cerebral infarction in 2007, a plethora of animal research and several clinical studies have demonstrated significant beneficial results for various diseases. Uniquely, molecular hydrogen selectively scavenges hydroxyl radicals and peroxy-nitric radicals that are responsible for oxidative stress and disease process, while sparing other reactive oxygen species such as hydrogen peroxide, superoxide and nitric oxide that are critical to normal cell physiology. An overwhelming excess of reactive oxygen species and free radicals creates oxidative stress that is central to the pathogenesis of neurological diseases including ischemic stroke, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI) and neurodegeneration. Thus, the selective antioxidant property and safety profile of molecular hydrogen create a tremendous potential for a wide range of clinical applications ranging from stroke treatment to antiaging therapy.
In this review, we aim to provide a succinct mechanistic overview of hydrogen therapy in neurological diseases based on related animal studies and an update of the evidence in human clinical studies.
| Search Strategy|| |
We used PubMed search to retrieve relevant published literature between 1978 to 2021. The terms used for the search were molecular hydrogen, hydrogen gas therapy, and neurological diseases. The search results obtained included both original research and review articles. All original research papers were classified as clinical, animal or in vitro studies. In this manuscript we review the studies focusing on neurological disorders in animal models and clinical settings.
| Delivery Methods|| |
With a safe biologic profile, molecular hydrogen can be administered clinically via several methods including hydrogen gas inhalation, intravascular hydrogenized saline infusions or orally drinking hydrogen water. In addition, increased intestinal hydrogen availability with drugs such as lactulose, acarbose and hydrogen rich tablets has been reported. Hydrogen gas is generally inert and not flammable at a concentration less than 4.7% in air, although it is highly flammable at higher concentrations., Inhalational method of delivery provides a simple and practical strategy to administer hydrogen gas at different concentrations (1%, 1.3%, 2%, 4%) through a ventilator circuit/face mask, supplied by gas tank. The hydrogen oxygen nebulizer devices that can provide a high concentration of hydrogen gas (66%) are now available and approved for clinical use. It employs a unique water electrolysis method, splitting the water molecules into its stoichiometric 2:1 hydrogen to oxygen ratio. As to hydrogen delivery through intravenous administration of hydrogen-rich saline, Nagatani et al. described the use of hydrogen-enriched glucose-electrolyte solution produced using a non-destructive hydrogen adding apparatus wherein bags of glucose electrolyte solution were immersed, without opening or altering the bag in a water tank placed in the water. To produce hydrogen water, molecular hydrogen was dissolved in water under high pressure (0.4 MPa) to a supersaturated level using a hydrogen water producing apparatus (Blue Mercury Inc., Tokyo, Japan). A comparative study evaluating the consumption of hydrogen-rich water orally, inhalational hydrogen gas, intraperitoneal/intravenous administration of hydrogen-rich saline in mouse models showed peak concentration of hydrogen in tissues about 1 minute after intravenous administration, 5 minutes after oral administration and 30 minutes after inhalational hydrogen gas. From the neurological perspective, no differences were noted in concentrations of hydrogen in the brain between hydrogen-rich water and hydrogen-rich saline administration, as hydrogen was noted to migrate to the brain regardless of any mode of administration.
| Hydrogen Therapy in Stroke|| |
As the second leading cause of death worldwide, ischemic cerebrovascular stroke is a major source of morbidity and mortality. Historically, the majority of treatments have focused on reperfusion most commonly via administration of recombinant tissue plasminogen activator, an enzyme that lyses fibrin cross links and ultimately resolves the clot, or by physically removing the clot via mechanical thrombectomy. Although the advent of these “clot busting” therapies has revolutionized the management of ischemic stroke, they are not without risk, largely due to secondary injury of damaged parenchyma from reperfusion due to oxidative stress, especially if it occurs too rapidly. Thus reducing reperfusion injury in stroke could potentially be a significant adjunct to the current treatment paradigm to improve clinical outcomes.
Ohsawa et al.,,,,, first reported that hydrogen gas acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals in a rat model of middle cerebral artery occlusion, followed by several other studies supporting those findings. Most studies of hydrogen gas therapy for ischemic cerebral stroke used animal models, particularly rat models of cerebral ischemia/reperfusion. Hydrogen sulfide has also been studied as a mode of hydrogen therapy in animal ischemic models with comparable beneficial neuroprotective results.,
Hyperglycemia is one of the major factors for hemorrhagic transformation after ischemic stroke. Chen et al. reported that 2.9% hydrogen gas inhalation significantly attenuated the hemorrhagic transformation in a rat focal cerebral ischemia model by scavenging free radicals.
Clinically, several studies have embarked on studies of hydrogen gas therapy in patients with ischemic stroke. In a randomized controlled trial in 2017, Ono et al. divided patients into two groups with the treatment group receiving hydrogen gas compared with a control that was administered the gas medium without hydrogen gas. The hydrogen gas treatment group demonstrated more rapid and complete recovery with earlier improvement in the National Institutes of Health Stroke Scale score and improved overall functional outcomes with higher modified Rankin scores, ability to perform activities of daily living, and greater functional independence. Furthermore, this trial highlighted the safety profile of hydrogen gas therapy in patients with ischemic stroke wherein no adverse effects reported. The same group reported significantly smaller areas of infarct, as measured with magnetic resonance imaging indices in patients treated with hydrogen gas therapy following ischemic stroke. The lack of any adverse effects of hydrogen therapy appears to hold true across multiple clinical studies.
Further clinical trials to better understand the efficacy and optimize the treatment regimen for hydrogen gas therapy could help unravel its exciting potential as a useful adjunct to current reperfusion therapies in treating ischemic strokes.
Intracerebral hemorrhage (ICH) is a type of stroke characterized by bleeding within the brain tissue. Hydrogen therapy provides a neuroprotective effect in animal models of hemorrhagic stroke., Manaenko et al. observed the beneficial effects of an hour of 2.9% hydrogen inhalation in animal ICH models likely due to reduction of redox stress and blood-brain barrier disruption mediated through suppression of mast cell activation and degranulation. Hydrogen gas inhalation at 1.3% consistently exerted a neuroprotective effect against early brain injury after ICH through anti-inflammatory, neuroprotective, anti-apoptotic, and antioxidative activity. However, clinical studies evaluating hydrogen therapy in ICH patients have not been reported.
| Sah|| |
SAH due to ruptured intracranial aneurysm is a devastating neurological condition with high mortality and severe morbidity. The neurological prognosis depends both on the severity of vasospasm that causes delayed ischemic neurological deficit and the acute brain injury that occurs after SAH. Mechanistic details underlying acute brain injury and cerebral vasospasm after SAH are not completely understood and therefore no definitive therapy exists to effectively prevent or treat these phenomena. Many studies however point to an important role of oxidative stress in the pathophysiology of SAH and its sequelae.,,,,, Oxyhemoglobin formed by the oxidation of extravasated blood breakdown products is known to generate free radicals and oxidative stress, which leads to inflammation and neuronal injury/death.,, Several downstream signaling pathways have been postulated for neuroinflammations, such as inflammasome signaling pathway and nuclear factor kappa B pathway, which are all triggered by excess reactive oxygen species. By inhibiting these pathways with its anti-oxidative, anti-inflammatory and anti-apoptotic properties, hydrogen has the potential to alleviate the early after-effects of SAH. Shao et al. demonstrated in rat SAH models that hydrogenated saline administration decreased neuronal apoptosis by inhibiting Akt/glycogen synthase kinase 3beta pathway and also decreased vasospasm by inhibiting oxidative stress and vascular inflammation. Other studies have demonstrated similar inhibition of oxidative stress and decreased endothelial cell injury, partly by inhibiting reactive oxygen species/NOD-, LRR- and pyrin domain-containing protein 3 axis, leading to improved neurobehavioral outcomes and decreased vasospasm., Zhan et al. noted that inhaled hydrogen within one hour of SAH induction ameliorated oxidative stress, reduced apoptosis, preserved blood-brain barrier, alleviated brain edema and improved neurological deficits. In a subsequent study the group also demonstrated improvement in neurobehavioral outcomes in the rat model with inhaled hydrogen. They studied the survival rate and 24-hour neuroprotection as primary outcome measures. They found an early administration of high concentration of inhaled hydrogen gas (66% at 3 L/min) reduced mortality and improved neurobehavioral function at 24 hours after SAH. However, no significant neurobehavioral difference was noted at 72 hours in the study.
In addition to animal models, some human studies are currently ongoing for evaluating hydrogen therapy in SAH. Takechi et al. initiated a double-blind randomized control trial that enrolled 450 patients with high grade SAH for evaluating the efficacy of hydrogen therapy in treating early brain injury, delayed cerebral ischemia and vasospasm. The study randomized patients into three arms based on the intervention they receive: combination intracisternal magnesium and intravenous hydrogen group, intracisternal magnesium group and a control group. Primary outcome measures studied include delayed cerebral ischemia and vasospasm. In addition, Rankin score at 3, 6, and 12 months are to be measured as secondary outcomes. The results of this trial are pending.
| Hydrogen Therapy in Neurodegenerative Diseases|| |
Parkinson’s disease (PD) is attributed to degeneration or loss of dopaminergic cells in the substantia nigra. Recent evidence demonstrates aggregation of extracellular alpha synuclein contributes to neuroinflammation and neuronal death. nuclear factor kappa B related signaling pathway is implicated in increased accumulation of alpha synuclein. Oxidative stress and mitochondrial dysfunction are known to be a common pathway for several etiologies and activation of inflammatory cellular signal cascades.,, The beneficial effects of hydrogen therapy for PD have been reported in both animal models and in clinical studies., Yoritaka et al. performed a clinical trial evaluating oxygen-rich water consumption for PD recently. In a placebo controlled, randomized double blind parallel group clinical pilot study, the authors assessed the efficacy of 1 L/d hydrogen water therapy in Japanese levodopa-medicated PD patients over 48 weeks. There was a significant improvement in the total unified PD rating scale in the hydrogen water group compared to the placebo group.
Alzheimer’s disease (AD) is a common neurodegenerative dementia disorder associated with advanced age. Deposition of amyloid beta protein outside the neurons and accumulation of phosphorylated tau protein inside nerve cells leading to neuronal loss is known to be the hallmark of the pathogenesis. Oxidative stress and neuroinflammation have been identified as causative mechanisms leading to the onset of AD.,,,,,, Oral hydrogen water intake ameliorated cognitive impairment in senescent accelerated mice. Similarly, hydrogen-rich saline administration intraperitoneally led to improved memory secondary to inhibition of oxidative stress, cytokine production and nuclear factor kappa B production.,
In AD mouse models, sustained release of bioactive hydrogen by palladium hydride nanoparticles could block synaptic and neuronal apoptosis, promote neuronal metabolism by eliminating oxidative stress, and activate anti-oxidative pathway, leading to amelioration of cognitive impairment. A sustained, continuous in situ release of hydrogen in mouse brain tissue using the nanoparticles has been reported. Efficacy of hydrogen therapy with human studies has not been reported thus far.
| Hydrogen Therapy in Neurotrauma|| |
The efficacy of molecular hydrogen in treating brain injury has been investigated in mouse models of both TBI and surgical brain injury.,, Inhalational hydrogen was reported to protect blood-brain barrier and decrease cerebral edema and inhibit the decrease in antioxidant enzymes such a superoxide dismutase and catalases in rat TBI model. Several mechanisms such as inhibition of hypoxia inducible factor-1, Matrix metallopeptidase-9, and cyclophilin A, modulation of cytokines and chemokines are implicated in neuroprotective mechanisms of hydrogen therapy in TBI. Another study by Eckermann et al. reported decreased cerebral edema and improved neurobehavioral scores after frontal lobectomy in surgical trauma mouse models.
There are no large clinical studies evaluating hydrogen therapy in TBI. However, anecdotal individual use cases have reported clinical benefits. An athlete given a buccal administration of hydrogen producing dissolving tablet immediately and every 2 hours for a day after concussive injury presented with an improvement in concussion score from moderate to mild category. In the future, larger clinical studies may provide more data on dose and efficacy of such therapies in the setting of TBI.
| Hydrogen Therapy in Global Brain Injury|| |
Hydrogen gas therapy has also been demonstrated to improve symptoms of septic encephalopathy in the mouse model of cecal ligation and puncture. Liu et al. performed a study using 2% inhaled hydrogen gas administration in mice, and demonstrated decreased brain edema, blood-brain barrier breakdown, cytokine production, and oxidative stress in the hippocampal CA1 region. In the rodent model of global brain ischemia/reperfusion, low-concentration hydrogen gas inhalation or hydrogen-rich saline intraperitoneal injection showed the neuroprotective effects and improved survival rate through anti-oxidant mechanism as well as mitochondrial protection., Recently, Huang et al., reported the water-electrolysis-generated 67% hydrogen improved the short- and long-term neurological deficits and decreased neuronal degeneration within the hippocampus in a rat model of asphyxia-induced cardiac arrest.
| Conclusion|| |
Numerous preclinical studies have pointed out the striking beneficial effects of hydrogen therapy across a wide range of diseases. Only a limited number of human studies have been reported till date, all of which have demonstrated the benefits of hydrogen therapy in the clinical setting. It is however remarkable to note that no adverse effects have been reported in the human studies related to administration of hydrogen therapy. With several ongoing studies and continued interest in hydrogen therapy, the future looks promising for its clinical use as an adjunctive treatment of various neurological diseases.
Conception and design: WB, LH; data acquisition of: WB, DR, TW, LH; manuscript revision: WB, DR, LH; review supervision: WB. All authors contributed to the article and approved the submitted version.
Conflicts of interest
None of the authors have any conflicts of interest relevant to the contents or the drafting of this manuscript.
Editor note: LH is an Editorial Board member of Medical Gas Research. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of the Editorial Board member and his research group.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution Non Commercial- Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
| References|| |
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med.
Camara R, Huang L, Zhang JH. The production of high dose hydrogen gas by the AMS-H-01 for treatment of disease. Med Gas Res.
Nagatani K, Nawashiro H, Takeuchi S, et al. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Med Gas Res.
Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci Rep.
Li H, Luo Y, Yang P, Liu J. Hydrogen as a complementary therapy against ischemic stroke: A review of the evidence. J Neurol Sci.
Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med.
Ji Q, Hui K, Zhang L, Sun X, Li W, Duan M. The effect of hydrogen-rich saline on the brain of rats with transient ischemia. J Surg Res.
Liu Y, Liu W, Sun X, et al. Hydrogen saline offers neuroprotection by reducing oxidative stress in a focal cerebral ischemia-reperfusion rat model. Med Gas Res.
Wang X, Zhang L, Zhao W, Liu T. The protective effects of hydrogen on HO-1 expression in the brainafter focal cerebral ischemia reperfusion in rats. Turk J Med Sci.
Huang L, Lenahan C, Boling W, Tang J, Zhang JH. Molecular hydrogen application in stroke: bench to bedside. Curr Pharm Des.
Cong HM, Gao QP, Song GQ, et al. Hydrogen-rich saline ameliorates hippocampal neuron apoptosis through up-regulating the expression of cystathionine β-synthase (CBS) after cerebral ischemia-reperfusion in rats. Iran J Basic Med Sci.
Dou Y, Wang Z, Chen G. The role of hydrogen sulfide in stroke. Med Gas Res.
Gheibi S, Aboutaleb N, Khaksari M, et al. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci.
Chen CH, Manaenko A, Zhan Y, et al. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience.
Ono H, Nishijima Y, Ohta S, et al. Hydrogen gas inhalation treatment in acute cerebral infarction: a randomized controlled clinical study on safety and neuroprotection. J Stroke Cerebrovasc Dis
Ono H, Nishijima Y, Adachi N, et al. 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. Med Gas Res.
Manaenko A, Lekic T, Ma Q, Zhang JH, Tang J. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med.
Dohi K, Satoh K, Miyamoto K, et al. Molecular hydrogen in the treatment of acute and chronic neurological conditions: mechanisms of protection and routes of administration. J Clin Biochem Nutr
Choi KS, Kim HJ, Do SH, Hwang SJ, Yi HJ. Neuroprotective effects of hydrogen inhalation in an experimental rat intracerebral hemorrhage model. Brain Res Bull.
Ljunggren B, Brandt L, Sundbärg G, Säveland H, Cronqvist S, Stridbeck H. Early management of aneurysmal subarachnoid hemorrhage. Neurosurgery.
Fumoto T, Naraoka M, Katagai T, Li Y, Shimamura N, Ohkuma H. The role of oxidative stress in microvascular disturbances after experimental subarachnoid hemorrhage. Transl Stroke Res.
Zhuang K, Zuo YC, Sherchan P, Wang JK, Yan XX, Liu F. Hydrogen inhalation attenuates oxidative stress related endothelial cells injury after subarachnoid hemorrhage in rats. Front Neurosci.
Zuo G, Zhang T, Huang L, et al. Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCɛ/ALDH2 pathway after subarachnoid hemorrhage in rats. Free Radic Biol Med
Shi G, Cui L, Chen R, Liang S, Wang C, Wu P. TT01001 attenuates oxidative stress and neuronal apoptosis by preventing mitoNEET-mediated mitochondrial dysfunction after subarachnoid hemorrhage in rats. Neuroreport.
Xu W, Li T, Gao L, et al. Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats. J Neuroinflammation.
Mo J, Enkhjargal B, Travis ZD, et al. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP- 2 pathway after subarachnoid hemorrhage in rats. Redox Biol.
Ducruet AF, Gigante PR, Hickman ZL, et al. Genetic determinants of cerebral vasospasm, delayed cerebral ischemia, and outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab.
Ayer RE, Zhang JH. Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl.
Crowley RW, Medel R, Kassell NF, Dumont AS. New insights into the causes and therapy of cerebral vasospasm following subarachnoid hemorrhage. Drug Discov Today.
Shao A, Wu H, Hong Y, et al. Hydrogen-rich saline attenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: possible involvement of NF-κB pathway and NLRP3 inflammasome. Mol Neurobiol.
Zhao H, Pan P, Yang Y, et al. Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats. J Neuroinflammation.
Zhan Y, Chen C, Suzuki H, Hu Q, Zhi X, Zhang JH. Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med.
Camara R, Matei N, Camara J, Enkhjargal B, Tang J, Zhang JH. Hydrogen gas therapy improves survival rate and neurological deficits in subarachnoid hemorrhage rats: a pilot study. Med Gas Res.
Takeuchi S, Mori K, Arimoto H, et al. Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial. BMC Neurol.
Liu P, Sun L, Zhao XL, Zhang P, Zhao XM, Zhang J. PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson’s disease. Brain Res.
Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell.
Jiang T, Sun Q, Chen S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. Prog Neurobiol.
Puspita L, Chung SY, Shim JW. Oxidative stress and cellular pathologies in Parkinson's disease. Mol Brain.
Ito M, Hirayama M, Yamai K, et al. 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. Med Gas Res.
Fu Y, Ito M, Fujita Y, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett.
Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of H therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord.
Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol.
Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer's disease. Biomed Rep.
Butterfield DA, Boyd-Kimball D. Oxidative Stress, Amyloid-ᵝPeptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease. J Alzheimers Dis.
Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol.
Simunkova M, Alwasel SH, Alhazza IM, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol.
Nunomura A, Perry G. RNA and oxidative stress in Alzheimer's disease: focus on microRNAs. Oxid Med Cell Longev.
Pohanka M. Oxidative stress in Alzheimer disease as a target for therapy. Bratisl Lek Listy.
Gu Y, Huang CS, Inoue T, et al. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr.
Wang C, Li J, Liu Q, et al. 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. Neurosci Lett.
Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ. Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res.
Zhang L, Zhao P, Yue C, et al. Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer’s disease. Biomaterials.
Dohi K, Kraemer BC, Erickson MA, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One.
Ji X, Liu W, Xie K, et al. Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress. Brain Res.
Eckermann JM, Chen W, Jadhav V, et al. Hydrogen is neuroprotective against surgically induced brain injury. Med Gas Res.
Javorac D, Stajer V, Ostojic SM. Case Report: Buccal administration of hydrogen-producing blend after a mild traumatic brain injury in a professional athlete. F1000Res.
Liu L, Xie K, Chen H, et al. Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res.
Zhang J, Liu C, Tai M, Qu K. Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia (Shock 37(6), 645-652, 2012). Shock.
2012;38:444; author reply 444-445.
Huang L, Applegate RL, 2nd, Applegate PM, Boling W, Zhang JH. Inhalation of high concentration hydrogen gas improves short-term outcomes in a rat model of asphyxia induced-cardiac arrest. Med Gas Res.
Huang L, Applegate Ii RL, Applegate PM, et al. Inhalation of high-concentration hydrogen gas attenuates cognitive deficits in a rat model of asphyxia induced-cardiac arrest. Med Gas Res.