|Year : 2021 | Volume
| Issue : 3 | Page : 114-120
Role of hydrogen in traumatic brain injury: a narrative review
Hong-Wei Hu1, Zhi-Guo Chen2, Jian-Gang Liu1, Gang Chen1
1 Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
2 Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
|Date of Submission||27-Jun-2020|
|Date of Decision||09-Jul-2020|
|Date of Acceptance||03-Aug-2020|
|Date of Web Publication||27-Apr-2021|
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province
Source of Support: None, Conflict of Interest: None
Traumatic brain injury (TBI) is a serious global public health problem. Survivors of TBI often suffer from long-term disability, which puts a heavy burden on society and families. Unfortunately, up to now, there is no efficacious treatment for TBI patients in clinical practice. As a reducing gas, hydrogen has been shown to be neuroprotective in multiple cerebral disease models; however, its efficacy in TBI remains controversial. In this review, we will focus on the results of hydrogen in experimental TBI, elaborate the potential mechanisms, and put forward for future researches based on our current understanding and views.
Keywords: anti-autophagy; anti-inflammation; anti-oxidation; experimental research; hydrogen; neuroprotection; therapeutic applications; traumatic brain injury; underlying mechanism
|How to cite this article:|
Hu HW, Chen ZG, Liu JG, Chen G. Role of hydrogen in traumatic brain injury: a narrative review. Med Gas Res 2021;11:114-20
Funding: The work was supported by the Scientific Research of Jiangsu Commission of Health of China (No. H2018065) and Scientific Research of Guizhou Commission of Health of China (No. gzwjkj2019-1-150).
| Introduction|| |
Traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology caused by an external force. Around the world, more than 50 million people suffer from TBI every year, and it is predicted that almost half of the world’s population will experience TBI once or more in their lifetime. TBI is one of the leading causes of morbidity, disability and mortality of all age groups in all countries, which has increased burden on families and society and becomes a global public health and medical problem.,
The clinical symptoms of TBI vary in severity, mainly depending on the extent of brain damage. Survivors of TBI often suffer from long-term physical, cognitive and psychological dysfunction. According to the pathophysiological mechanism of brain injury, TBI can be divided into two categories: primary and secondary brain injury. Primary injury is directly caused by mechanical forces which occurs at the exact moment of insult and results in the disruption of the integrity of brain cells. Then a series of events happened. It includes the release of excitatory amino acids and the opening of Ca2+ channel, the generation of free radicals and lipid peroxidation, the release of inflammatory cell mediators, apoptosis and so on. These mechanisms not only have simultaneous effects, but also constitute a chain reaction. Altogether, these events lead to brain edema, ischemia, cytotoxic cell swelling and intracranial pressure rise, and finally lead to secondary injury after TBI, which is considered to be the main cause of death after brain injury. To sum up, for the primary brain injury, all we can do is to prevent and reduce the injury. However, investigations on the secondary injury after TBI are of great significance, which are helpful for us to determine the therapeutic target of TBI and to improve the prognosis.
Hydrogen is a kind of colorless, tasteless and reductive small molecular gas. It was thought that hydrogen was a physiologically inert gas in mammalian cells until 1975, when it was first reported in Science that hydrogen plays a therapeutic role in mouse skin cancer model by scavenging hydroxyl radicals. In 2007, it was reported that hydrogen could reduce the cerebral ischemia-reperfusion injury by selectively reducing cytotoxic reactive oxygen species. Since then, hydrogen has opened a new chapter in the field of medical research and application. And a large number of studies have shown that hydrogen plays a therapeutic role through the mechanism of antioxidant stress in a variety of diseases, such as central nervous system diseases, respiratory system diseases, cardiovascular system diseases, digestive system diseases, urinary system diseases and other diseases. Central nervous system diseases are the focus of hydrogen medicine research. Compared with other organs of the body, brain tissue is more vulnerable to oxidative stress because of its high oxygen consumption, low antioxidant enzymes and high content of unsaturated fatty acids. Unfortunately, there is no ideal antioxidant for the treatment of nervous system diseases. However, hydrogen, as a reducing gas, has the advantages of easy access, convenient administration (such as inhalation and intraperitoneal injection of hydrogen, oral administration of hydrogen-rich water, and injection of hydrogen-rich sodium chloride solution), easy diffusion, quick onset and no obvious toxicity, which will provide a new idea for the prevention and treatment of nervous system diseases. From January 2007 to May 2020, a search was performed at Web of Science database. In this review, we will discuss the role of hydrogen in TBI, elaborate the potential mechanisms and put forward our current understanding and views for future researches.
| Application of Hydrogen on Central Nervous System Diseases|| |
Since 2007, due to the moderate reduction activity of hydrogen that can quickly diffuse through the blood-brain barrier, more and more researches have focused on the application of hydrogen in central nervous system diseases.
Stroke is a severe acute cerebrovascular disease, which is caused by occlusion or rupture of cerebral blood vessels, including ischemic stroke and hemorrhagic stroke. Oxidative stress, inflammatory response,, mitochondrial damage and apoptosis, are key elements of stroke pathophysiology. In 2007, Ohsawa and colleagues first reported that inhalation of hydrogen markedly suppressed brain injury in a focal cerebral ischemia/reperfusion injury rat model. The potential mechanism might be associated with that hydrogen could selectively reduce the hydroxyl radical, which was the most cytotoxic of reactive oxygen species. Since then, a large number of researches have reported that hydrogen plays a role of protection in stroke. In a common carotid artery occlusion rat model, inhalation of hydrogen alleviated cognitive impairment by decreasing the levels of oxidative stress products malondialdehyde (MDA) and 8-iso-prostaglandin-2α, and increasing the activities of anti-oxidative enzymes superoxidase dismutase and catalase. In another study, after cerebral ischemia/reperfusion injury (middle cerebral artery occlusion rat model), the levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukine-6 and interleukine-1β, were reduced by hydrogen treatment. However, transforming growth factor-1β (a kind of anti-inflammatory cytokine) increased. It indicated that hydrogen could ameliorate cerebral ischemia/reperfusion injury via anti-inflammation. Lately, it was reported that hydrogen exerted neuroprotective effects on oxygen-glucose deprivation/re-oxygenation damaged neurons in rat hippocampal. And the underlying mechanism was protecting mitochondrial function via regulating mitophagy mediated by phosphatase and tensin homolog-induced kinase 1/Parkin signaling pathway. Besides application on ischemic stroke, hydrogen can also applicate on hemorrhagic stroke. It is well known that hemorrhagic stroke including subarachnoid hemorrhage and intracerebral hemorrhage. After hemorrhage, microglia and inflammatory cells are activated and free radicals are produced., Then a series of pathophysiological changes, such as hematoma formation, hemoglobin decomposition, can deteriorate oxidative stress. In 2019, it was reported that inhalation of 66% hydrogen increased 72-hour survival rate and improved 24-hour neurological deficits after subarachnoid hemorrhage in rats; however, it had no detrimental effects on subarachnoid hemorrhage grade 24 hours after subarachnoid hemorrhage compared to air group. In a rat model of intracerebral hemorrhage, inhalation of 1.3% hydrogen for 1 hour significantly reduced the levels of MDA, tumor necrosis factor-α, interleukine-1β and Caspase-3 protein and increased brain-derived neurotrophic factor expression, suggesting that hydrogen exerted a neuroprotective effect against brain injury after intracerebral hemorrhage through antioxidative activity, anti-inflammatory, anti-apoptotic, and neuroprotective.
The neurodegenerative disease is characterized as the loss of brain and spinal cord cells, which are usually not renewable. With the passage of time, neurological function deteriorated, and eventually irreversible neurological dysfunction appeared. Alzheimer’s and Parkinson’s diseases are two of the most common neurodegenerative diseases. And inflammation and oxidative stress are recognized as the main causes of Alzheimer’s and Parkinson’s diseases. In a dementia mice model (transgenic mice (DAL101) lacking aldehyde dehydrogenase 2), drinking hydrogen-water could reduce oxidative stress, suppress the decline in learning and memory impairment, decrease neurodegeneration and extend the mean of lifespan of mice. Recently, Zhang et al. developed a small-sized palladium hydride nanoparticle that could release hydrogen sustainably in Alzheimer’s disease brain, and they demonstrated that it could overcome the cognitive impairment in Alzheimer’s disease mice via recovering mitochondrial dysfunction, inhibiting β-amyloid generation and aggregation, reducing oxidative stress and activating the anti-oxidative pathway. Additionally, drinking hydrogen water could alleviate cognitive impairment and inhibit hippocampal neurodegeneration in a mouse model of Parkinson’s disease. In a 6-hydroxydopamine-induced Parkinson’s disease rat model, it has demonstrated that hydrogen could prevent both development and progression of the nigrostriatal degeneration.
| Therapeutic Effects of Hydrogen on Traumatic Brain Injury|| |
The application of hydrogen in the treatment of TBI began in 2010. The first study reported that hydrogen could exert neuroprotection in a rat model of controlled cortical impact (CCI) brain injury. It demonstrated that inhalation of 2% hydrogen from 5 minutes to 5 hours significantly attenuated blood-brain barrier damage, brain edema and lesion volume and improved neurological outcome after TBI. In the following years, many studies on the therapeutic effect of hydrogen on TBI have been reported [Table 1]. One study examined the role of hydrogen in brain injury induced by surgery. The results showed that inhalation of 2.9% hydrogen could also reduce brain edema and improve neurological function. However, through myeloperoxidase and lipid peroxidation assay, it was found that hydrogen failed to reduce oxidative stress and inflammation. Unfortunately, the authors did not give the possible reasons. Recently, another study investigated the effects of different concentrations of hydrogen inhalation on the neurological function of a lateral fluid percussion injury model of diabetic rat after TBI. It found that inhalation of 42% hydrogen was shown to alleviate nerve damage and improve neurological function after TBI in diabetic rats; however, inhalation of 3% hydrogen did not. The potential mechanism might include reducing oxidative stress and neuron apoptosis. In addition, it reported that 2% of hydrogen treatment could also improve the neurological outcome after TBI induced by CCI via increasing the expression of miR-21.
|Table 1: Experimental studies regarding hydrogen in traumatic brain injury|
Click here to view
In recent years, there were many kinds of researches on the role of other forms of hydrogen on TBI, such as hydrogen-rich saline, hydrogen-rich water and hydrogen in drinking water. Hou et al. reported that after mild TBI induced by fluid percussion injury, treatment with hydrogen-rich saline attenuated oxidative stress injury and cognitive impairment. In the same year, another study revealed that hydrogen-rich saline intraperitoneally injection also exerted the similar neuroprotective effects after TBI induced by CCI, and these protective effects were dose-dependent. In 2014, Dohi and colleagues found that the molecular hydrogen in drinking water relieved brain edema, blood-brain barrier disruption, and neuroinflammation after CCI induced TBI model of mice. Then, Tian et al. studied the role of hydrogen-rich water in a CCI induced TBI rat model. They found that intraperitoneal injection of hydrogen-rich water could reduce the mortality rate, attenuate blood-brain barrier disruption and brain edema and improve the cognitive function of CCI-induced TBI rats. In a Feeny weight-drop model of the rat after TBI, compared with TBI group, intraperitoneal injection of hydrogen-rich water significantly increased the 7-day survival rate, ameliorated neurological severity score (modified neurological severity score) and lowered intracellular oxidative stress level.
Currently, the application of hydrogen-rich medium in an in vitro model of TBI has been investigated. In 2020, using an in vitro model of TBI (PC12 cells), a report indicated that the hydrogen-rich medium played a neuroprotective role against neuronal apoptosis and impaired nerve regeneration. Another similar study revealed that hydrogen-rich medium improved the cell viability in a microvascular endothelial cell model of TBI (bEnd.3, an immortalized mouse brain endothelial cell line) though inhibition of autophagy.
| Mechanisms of the Hydrogen Therapy in Traumatic Brain Injury|| |
It is well known that TBI is a major cause of death and disability among young people globally. And the survivors after TBI often have neurological deficits, seizures, behavioral changes, cognitive impairment and so on, which seriously affect the quality of life and bring heavy burden to both family and society. So far, to all organs in the body, TBI is one of the most complex diseases. Because of the high heterogeneity of brain injury and neuroendocrine dysfunction, the underlying pathophysiological mechanism occurring in TBI is more complex. At present, it is believed that the brain tissue will have violent collision, acceleration, deceleration, or rotation movement when the head is subjected to external force. Then, the mechanical destruction of the brain tissue causes axon shearing and blood vessels tearing, which can lead to contusion and hemorrhage. All these events result in a secondary cascade of molecular and biochemical changes in minutes of the initial impact, which is called secondary brain injury. The secondary injury mechanisms mainly include mitochondrial dysfunction, excitotoxicity, calcium overload, neuroinflammatory response and oxidative stress. These induce membrane cellular and vascular system destruction, which will lead to blood-brain barrier damage, cerebral blood flow alteration, ischemia and hypoxia, energy deficit, and eventually bring about apoptosis or necrosis. Some experiments have shown that TBI rats can have brain edema, neurological dysfunction and prolonged remodeling time. Oxidative stress, neuroinflammation and apoptosis are important factors leading to these pathological changes.,,
At present, many studies have shown that hydrogen plays neuroprotective roles in TBI through a variety of mechanisms. The potential mechanisms include anti-oxidation, anti-inflammation, inhibition of apoptosis and so on [Figure 1].
|Figure 1: The potential mechanism of hydrogen against TBI.|
Note: Hydrogen plays an important role in TBI via anti-oxidation, anti-inflammation, anti-apoptosis, anti-autophagy and other mechanisms. AQP-4: Aquaporin-4; BBB: blood-brain barrier; BDNF: brain-derived neurotrophic factor; CAT: catalase; CHO: choline; GSK3β: glycogen synthase kinase-3β; H2: hydrogen; HIF: hypoxia-inducible factor; Iba-1: ionized calcium-binding adapter molecule-1; IL: interleukine; MDA: malondialdehyde; MMP: matrix metalloproteinase; Nrf2: nuclear factor erythroid 2-related factor-2; PGF2α: prostaglandin-2α; PI3K: phosphoinositide 3-kinase; Sir2: silent information regulator 2; SOD: superoxidase dismutase; TBI: traumatic brain injury; TNF-α: tumor necrosis factor-α.
Click here to view
Increasing evidences have shown that oxidative stress is considered to be the key factor for secondary injury in the pathophysiology of TBI. Further studies found that excessive production of reactive oxygen species and reduction of antioxidant defense systems play an important role in the pathogenesis of TBI. Also, oxidative stress is involved in the development of cerebral edema, inflammation, and secondary neuronal damage.,, No matter hydrogen, hydrogen-rich water, hydrogen-rich saline or hydrogen in drinking water, they have been reported to have antioxidant stress effect in many studies.,, Hydrogen plays a similar role in TBI model. MDA is the end product of lipid peroxidation induced by free radicals and its level is related to the degree of damage induced by free radicals. Additionally, 8-iso-prostaglandin-2α is a specific product after lipid peroxidation of arachidonic acid on free radical catalyzed biofilm, which can sensitively reflect the level of oxidative stress in vivo and is related to the severity of disease. The determination of MDA and 8-iso-prostaglandin-2α is considered to be an ideal index to evaluate oxidative stress., Meanwhile, the harmful effects of free oxygen radicals can be alleviated by the action of antioxidant enzymes superoxidase dismutase and catalase.64 Related reports showed that inhalation of hydrogen or intraperitoneal injection of hydrogen-rich saline after TBI exerted anti-oxidative stress effects by decreasing the level of MDA and 8-iso-prostaglandin-2α and increasing the activities of superoxidase dismutase and catalase., Silent information regulator 2 (Sir2) is a nicotinamide adenine dinucleotide+-dependent deacetylase, which is involved in the regulation of cell cycle, energy metabolism, fatty acid oxidation and other processes. And Sir2 may play an antioxidant stress role by promoting the antioxidant system. Besides, Sir2 is involved in the regulation of oxidative stress after TBI. In 2012, Hou et al. confirmed that hydrogen-rich saline could play an anti-oxidative stress role by promoting Sir2 expression after TBI. Nuclear factor erythroid 2-related factor-2 is an important regulator factor of cellular antioxidants, which plays an important role in protecting neurons from oxidative stress after TBI. A study demonstrated that intraperitoneal injection of hydrogen-rich water could attenuate oxidative stress in rats with TBI induced by Feeney weight-drop method via nuclear factor erythroid 2-related factor-2 pathway.
Inflammation is a common pathological process in most diseases. The activation of immune cells and the release of inflammatory cytokines are related to inflammation. Neuroinflammation is an immune response activated by microglia and astrocytes and it usually occurs under the stimulation of trauma, infection, toxin or the action of autoimmunity. Although transient neuroinflammatory signal transduction plays a protective role during development and tissue repair after injury, chronic neuroinflammation is related to the progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Using hydrogen-rich water as the hydrogen source, a study found a significant difference between TBI and hydrogen-rich water-treated TBI rats in measures of inflammatory cytokines levels and inflammatory metabolites. Intraperitoneal injection of hydrogen-rich water significantly attenuated the levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukine-1β and high mobility group box-1), inflammatory cells (ionized calcium-binding adapter molecule-1) and inflammatory metabolites (choline), while observably increased the level of anti-inflammatory cytokine (interleukine-10). It suggested that hydrogen could play a neuroprotective role through anti-inflammatory response after TBI.
According current studies, neuronal apoptosis is the main pathological change type of secondary brain injury after TBI and plays an important role in delayed neuron loss after acute and chronic central nervous system injury. It has been reported that there are two pathways of neuronal apoptosis, one is caspase-dependent apoptosis by activating caspase family, the other is independent caspase pathway initiated by apoptosis-inducing factors in mitochondria. Both pathways are regulated by the Bcl-2 family of proteins. It is generally believed that Bcl-2 plays an anti-apoptotic role, while Bax and caspase-3 play a part in pro-apoptotic, which are commonly used to detect apoptosis markers., Recently, a study showed that inhalation of 42% hydrogen could significantly decrease the expression of Bax and caspase-3 and increase the expression of Bcl-2 after TBI in diabetic rats. Besides, neurological function scores were also improved after hydrogen treatment. Therefore, it revealed that hydrogen could inhibit apoptosis exerting neuroprotective effects. Similarly, the anti-apoptotic effect of hydrogen was also verified in vitro. In an in vitro model of TBI (PC12 cells), after hydrogen-rich medium treatment, the researchers measured the expression of Bax and Bcl-2 proteins and detected the degree of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The results showed that compared with TBI group, hydrogen intervention significantly decreased the expression of Bax and increased the level of Bcl-2, and reduced apoptosis.
Autophagy is a process in which eukaryotic cells mediate the degradation of damaged organelles, protein aggregates and invading pathogens through lysosome dependent pathways. Some studies have shown that autophagy is involved in oxidative stress, inflammatory response, apoptosis and other pathophysiological processes. Furthermore, autophagy pathway is also involved in brain injury after TBI. An in vitro experiment found that hydrogen treatment would not change the autophagy level of normal microvascular endothelial cell (bEnd.3). While further study confirmed that the autophagy level in bEnd.3 cells was activated after TBI, which can be inhibited by hydrogen treatment through the up-regulation of phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β signal pathway.
Other potential mechanisms
In addition to the above mechanisms, hydrogen also has been reported to play a role in TBI through the following potential mechanisms. The levels of aquaporin-4, hypoxia-inducible factor-1α, matrix metalloproteinase-2 & -9 were altered by molecular hydrogen in drinking water treatment after TBI in a CCI model, which could affect brain edema, blood-brain barrier disruption and alterations in brain interstitial fluid circulation. And the pathological phosphorylated tau changes induced by CCI were blocked by molecular hydrogen in drinking water intervention. Moreover, molecular hydrogen in drinking water increased adenosine triphosphate and nucleotide-binding after TBI and altered pathological gene expressions that regulate oxidation, carbohydrate metabolism and suppressed cytokine activation. In another study, researchers demonstrated that hydrogen-rich saline treatment improved rat cognitive performance after mild TBI via increasing the expression of molecules associated with brain-derived neurotrophic factor-mediated synaptic plasticity. MicroRNA is a kind of non-coding single-stranded RNA molecules with a length of about 22 nucleotides, which involved in the regulation of post-transcriptional gene expression and related to the pathophysiology of many diseases, including TBI. More and more researches on micro-RNA in TBI have been carried out. Recently, relevant researches showed that miR-21 expression increased after TBI, and it could improve neurological outcome., Further studies confirmed that hydrogen could play a neuroprotective role in TBI in vivo or in vitro model via increasing the expression of miR-21.,
| Conclusion and Prospects|| |
To sum up, the neuroprotective effect of hydrogen after TBI has been confirmed by many experiments. Its potential mechanism may be related to anti-oxidation, anti-inflammatory, anti-apoptosis, anti-autophagy and regulation of cell signaling pathway. Because hydrogen is non-toxic and easy to diffuse and reductive, it is a promising gas in the treatment of TBI. At present, the researches on the role of hydrogen in TBI are mainly focused on antioxidant stress. However, the pathophysiological mechanism of TBI is complex. Whether hydrogen can play a protective role in TBI secondary brain injury through other mechanisms remains to be studied further, which provides a theoretical basis for the application of hydrogen in TBI. Moreover, the relationship between the neuroprotective mechanisms of hydrogen is also not clear. In addition, it is still lack of large-scale researches on the way of hydrogen administration, the optimal concentration, safety and clinical application. All of these are potential research directions in the future.
The authors would like to express our sincere thanks to all those who have lent our hands in the course of my writing this paper. We thank Professor Yu-Lun Huang (The First Affiliated Hospital of Soochow University) for the modification of the manuscript’s figure. We also acknowledge Qing-Zhi E (Soochow University) for the grammar review and editing.
Manuscript writing: HWH; manuscript revision: ZGC; manuscript drafting: JGL and GC. All authors read and approved the final version of the manuscript for publication.
Conflicts of interest
The authors declare that they have no competing interests.
The work was supported by the Scientific Research of Jiangsu Commission of Health of China (No. H2018065) and Scientific Research of Guizhou Commission of Health of China (No. gzwjkj2019-1-150).
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Checked twice by iThenticate.
Externally peer reviewed.
Open access statement
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 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|| |
Menon DK, Schwab K, Wright DW, Maas AI. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil
Maas AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol
Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg
Rowland MJ, Veenith T, Hutchinson PJ, Perkins GD. Osmotherapy in traumatic brain injury. Lancet Neurol
Ng SY, Lee AYW. Traumatic brain injuries: pathophysiology and potential therapeutic targets. Front Cell Neurosci
Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol
Sulhan S, Lyon KA, Shapiro LA, Huang JH. Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets. J Neurosci Res
Morganti-Kossmann MC, Semple BD, Hellewell SC, Bye N, Ziebell JM. The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments. Acta Neuropathol
Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med
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
Meng J, Liu L, Wang D, Yan Z, Chen G. Hydrogen gas represses the progression of lung cancer via down-regulating CD47. Biosci Rep
Li L, Li X, Zhang Z, Liu L, Zhou Y, Liu F. Protective mechanism and clinical application of hydrogen in myocardial ischemia-reperfusion injury. Pak J Biol Sci
Li S, Fujino M, Ichimaru N, et al. Molecular hydrogen protects against ischemia-reperfusion injury in a mouse fatty liver model via regulating HO-1 and Sirt1 expression. Sci Rep
Kobayashi Y, Imamura R, Koyama Y, et al. Renoprotective and neuroprotective effects of enteric hydrogen generation from Si-based agent. Sci Rep
Ge L, Yang M, Yang NN, Yin XX, Song WG. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. Oncotarget
Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res
Simpkins AN, Janowski M, Oz HS, et al. Biomarker application for precision medicine in stroke. Transl Stroke Res
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
Ren H, Han R, Chen X, et al. Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update. J Cereb Blood Flow Metab
Saand AR, Yu F, Chen J, Chou SH. Systemic inflammation in hemorrhagic strokes - a novel neurological sign and therapeutic target? J Cereb Blood Flow Metab
Tseng N, Lambie SC, Huynh CQ, et al. Mitochondrial transfer from mesenchymal stem cells improves neuronal metabolism after oxidant injury in vitro: the role of Miro1. J Cereb Blood Flow Metab
Datta A, Sarmah D, Mounica L, et al. Cell death pathways in ischemic stroke and targeted pharmacotherapy. Transl Stroke Res
Zhang P, Wang T, Zhang D, et al. Exploration of MST1-mediated secondary brain injury induced by intracerebral hemorrhage in rats via Hippo signaling pathway. Transl Stroke Res
Ge P, Zhao J, Li S, Ding Y, Yang F, Luo Y. Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress. Neurol Res
Cui J, Chen X, Zhai X, et al. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia-reperfusion injury in rats - A possible new hydrogen resource for clinical use. Neuroscience
Wu X, Li X, Liu Y, et al. Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway. Brain Res
Feng Z, Ye L, Klebe D, et al. Anti-inflammation conferred by stimulation of CD200R1 via Dok1 pathway in rat microglia after germinal matrix hemorrhage. J Cereb Blood Flow Metab
Deng W, Mandeville E, Terasaki Y, et al. Transcriptomic characterization of microglia activation in a rat model of ischemic stroke. J Cereb Blood Flow Metab
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
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
Hayden EY, Huang JM, Charreton M, et al. Modeling mixed vascular and Alzheimer’s dementia using focal subcortical ischemic stroke in human ApoE4-TR:5XFAD transgenic mice. Transl Stroke Res
Nishimaki K, Asada T, Ohsawa I, et al. Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment. Curr Alzheimer Res
Zhang L, Zhao P, Yue C, et al. Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer’s disease. Biomaterials
Gu Y, Huang CS, Inoue T, et al. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr
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
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
Li TT, Yang WC, Wang YZ, et al. Effects of a high concentration of hydrogen on neurological function after traumatic brain injury in diabetic rats. Brain Res
Wang L, Zhao C, Wu S, et al. Hydrogen gas treatment improves the neurological outcome after traumatic brain injury via increasing miR-21 expression. Shock
Hou Z, Luo W, Sun X, et al. Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull
Ji X, Tian Y, Xie K, Liu W, Qu Y, Fei Z. Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress. J Surg Res
Dohi K, Kraemer BC, Erickson MA, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One
Tian R, Hou Z, Hao S, et al. Hydrogen-rich water attenuates brain damage and inflammation after traumatic brain injury in rats. Brain Res
Yuan J, Wang D, Liu Y, et al. Hydrogen-rich water attenuates oxidative stress in rats with traumatic brain injury via Nrf2 pathway. J Surg Res
Wang L, Yin Z, Wang F, et al. Hydrogen exerts neuroprotection by activation of the miR-21/PI3K/AKT/GSK-3β pathway in an in vitro model of traumatic brain injury. J Cell Mol Med
Wang Y, Wang L, Hu T, et al. Hydrogen improves cell viability partly through inhibition of autophagy and activation of PI3K/Akt/GSK3β signal pathway in a microvascular endothelial cell model of traumatic brain injury. Neurol Res
O’Leary R A, Nichol AD. Pathophysiology of severe traumatic brain injury. J Neurosurg Sci
Dixon KJ. Pathophysiology of Traumatic Brain Injury. Phys Med Rehabil Clin N Am
McGinn MJ, Povlishock JT. Pathophysiology of traumatic brain injury. Neurosurg Clin N Am
Capizzi A, Woo J, Verduzco-Gutierrez M. Traumatic brain injury: an overview of epidemiology, pathophysiology, and medical management. Med Clin North Am
Kaur P, Sharma S. Recent advances in pathophysiology of traumatic brain injury. Curr Neuropharmacol
Zhang L, Fei M, Wang H, Zhu Y. Sodium aescinate provides neuroprotection in experimental traumatic brain injury via the Nrf2-ARE pathway. Brain Res Bull
Che X, Fang Y, Si X, et al. The role of gaseous molecules in traumatic brain injury: an updated review. Front Neurosci
Dumitrescu L, Popescu-Olaru I, Cozma L, et al. Oxidative stress and the microbiota-gut-brain axis. Oxid Med Cell Longev
Huang Y, Long X, Tang J, et al. The attenuation of traumatic brain injury via inhibition of oxidative stress and apoptosis by Tanshinone IIA. Oxid Med Cell Longev
Abdul-Muneer PM, Chandra N, Haorah J. Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol
Qiu X, Dong K, Guan J, He J. Hydrogen attenuates radiation-induced intestinal damage by reducing oxidative stress and inflammatory response. Int Immunopharmacol
Fang W, Tang L, Wang G, et al. Molecular hydrogen protects human melanocytes from oxidative stress by activating Nrf2 signaling. J Invest Dermatol
Tsikas D. Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges. Anal Biochem
Sakamoto M, Takaki E, Yamashita K, et al. Nonenzymatic derived lipid peroxide, 8-iso-PGF2 alpha, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model. Neurol Res
Kelly PJ, Morrow JD, Ning M, et al. Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke
Hao M, Liu R. Molecular mechanism of CAT and SOD activity change under MPA-CdTe quantum dots induced oxidative stress in the mouse primary hepatocytes. Spectrochim Acta A Mol Biomol Spectrosc
Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol
Kume S, Haneda M, Kanasaki K, et al. Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation. Free Radic Biol Med
Wu A, Ying Z, Gomez-Pinilla F. Oxidative stress modulates Sir2alpha in rat hippocampus and cerebral cortex. Eur J Neurosci
Bhowmick S, D’Mello V, Caruso D, Abdul-Muneer PM. Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death. J Mol Med (Berl)
Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RS. Bench-to-bedside review: Apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care
Liu HC, Zhang Y, Zhang S, et al. Correlation research on the protein expression (p75NTR, bax, bcl-2, and caspase-3) and cortical neuron apoptosis following mechanical injury in rat. Eur Rev Med Pharmacol Sci
Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell
Yang Y, White E. Autophagy suppresses TRP53/p53 and oxidative stress to enable mammalian survival. Autophagy
Mo Y, Sun YY, Liu KY. Autophagy and inflammation in ischemic stroke. Neural Regen Res
Machado-Neto JA, Coelho-Silva JL, Santos FPS, et al. Autophagy inhibition potentiates ruxolitinib-induced apoptosis in JAK2(V617F) cells. Invest New Drugs
Zeng Z, Zhang Y, Jiang W, He L, Qu H. Modulation of autophagy in traumatic brain injury. J Cell Physiol
Atif H, Hicks SD. A review of microRNA biomarkers in traumatic brain injury. J Exp Neurosci
. 2019. doi:10.1177/1179069519832286.
Li D, Huang S, Zhu J, et al. Exosomes from MiR-21-5p-increased neurons play a role in neuroprotection by suppressing Rab11a-mediated neuronal autophagy in vitro after traumatic brain injury. Med Sci Monit
Ge X, Li W, Huang S, et al. Increased miR-21-3p in injured brain microvascular endothelial cells after traumatic brain injury aggravates blood-brain barrier damage by promoting cellular apoptosis and inflammation through targeting MAT2B. J Neurotrauma