• Users Online: 273
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2019  |  Volume : 9  |  Issue : 4  |  Page : 221-228

The role of medical gas in stroke: an updated review

1 Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
2 Burrell College of Osteopathic Medicine, Las Cruces, NM; Center for Neuroscience Research, School of Medicine, Loma Linda University, Loma Linda, CA, USA

Date of Submission09-Nov-2019
Date of Decision12-Nov-2019
Date of Acceptance02-Dec-2019
Date of Web Publication30-Dec-2019

Correspondence Address:
Sheng Chen
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2045-9912.273960

Rights and Permissions

Medical gas is a large class of bioactive gases used in clinical medicine and basic scientific research. At present, the role of medical gas in neuroprotection has received growing attention. Stroke is a leading cause of death and disability in adults worldwide, but current treatment is still very limited. The common pathological changes of these two types of stroke may include excitotoxicity, free radical release, inflammation, cell death, mitochondrial disorder, and blood-brain barrier disruption. In this review, we will discuss the pathological mechanisms of stroke and the role of two medical gases (hydrogen and hydrogen sulfide) in stroke, which may potentially provide a new insight into the treatment of stroke.

Keywords: stroke; medical gas; hydrogen; hydrogen sulfide; cell death

How to cite this article:
Zhang ZY, Fang YJ, Luo YJ, Lenahan C, Zhang JM, Chen S. The role of medical gas in stroke: an updated review. Med Gas Res 2019;9:221-8

How to cite this URL:
Zhang ZY, Fang YJ, Luo YJ, Lenahan C, Zhang JM, Chen S. The role of medical gas in stroke: an updated review. Med Gas Res [serial online] 2019 [cited 2022 Dec 6];9:221-8. Available from: https://www.medgasres.com/text.asp?2019/9/4/221/273960

Ze-Yu Zhang, Yuan-Jian Fang
#These authors contributed equally to this work.
Funding: This study was supported by National Natural Science Foundation of China, No. 81971107, and the Fundamental Research Funds for the Central Universities, China, No. 2019QNA7038.

  Introduction Top

Medical gas is a large class of gases used in both clinical medicine and basic science research, including oxygen, hydrogen, carbon monoxide, carbon dioxide, nitrogen, xenon, hydrogen sulfide, nitrous oxide, carbon disulfide, argon, helium, and other noble gases.[1] Gas-based treatments are widely available clinically. For example, oxygen therapy for patients with dyspnea, nitrous oxide for analgesia and anesthesia, liquid nitrogen cryotherapy for secondary cellulitis, argon-helium knife therapy for liver cancer.[2],[3],[4] For decades, studies have found that certain medical gases possess neuroprotective properties leading to extensive interest.[5] Current research on neuroprotective gases focuses primarily on oxygen, xenon, hydrogen, hydrogen sulfide, nitric oxide, and argon, and their involvement with central nervous system diseases, such as stroke, traumatic brain injury, subarachnoid hemorrhage, and neurodegenerative disease, showing great translational potential.[6],[7],[8],[9],[10],[11]

Stroke is the second leading cause of death, and one of the main causes of adult disability in the world, causing a heavy burden for medical and health care costs.[12],[13] The two main subtypes of stroke include ischemic and hemorrhagic stroke. According to epidemiological statistics, 85% of strokes are categorized as ischemic, with the remaining 15% considered hemorrhagic. Tissue plasminogen activator (tPA) thrombolysis is the gold standard treatment and the only U.S. Food and Drug Administration-approved therapy for ischemic stroke.[14],[15] However, the time-constrained therapeutic window greatly limits the use of tPA in acute ischemic stroke.[16] Although studies have shown that it is safe to administer intravenous thrombolytic drugs within 4.5 hours of stroke onset, thrombolysis treatment outside the therapeutic window is likely to cause complications, such as hemorrhagic transformation, reperfusion injury, and brain edema, with the former being the most feared complication.[17] Regarding hemorrhagic stroke, the current treatment is surgical removal of the hematoma, and reduction of intracranial pressure. However, this method can only prevent the deterioration of the disease, and has little effect in neurological recovery. It is apparent that current treatment of stroke is very limited. However, an increasing amount of recent studies have found the potential of blood-brain barrier (BBB) protection, stem cells, and medical gas in stroke therapy, offering new hope in the treatment of stroke.

It should be emphasized that research on the role of medical gases in stroke is receiving more and more attention, although their mechanisms of action differ. The thorough study of the relationship between medical gas and stroke will broaden horizons to guide the development of stroke treatment. In the present review, we will discuss the pathological mechanisms of stroke and advances in the research on the role of two medical gases (hydrogen and hydrogen sulfide) in stroke. We searched the researches in PubMed by the keywords “stroke” and “pathology” or “stroke” and “hydrogen” or “stroke” and “hydrogen sulfide.”

  Pathological Mechanisms of Stroke-Induced Brain Injury Top

The main subtypes of stroke include ischemic and hemorrhagic stroke. The former is caused by arterial embolism, in situ thrombosis, hemodynamic insufficiency, and branch occlusive disease. The latter is primarily caused by cerebral vascular rupture, including intracerebral hemorrhage and subarachnoid hemorrhage.[18],[19] The common pathological changes of these two types of stroke may include excitotoxicity, free radical release, inflammation, cell death, mitochondrial disorder, and BBB disruption. Herein, we will discuss these related mechanisms of brain damage after stroke.


Excitotoxicity caused by glutamate is one of the most frequently studied pathological mechanisms of central nervous system diseases.[20],[21],[22] The process by which excess quantities of the excitatory neurotransmitter, glutamate, activates N-methyl-D-aspartate receptors (NMDARs) is a key step in the production of excitotoxicity.[23],[24],[25] After stroke, ischemia and hypoxia cause ion disorder in the neural cells, subsequently leading to cell depolarization and release of excitatory glutamate into the synaptic space. Thus, glutamate-induced NMDARs accumulation induces calcium inflow to the neurons.[26] Intracellular calcium overload leads to cell death by calpain activation, reactive oxygen species (ROS) generation, and mitochondrial damage.[27] In addition, there is evidence that excitotoxicity caused by glutamate can also be involved in brain damage following hemorrhagic stroke.[28] Many drugs targeting excitotoxicity presented an effective function in animal models of cerebral ischemia. For example, NDRG2 facilitates interstitial glutamate uptake to protect the brain from excitotoxicity after middle cerebral artery occlusion.[29] Glutamate oxaloacetate transaminase displays neuroprotection in ischemic stroke by reducing glutamate levels at the stroke site.[30],[31]

Free radical release

Numerous experimental evidence indicates that in all forms of stroke damage, the formation of free radicals was increased, leading to nutritive oxidative stress.[32],[33],[34] There are several mechanisms of free radical production during ischemia, including intracellular calcium overload, mitochondrial dysfunction, NMDAR-mediated excitotoxicity, and release of inducible nitric oxide synthase.[35],[36],[37],[38] Excessive free radicals, such as ROS and hydroxyl radical, can damage cellular macromolecules, and lead to autophagy, apoptosis, and necrosis of cells by affecting signaling pathways.[39],[40] In addition, free radicals also cause DNA damage and cellular aging.[41],[42] Based on these mechanisms, many free radical scavenging antioxidant therapies have been extensively studied.[43],[44] For example, the iron chelator, deferoxamine mesylate, exhibits neuroprotection by inhibiting the formation of iron-induced hydroxyl radicals in various ischemic and hemorrhagic stroke animal models.[45] Melatonin, an effective free radical scavenger and antioxidant, shows neuroprotective effects in experimental models of hemorrhagic stroke.[46],[47] However, since many free radicals are essential signaling molecules that contribute to normal neuronal function, related antioxidant therapy is required to only remove harmful free radicals without interfering with endogenous signaling.[48],[49]


Inflammation is a key mechanism, contributing significantly to the pathophysiology and prognosis of stroke.[50] After stroke, a variety of agents, such as necrotic cells, impaired tissues, and free radical formation, are involved in the activation of inflammatory cells and trigger an inflammatory response.[51],[52] In the early stages of inflammation, microglial cells are recruited and activated, converting to phagocytic cells.[53] Activated microglia not only release pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α), but also play a neuroprotective role by the release of insulin-like growth factor I and brain-derived neurotrophic factor.[54],[55],[56] Later, neutrophils and monocytes cross the BBB into the ischemic area, which appears to be associated with cell adhesion molecules and chemokine signaling processes.[57],[58],[59] Moreover, the products of oxidative stress induce the expression of pro-inflammatory genes, such as nuclear factor kappa B (NF-κB), which increase the expression of cytokines and adhesion molecules, promoting the migration of leukocytes through brain endothelial cells.[60] Extensive research has shown that the inflammatory response after stroke not only causes brain tissue damage, but also participates in tissue remodeling after brain injury.[61] The latter seems to be an exciting area for translational research.

Cell death

In stroke, damage causes cell death through a variety of mechanisms, including apoptosis, necrosis, and autophagy.[62] Necrosis and apoptosis are the primary mechanisms.[63],[64] Sodium pump failure, calcium overload, and excessive free radicals are involved in the induction of cell death. Apoptosis is a programmed cell death that terminates the cell’s own life through signaling pathways such as mitochondrial signaling pathways, which can be induced by extracellular signals such as TNF-α, TRAIL (TNF related apoptosis inducing ligand) and Fas (CD95/APO1).[65],[66],[67] In animal models, some substances improve the prognosis of ischemic and hemorrhagic stroke through anti-apoptosis, including melatonin, Protein-L-isoaspartate (D-aspartate) O-methyltransferase, and Dl-3-n-butylphthalide.[68],[69],[70] Autophagy is another programmed cell death pathway, mediated by lysosomes, showing a two-sided effect in stroke. Several reports showed that excessive autophagy activation led to cell death, but many researchers have illustrated that appropriate autophagic activity is neuroprotective.[71],[72],[73] Studies have shown that autophagy may have the potential to protect the BBB integrity, demonstrating neuroprotection.[74] In addition, a large amount of cathepsin B release, caused by dysfunction of membrane trafficking after cerebral ischemia, can also induce cell death.[75]

Mitochondrial dysfunction

Growing evidence suggests that mitochondria regulates autophagy and apoptosis of cells.[76] Excitotoxicity and calcium overload lead to mitochondrial swelling during cerebral ischemia, triggering a cascade of cell death.[77] ROS produced by mitochondria also play a key role in brain damage following ischemic stroke.[78] Moreover, mitochondria regulate cell death at the level of protein modification by equilibrium fusion and fission.[79] For example, hyperglycemia promotes cell death following cerebral ischemia by inducing an increase in fission proteins dynamin-related protein 1, fission 1, and a decrease in fusion proteins optic atrophy 1 and mitofusin 2.[80]

BBB disruption

BBB destruction promotes stroke-induced brain damage, and causes complications, such as hemorrhagic transformation, playing an important role in stroke.[81] The immunoinflammatory reaction after cerebral ischemia can increase the production of matrix metalloproteins and myeloperoxidase, which may be the main contributor in the destruction of the BBB.[82] Furthermore, post-stroke changes in tight junction proteins, such as modification, translocation, and degradation lead to increased BBB permeability, which also worsens the prognosis of stroke.[81] Drugs have been investigated as a potential therapy in stroke recovery by improving BBB integrity.[83],[84] For example, studies have found that baicalin attenuates brain injury after subarachnoid hemorrhagic by modulating BBB dysfunction and protecting BBB integrity.[85]

Other mechanisms

In addition to the above mentioned, the mechanisms of brain damage after stroke also include protein misfolding, reperfusion injury, innate and adaptive immune response, astrocytic changes, and white matter injury.[86],[87] For example, misfolded proteins trigger the protein kinase R-like endoplasmic reticulum kinase pathway regulating eukaryotic initiation factor 2 kinase activation, which prevents new proteins synthesis after stroke.[88] Furthermore, changes in astrocytes after stroke affect the connection and signaling of neural activity, which may increase the damage of stroke and inhibit post-stroke recovery.[86] An exploration on the pathological mechanisms of stroke is conducive to pushing us closer to new potential therapies.

  Advances in Research on the Role of Hydrogen and Hydrogen Sulfide in Stroke Top

Recently, the neuroprotective capacity of certain gases has received increasing attention. Among these gases, oxygen, hydrogen, hydrogen sulfide, NO, and some inert gases are probably the most studied gases. We will focus on the role of hydrogen and hydrogen sulfide in stroke and its related molecular mechanisms, and the research progress in recent years.

The role of hydrogen in stroke

Since it was often expressed as an inert gas in mammalian cells, it was previously thought that molecular hydrogen is nonfunctional in body cells.[89] However, the study by Ohsawa et al.[90] in 2007 indicated that hydrogen acts as an antioxidant to selectively reduce strong oxidants in cells, having a potential therapeutic effect in certain diseases. Since then, numerous studies have explored the role of hydrogen therapy in stroke. The mechanisms underlying the hydrogen-induced neuroprotection in stroke include anti-oxidative, anti-inflammatory and anti-apoptotic effects and changes in gene expression[91] [Table 1].
Table 1: Mechanisms of neuroprotection of H2 in stroke

Click here to view

In animal experiments, hydrogen treatment significantly altered the survival and neurological function of animals after stroke. In a study by Nagatani et al.,[102] the 7-day survival rate of mice after bilateral common carotid artery occlusion was 8.3%, which significantly increased to 50% after inhalation of 1.3% hydrogen. Moreover, multiple studies have shown that the neurological function of mice that inhaled hydrogen is significantly improved after ischemic stroke.[103],[104],[105] In addition, hydrogen therapy also altered the morphology of brain tissue after stroke. Triphenyl tetrazolium chloride staining showed that hydrogen treatment reduced the infarction area after injury in stroke.[106],[107],[108]

As mentioned previously, the production of free radicals is an important pathological mechanism of brain damage after stroke. Currently, the most commonly studied neuroprotective mechanism of hydrogen therapy for stroke is that molecular hydrogen acts as a strong reducing agent to selectively scavenge certain free radicals in cells.[109] Hydroxyl radicals are considered the main trigger for free radical chain reactions.[110] In 2007, Ohsawa et al.[90] demonstrated that hydrogen selectively reduced hydroxyl radicals after the use of antimycin A. Another study showed that hydrogen eye drops directly decreased hydroxyl radicals in ischemia/reperfusion of retinas.[92] Hydrogen can also reduce 8-hydroxy-deoxyguanine, decreasing DNA oxidation.[93],[111] Peroxynitrite is a strong biological oxidant which could induce neuronal death. The removal of peroxynitrite is related to hydrogen, so molecular hydrogen could directly reduce peroxynitrite to protect nerve cells.[94] Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exhibits reduced oxidative stress and neuroprotective properties, and has been identified as one of the goals of stroke therapy.[112] In addition, many studies have shown that hydrogen attenuates oxidative stress via Nrf2 pathway.[95],[113],[114]

Inflammation also plays an important role in stroke. Many studies have pointed out that hydrogen has an anti-inflammatory effect on cells.[115],[116],[117] In addition to antioxidant effects, the anti-inflammatory effects of hydrogen also play a non-negligible role in stroke.[118] Hydrogen may exhibit neuroprotection by reducing the number of microglia and astrocytes in damaged brain tissue, or by inhibiting activated microglia.[96],[119] In the central nervous system, macrophages transformed by microglia can polarize to classic type (pro-inflammatory; M1-like) and alternative type (anti-inflammatory or protective; M2-like).[120],[121] A recent study found that hydrogen treatment inhibits the increase in M1-like macrophages, but has no influence on M2-like cells, therefore implying anti-inflammatory effects in a stroke model.[97] In addition to cellular activation, hydrogen can also regulate gene expression of pro-inflammatory cytokines.[89],[91] In most models, hydrogen treatment reduces the expression of pro-inflammatory factors such as IL-1β, IL-6, IL-10, TNF-α, interferon-γ, and NF-κB.[98],[122] Hydrogen treatment also increases anti-inflammatory cytokines such as transforming growth factor-1β.[99]

Hydrogen therapy also shows anti-apoptotic properties. Hydrogen treatment reduces the levels of miR-21, an effective anti-apoptotic factor.[99] In addition, hydrogen can induce angiogenesis, reduce cyclooxygenase-2 levels, and inhibit mitochondrial swelling under pathological conditions.[101],[123] More mechanisms have yet to be studied.

Methods of ingesting molecular hydrogen include inhalation of hydrogen gas, oral ingestion by drinking hydrogen water, injection of hydrogen-saline, and topical application such as eye drops, bodywash, and cosmetics.[93] Hydrogen is not cytotoxic at any concentration, so hydrogen-based treatments are considered safe.[124] In addition, hydrogen has the advantage of being highly-selective reaction with ROS and rapidly diffusing, showing great potential in future stroke treatment.[90],[92],[125]

The role of hydrogen sulfide in stroke

In the past, hydrogen sulfide had always been considered a toxic gas that smelled of rotten eggs. However, later studies have found that endogenously produced hydrogen sulfide plays an important role as an important signaling molecule in the cardiovascular system and nervous system[126],[127] [Table 2]. Hydrogen sulfide is found in many organs and tissues, including the liver, blood, heart, and brain. A previous report has stated that the concentration of hydrogen sulfide within the brain is substantial.[128] Hydrogen sulfide is endogenously synthesized by cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase.[129] Many studies have found that cystathionine β-synthase is ubiquitous in many areas of the brain, and may be the main hydrogen sulfide synthase in the central nervous system.[130],[131],[132] Current research suggests that the role of hydrogen sulfide in stroke is related to the concentration of administration; low concentrations of hydrogen sulfide may have neuroprotective effects on stroke, while high concentrations of hydrogen sulfide may cause neurotoxicity.[133]
Table 2: Mechanisms of neuroprotection of H2S in stroke

Click here to view

The mechanisms by which low concentrations of hydrogen sulfide exhibit neuroprotection in stroke include anti-inflammation, anti-oxidation, anti-apoptosis, and anti-endoplasmic reticulum stress.[141] Hypothermia has long been considered to have a protective effect through angiogenesis and anti-inflammation in brain damage, including stroke.[142],[143],[144] Blackstone and his colleagues[145],[146] found that exposure to gaseous hydrogen sulfide at 80 ppm can reduce core body temperature, therefore illustrating the protective effects in fatal hypoxia in mice. Some researchers reported that slow release of hydrogen sulfide from donors inhibits inflammation-induced matrix metalloprotein-9, and thus reduces affected areas of transient middle cerebral artery occlusion mice.[134] Hydrogen sulfide also inhibits the release of nitric oxide, TNF-α, and IL-1β from astrocytes and microglia to achieve an anti-inflammatory effect.[135] In addition, free radicals and other reactive species can be scavenged by hydrogen sulfide, which may protect neurons from oxidative stress.[136],[147] Kimura and his colleagues found that hydrogen sulfide could promote the activation of cystine/glutamate antiporter and increase the concentration of intracellular cystine, a substrate necessary for the generation and synthesis of glutathione.[137],[148] As an important intracellular antioxidant, glutathione can scavenge ROS in mitochondria and protect neurons from oxidative stress. Inhibition of apoptosis is another role of hydrogen sulfide in stroke. In 2016, Ji et al.[138],[149] reported that heat shock protein 70 could be up-regulated through the phosphoinositide 3-kinase/Akt/Nrf2 pathway and may prevent the recruitment of procaspase-9 by the apoptotic protease activating factor-1 apoptosome, thus inhibiting apoptosis. Moreover, hydrogen sulfide promotes the nuclear translocation of NF-κB, facilitating activation of anti-apoptotic gene.[139] As mentioned above, misfolding of proteins is also one of pathological mechanisms of stroke. Hydrogen sulfide may inhibit endoplasmic reticulum stress response by reducing protein misfolding via upregulation of the brain-derived neurotrophic factor-tyrosine protein kinase B pathway.[140] In addition, hydrogen sulfide also exhibits neuroprotective effects in stroke through other mechanisms, such as regulating calcium concentration or facilitating long-term potentiation.[150]

The high concentration of hydrogen sulfide is neurotoxic, and may be associated with inhibition of mitochondrial respiration.[151] Current research suggests that hydrogen sulfide can inhibit mitochondrial oxidative phosphorylation by inhibiting cytochrome C oxidase (complex IV).[152],[153] It has also been reported that hydrogen sulfide may activate NMDA receptors, leading to calcium overload, and enhancing receptor-mediated glutamate excitotoxicity in stroke.[154],[155]

Although there are no clinical trials with direct evidence suggesting that hydrogen sulfide has neuroprotective effects, it has been reported that plasma hydrogen sulfide levels below a certain level positively correlate with the prognosis of stroke in patients.[150] Animal experiments have also shown a slight increase in plasma hydrogen sulfide levels in transient middle cerebral artery occlusion or permanent middle cerebral artery occlusion mice.[134],[156] Therefore, the role of hydrogen sulfide in stroke is worthy of recognition, and is expected to show translational potential in the future. However, it should be noted that high concentrations of hydrogen sulfide are toxic, leading to respiratory failure, nerve dysfunction, brain edema, and disturbance of consciousness, which is one of the problems that should be addressed in the future [Figure 1].[157],[158]
Figure 1: Major mechanisms of H2 and H2S in stroke.
Note: H2 and H2S exert neuroprotective effects in stroke through various mechanisms. H2: Hydrogen; H2S: hydrogen sulfide; BBB: blood-brain barrier.

Click here to view

  Future Perspectives and Translation Top

Through extensive experimental studies in animal models of stroke, we have found that hydrogen and hydrogen sulfide are important signaling molecules that exhibit neuroprotection in stroke through various mechanisms. Specific mechanisms include anti-oxidation, anti-inflammation, anti-apoptosis, etc. In summary, medical gases, including hydrogen and hydrogen sulfide, play a significant role in stroke. However, some important issues have not been resolved, such as insufficient clinical evidence, cytotoxicity of hydrogen sulfide, occurrence of complications, methods of administration and dosage, and combined use of drugs. Therefore, more animal experiments and clinical trials are needed to establish the standard of use of medical gases, to clarify the exact mechanism of medical gas therapy, and to ensure the safety of treatment. We believe that medical gases are expected to be an important complementary therapy for stroke in the future.

Author contributions

Study design: SC, ZYZ; literature search: ZYZ; manuscript preparation and writing: ZYZ; manuscript revision and editing: YJF, SC, CL, YJL; figures and tables preparation: ZYZ, YJF; manuscript review: SC, JMZ. All authors approved the final manuscript for publication.

Conflicts of interest


Financial support

This study was supported by the National Natural Science Foundation of China (No. 81971107, to SC), and the Fundamental Research Funds for the Central Universities, China (No. 2019QNA7038, to SC).

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Plagiarism check

Checked twice by iThenticate.

Peer review

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 Top

Zhang JH. Welcome to medical gas research. Med Gas Res. 2011;1:1.  Back to cited text no. 1
Lew V, McKay E, Maze M. Past, present, and future of nitrous oxide. Br Med Bull. 2018;125:103-119.  Back to cited text no. 2
Huang CM, Lu EY, Kirchhof MG. Cellulitis secondary to liquid nitrogen cryotherapy: case report and literature review. J Cutan Med Surg. 2017;21:334-338.  Back to cited text no. 3
Wang H, Shu S, Li J, Jiang H. Management of liver cancer argon-helium knife therapy with functional computer tomography perfusion imaging. Technol Cancer Res Treat. 2016;15:29-35.  Back to cited text no. 4
Deng J, Lei C, Chen Y, et al. Neuroprotective gases--fantasy or reality for clinical use? Prog Neurobiol. 2014;115:210-245.  Back to cited text no. 5
Parmar S, Moore-Langston S, Fredrickson V, et al. Neuroprotective mechanisms of oxygen and ethanol: a potential combination therapy in stroke. Curr Med Chem. 2015;22:1194-1204.  Back to cited text no. 6
Iketani M, Ohsawa I. Molecular hydrogen as a neuroprotective agent. Curr Neuropharmacol. 2017;15:324-331.  Back to cited text no. 7
Yang YW, Wang YL, Lu JK, Tian L, Jin M, Cheng WP. Delayed xenon post-conditioning mitigates spinal cord ischemia/reperfusion injury in rabbits by regulating microglial activation and inflammatory factors. Neural Regen Res. 2018;13:510-517.  Back to cited text no. 8
Sutherland BA, Harrison JC, Nair SM, Sammut IA. Inhalation gases or gaseous mediators as neuroprotectants for cerebral ischaemia. Curr Drug Targets. 2013;14:56-73.  Back to cited text no. 9
Ulbrich F, Goebel U. The molecular pathway of argon-mediated neuroprotection. Int J Mol Sci. 2016;17:1816.  Back to cited text no. 10
Chen WL, Niu YY, Jiang WZ, et al. Neuroprotective effects of hydrogen sulfide and the underlying signaling pathways. Rev Neurosci. 2015;26:129-142.  Back to cited text no. 11
Regenhardt RW, Das AS, Lo EH, Caplan LR. Advances in understanding the pathophysiology of lacunar stroke: a review. JAMA Neurol. 2018;75:1273-1281.  Back to cited text no. 12
Zents K, Copray S. The therapeutic potential of induced pluripotent stem cells after stroke: evidence from rodent models. Curr Stem Cell Res Ther. 2016;11:166-174.  Back to cited text no. 13
Knecht T, Story J, Liu J, Davis W, Borlongan CV, Dela Peña IC. Adjunctive therapy approaches for ischemic stroke: innovations to expand time window of treatment. Int J Mol Sci. 2017;18:2756.  Back to cited text no. 14
Liu S, Feng X, Jin R, Li G. Tissue plasminogen activator-based nanothrombolysis for ischemic stroke. Expert Opin Drug Deliv. 2018;15:173-184.  Back to cited text no. 15
Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;7:CD000213.  Back to cited text no. 16
Cheripelli BK, Huang X, MacIsaac R, Muir KW. Interaction of recanalization, intracerebral hemorrhage, and cerebral edema after intravenous thrombolysis. Stroke. 2016;47:1761-1767.  Back to cited text no. 17
Wong KS, Caplan LR, Kim JS. Stroke mechanisms. Front Neurol Neurosci. 2016;40:58-71.  Back to cited text no. 18
Wu X, Luo X, Zhu Q, et al. The roles of thrombospondins in hemorrhagic stroke. Biomed Res Int. 2017;2017:8403184.  Back to cited text no. 19
Hernández DE, Salvadores NA, Moya-Alvarado G, Catalán RJ, Bronfman FC, Court FA. Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis. J Cell Sci. 2018;131:jcs214684.  Back to cited text no. 20
Olloquequi J, Cornejo-Córdova E, Verdaguer E, et al. Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications. J Psychopharmacol. 2018;32:265-275.  Back to cited text no. 21
Wen SY, Li AM, Mi KQ, et al. In vitro neuroprotective effects of ciliary neurotrophic factor on dorsal root ganglion neurons with glutamate-induced neurotoxicity. Neural Regen Res. 2017;12:1716-1723.  Back to cited text no. 22
Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science. 1969;164:719-721.  Back to cited text no. 23
Garthwaite G, Williams GD, Garthwaite J. Glutamate toxicity: an experimental and theoretical analysis. Eur J Neurosci. 1992;4:353-360.  Back to cited text no. 24
Choi DW, Koh JY, Peters S. Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci. 1988;8:185-196.  Back to cited text no. 25
Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain. 2018;11:15.  Back to cited text no. 26
Kristián T, Siesjö BK. Calcium in ischemic cell death. Stroke. 1998;29:705-718.  Back to cited text no. 27
Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11:720-731.  Back to cited text no. 28
Yin A, Guo H, Tao L, et al. NDRG2 protects the brain from excitotoxicity by facilitating interstitial glutamate uptake. Transl Stroke Res. 2019. doi:10.1007/s12975-019-00708-9.  Back to cited text no. 29
Khanna S, Briggs Z, Rink C. Inducible glutamate oxaloacetate transaminase as a therapeutic target against ischemic stroke. Antioxid Redox Signal. 2015;22:175-186.  Back to cited text no. 30
Khanna S, Stewart R, Gnyawali S, et al. Phytoestrogen isoflavone intervention to engage the neuroprotective effect of glutamate oxaloacetate transaminase against stroke. FASEB J. 2017;31:4533-4544.  Back to cited text no. 31
Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke. 2009;4:461-470.  Back to cited text no. 32
Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001;21:2-14.  Back to cited text no. 33
Kontos HA. Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke. 2001;32:2712-2716.  Back to cited text no. 34
Szydlowska K, Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium. 2010;47:122-129.  Back to cited text no. 35
Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci. 2017;74:3863-3881.  Back to cited text no. 36
Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J. NMDA-dependent superoxide production and neurotoxicity. Nature. 1993;364:535-537.  Back to cited text no. 37
Garcia-Bonilla L, Moore JM, Racchumi G, et al. Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol. 2014;193:2531-2537.  Back to cited text no. 38
Rodrigo R, Fernández-Gajardo R, Gutiérrez R, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets. 2013;12:698-714.  Back to cited text no. 39
Sugawara T, Chan PH. Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal. 2003;5:597-607.  Back to cited text no. 40
Dizdaroglu M, Jaruga P. Mechanisms of free radical-induced damage to DNA. Free Radical Res. 2012;46:382-419.  Back to cited text no. 41
Pomatto LCD, Davies KJA. Adaptive homeostasis and the free radical theory of ageing. Free Radical Biol Med. 2018;124:420-430.  Back to cited text no. 42
Margaill I, Plotkine M, Lerouet D. Antioxidant strategies in the treatment of stroke. Free Radical Biol Med. 2005;39:429-443.  Back to cited text no. 43
Naritomi H, Moriwaki H. Prevention of post-stroke disuse muscle atrophy with a free radical scavenger. Front Neurol Neurosci. 2013;32:139-147.  Back to cited text no. 44
Selim M. Treatment with the iron chelator, deferoxamine mesylate, alters serum markers of oxidative stress in stroke patients. Transl Stroke Res. 2010;1:35-39.  Back to cited text no. 45
Wu HJ, Wu C, Niu H-J, et al. Neuroprotective mechanisms of melatonin in hemorrhagic stroke. Cell Mol Neurobiol. 2017;37:1173-1185.  Back to cited text no. 46
Watson N, Diamandis T, Gonzales-Portillo C, Reyes S, Borlongan CV. Melatonin as an antioxidant for stroke neuroprotection. Cell Transplant. 2016;25:883-891.  Back to cited text no. 47
Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol (1985). 2006;100:739-743.  Back to cited text no. 48
Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci. 2007;8:803-808.  Back to cited text no. 49
Chamorro A, Hallenbeck J. The harms and benefits of inflammatory and immune responses in vascular disease. Stroke. 2006;37:291-293.  Back to cited text no. 50
Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J. 2009;276:13-26.  Back to cited text no. 51
Kriz J. Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol. 2006;18:145-157.  Back to cited text no. 52
Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 2010;119:89-105.  Back to cited text no. 53
Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147 Suppl 1:S232-S240.  Back to cited text no. 54
Butovsky O, Ziv Y, Schwartz A, et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149-160.  Back to cited text no. 55
Lalancette-Hébert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007;27:2596-2605.  Back to cited text no. 56
Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K. Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis. 2007;16:203-207.  Back to cited text no. 57
Greenwood J, Heasman SJ, Alvarez JI, Prat A, Lyck R, Engelhardt B. Review: leucocyte-endothelial cell crosstalk at the blood-brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol. 2011;37:24-39.  Back to cited text no. 58
Zhang R, Chopp M, Zhang Z, Jiang N, Powers C. The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res. 1998;785:207-214.  Back to cited text no. 59
Yilmaz G, Granger DN. Cell adhesion molecules and ischemic stroke. Neurol Res. 2008;30:783-793.  Back to cited text no. 60
Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009;7:97.  Back to cited text no. 61
Sekerdag E, Solaroglu I, Gursoy-Ozdemir Y. Cell death mechanisms in stroke and novel molecular and cellular treatment options. Curr Neuropharmacol. 2018;16:1396-1415.  Back to cited text no. 62
Yuan J. Divergence from a dedicated cellular suicide mechanism: exploring the evolution of cell death. Mol Cell. 2006;23:1-12.  Back to cited text no. 63
Yuan J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14:469-477.  Back to cited text no. 64
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11:700-714.  Back to cited text no. 65
Adams JM. Ways of dying: multiple pathways to apoptosis. Genes Dev. 2003;17:2481-2495.  Back to cited text no. 66
Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99-163.  Back to cited text no. 67
Wang S, Ma F, Huang L, et al. Dl-3-n-butylphthalide (NBP): a promising therapeutic agent for ischemic stroke. CNS Neurol Disord Drug Targets. 2018;17:338-347.  Back to cited text no. 68
Liang F, Shi L, Zheng J, Chen S, Wang Y, Zhang J. Neuroprotective effects of CGP3466B on apoptosis are modulated by protein-L-isoaspartate (D-aspartate) O-methyltransferase/Mst1 pathways after traumatic brain injury in rats. Sci Rep. 2017;7:9201.  Back to cited text no. 69
Xu W, Lu X, Zheng J, et al. Melatonin protects against neuronal apoptosis via suppression of the ATF6/CHOP pathway in a rat model of intracerebral hemorrhage. Front Neurosci. 2018;12:638.  Back to cited text no. 70
Wen YD, Sheng R, Zhang LS, et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy. 2008;4:762-769.  Back to cited text no. 71
Shacka JJ, Roth KA, Zhang J. The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy. Front Biosci. 2008;13:718-736.  Back to cited text no. 72
Zhang P, Yang L, He H, Deng Y. Differential variations of autophagy and apoptosis in permanent focal cerebral ischaemia rat model. Brain Inj. 2017;31:1151-1158.  Back to cited text no. 73
Kim KA, Shin D, Kim JH, et al. Role of autophagy in endothelial damage and blood-brain barrier disruption in ischemic stroke. Stroke. 2018;49:1571-1579.  Back to cited text no. 74
Yuan D, Liu C, Hu B. Dysfunction of membrane trafficking leads to ischemia-reperfusion injury after transient cerebral ischemia. Transl Stroke Res. 2018;9:215-222.  Back to cited text no. 75
Kasahara A, Scorrano L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol. 2014;24:761-770.  Back to cited text no. 76
Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147-157.  Back to cited text no. 77
Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014;2:702-714.  Back to cited text no. 78
van der Bliek AM, Shen Q, Kawajiri S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol. 2013;5:a011072.  Back to cited text no. 79
Kumari S, Anderson L, Farmer S, Mehta SL, Li PA. Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. Transl Stroke Res. 2012;3:296-304.  Back to cited text no. 80
Jiang X, Andjelkovic AV, Zhu L, et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018;163-164:144-171.  Back to cited text no. 81
Bao Dang Q, Lapergue B, Tran-Dinh A, et al. High-density lipoproteins limit neutrophil-induced damage to the blood-brain barrier in vitro. J Cereb Blood Flow Metab. 2013;33:575-582.  Back to cited text no. 82
Keep RF, Andjelkovic AV, Xiang J, et al. Brain endothelial cell junctions after cerebral hemorrhage: Changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab. 2018;38:1255-1275.  Back to cited text no. 83
Sifat AE, Vaidya B, Abbruscato TJ. Blood-brain barrier protection as a therapeutic strategy for acute ischemic stroke. AAPS J. 2017;19:957-972.  Back to cited text no. 84
Shi X, Fu Y, Zhang S, Ding H, Chen J. Baicalin attenuates subarachnoid hemorrhagic brain injury by modulating blood-brain barrier disruption, inflammation, and oxidative damage in mice. Oxid Med Cell Longev. 2017;2017:1401790.  Back to cited text no. 85
George PM, Steinberg GK. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron. 2015;87:297-309.  Back to cited text no. 86
Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF. Pathogenic mechanisms following ischemic stroke. Neurol Sci. 2017;38:1167-1186.  Back to cited text no. 87
Althausen S, Mengesdorf T, Mies G, et al. Changes in the phosphorylation of initiation factor eIF-2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. J Neurochem. 2001;78:779-787.  Back to cited text no. 88
Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014;144:1-11.  Back to cited text no. 89
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688-694.  Back to cited text no. 90
Li H, Luo Y, Yang P, Liu J. Hydrogen as a complementary therapy against ischemic stroke: A review of the evidence. J Neurol Sci. 2019;396:240-246.  Back to cited text no. 91
Oharazawa H, Igarashi T, Yokota T, et al. Protection of the retina by rapid diffusion of hydrogen: administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Invest Ophthalmol Visual Sci. 2010;51:487-492.  Back to cited text no. 92
Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol. 2015;555:289-317.  Back to cited text no. 93
Cejka C, Kossl J, Hermankova B, et al. Therapeutic effect of molecular hydrogen in corneal UVB-induced oxidative stress and corneal photodamage. Sci Rep. 2017;7:18017.  Back to cited text no. 94
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. 2018;228:238-246.  Back to cited text no. 95
Imai K, Kotani T, Tsuda H, et al. Neuroprotective potential of molecular hydrogen against perinatal brain injury via suppression of activated microglia. Free Radical Biol Med. 2016;91:154-163.  Back to cited text no. 96
Ning K, Liu WW, Huang JL, Lu HT, Sun XJ. Effects of hydrogen on polarization of macrophages and microglia in a stroke model. Med Gas Res. 2019;8:154-159.  Back to cited text no. 97
Shi Y, Wang G, Li J, Yu W. Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Neuroreport. 2017;28:1170-1175.  Back to cited text no. 98
Li Q, Yu P, Zeng Q, et al. Neuroprotective effect of hydrogen-rich saline in global cerebral ischemia/reperfusion rats: up-regulated tregs and down-regulated miR-21, miR-210 and NF-κB expression. Neurochem Res. 2016;41:2655-2665.  Back to cited text no. 99
Matei N, Camara R, Zhang JH. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res. 2018;8:98-102.  Back to cited text no. 100
Ergul A, Alhusban A, Fagan SC. Angiogenesis: a harmonized target for recovery after stroke. Stroke. 2012;43:2270-2274.  Back to cited text no. 101
Nagatani K, Wada K, Takeuchi S, et al. Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia. Shock. 2012;37:645-652.  Back to cited text no. 102
Hayashida K, Sano M, Kamimura N, et al. H(2) gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc. 2012;1:e003459.  Back to cited text no. 103
Cai J, Kang Z, Liu K, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2009;1256:129-137.  Back to cited text no. 104
Huang G, Zhou J, Zhan W, et al. The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest. Resuscitation. 2013;84:690-695.  Back to cited text no. 105
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. 2016;335:232-241.  Back to cited text no. 106
Han L, Tian R, Yan H, et al. Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins. Brain Res. 2015;1615:129-138.  Back to cited text no. 107
Zhai X, Chen X, Shi J, et al. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression. Free Radical Biol Med. 2013;65:731-741.  Back to cited text no. 108
Slezák J, Kura B, Frimmel K, et al. Preventive and therapeutic application of molecular hydrogen in situations with excessive production of free radicals. Physiol Res. 2016;65 Suppl 1:S11-S28.  Back to cited text no. 109
Niki E. Lipid peroxidation: physiological levels and dual biological effects. Free Radical Biol Med. 2009;47:469-484.  Back to cited text no. 110
Kawai D, Takaki A, Nakatsuka A, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology. 2012;56:912-921.  Back to cited text no. 111
Wu G, Zhu L, Yuan X, et al. Britanin ameliorates cerebral ischemia-reperfusion injury by inducing the Nrf2 protective pathway. Antioxid Redox Signal. 2017;27:754-768.  Back to cited text no. 112
Tamaki N, Orihuela-Campos RC, Fukui M, Ito HO. Hydrogen-rich water intake accelerates oral palatal wound healing via activation of the Nrf2/antioxidant defense pathways in a rat model. Oxid Med Cell Longev. 2016;2016:5679040.  Back to cited text no. 113
Diao M, Zhang S, Wu L, et al. Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation. 2016;39:2029-2039.  Back to cited text no. 114
Gao Q, Song H, Wang XT, et al. Molecular hydrogen increases resilience to stress in mice. Sci Rep. 2017;7:9625.  Back to cited text no. 115
Wallace JL, Ianaro A, Flannigan KL, Cirino G. Gaseous mediators in resolution of inflammation. Semin Immunol. 2015;27:227-233.  Back to cited text no. 116
Qian L, Liu X, Shen J, Zhao D, Yin W. Therapeutic effects of hydrogen on chronic graft-versus-host disease. J Cell Mol Med. 2017;21:2627-2630.  Back to cited text no. 117
Li J, Dong Y, Chen H, et al. Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines. Brain Res. 2012;1486:103-111.  Back to cited text no. 118
Hayashida K, Sano M, Kamimura N, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation. 2014;130:2173-2180.  Back to cited text no. 119
Hu X, Li P, Guo Y, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43:3063-3070.  Back to cited text no. 120
Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation. 2011;8:174.  Back to cited text no. 121
Yuan L, Shen J. Hydrogen, a potential safeguard for graft-versus-host disease and graft ischemia-reperfusion injury? Clinics (Sao Paulo). 2016;71:544-549.  Back to cited text no. 122
Hugyecz M, Mracskó E, Hertelendy P, Farkas E, Domoki F, Bari F. Hydrogen supplemented air inhalation reduces changes of prooxidant enzyme and gap junction protein levels after transient global cerebral ischemia in the rat hippocampus. Brain Res. 2011;1404:31-38.  Back to cited text no. 123
Cole AR, Raza A, Ahmed H, et al. Safety of inhaled hydrogen gas in healthy mice. Med Gas Res. 2019;9:133-138.  Back to cited text no. 124
Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 2008;373:30-35.  Back to cited text no. 125
Liu YH, Lu M, Hu LF, Wong PTH, Webb GD, Bian JS. Hydrogen sulfide in the mammalian cardiovascular system. Antioxid Redox Signal. 2012;17:141-185.  Back to cited text no. 126
Tan BH, Wong PTH, Bian JS. Hydrogen sulfide: a novel signaling molecule in the central nervous system. Neurochem Int. 2010;56:3-10.  Back to cited text no. 127
Yu Q, Lu Z, Tao L, et al. ROS-dependent neuroprotective effects of nahs in ischemia brain injury involves the PARP/AIF pathway. Cell Physiol Biochem. 2015;36:1539-1551.  Back to cited text no. 128
Kabil O, Banerjee R. Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal. 2014;20:770-782.  Back to cited text no. 129
Robert K, Vialard F, Thiery E, et al. Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain. J Histochem Cytochem. 2003;51:363-371.  Back to cited text no. 130
Enokido Y, Suzuki E, Iwasawa K, Namekata K, Okazawa H, Kimura H. Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB J. 2005;19:1854-1856.  Back to cited text no. 131
Chan SJ, Chai C, Lim TW, et al. Cystathionine β-synthase inhibition is a potential therapeutic approach to treatment of ischemic injury. ASN Neuro. 2015;7:1759091415578711.  Back to cited text no. 132
Chan SJ, Wong PTH. Reprint of: Hydrogen sulfide in stroke: protective or deleterious? Neurochem Int. 2017;107:78-87.  Back to cited text no. 133
Wang Y, Jia J, Ao G, et al. Hydrogen sulfide protects blood-brain barrier integrity following cerebral ischemia. J Neurochem. 2014;129:827-838.  Back to cited text no. 134
Seifert HA, Pennypacker KR. Molecular and cellular immune responses to ischemic brain injury. Transl Stroke Res. 2014;5:543-553.  Back to cited text no. 135
Qu K, Lee SW, Bian JS, Low CM, Wong PTH. Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int. 2008;52:155-165.  Back to cited text no. 136
Kimura Y, Goto YI, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal. 2010;12:1-13.  Back to cited text no. 137
Ji K, Xue L, Cheng J, Bai Y. Preconditioning of H2S inhalation protects against cerebral ischemia/reperfusion injury by induction of HSP70 through PI3K/Akt/Nrf2 pathway. Brain Res Bull. 2016;121:68-74.  Back to cited text no. 138
Sen N, Paul BD, Gadalla MM, et al. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol Cell. 2012;45:13-24.  Back to cited text no. 139
Wei HJ, Xu JH, Li MH, et al. Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway. Acta Pharmacol Sin. 2014;35:707-715.  Back to cited text no. 140
Chan SJ, Wong PTH. Hydrogen sulfide in stroke: Protective or deleterious? Neurochem Int. 2017;105:1-10.  Back to cited text no. 141
Zhang M, Wang H, Zhao J, et al. Drug-induced hypothermia in stroke models: does it always protect? CNS Neurol Disord Drug Targets. 2013;12:371-380.  Back to cited text no. 142
Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci. 2012;13:267-278.  Back to cited text no. 143
Sandu RE, Uzoni A, Ciobanu O, et al. Post-stroke gaseous hypothermia increases vascular density but not neurogenesis in the ischemic penumbra of aged rats. Restor Neurol Neurosci. 2016;34:401-414.  Back to cited text no. 144
Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science. 2005;308:518-518.  Back to cited text no. 145
Blackstone E, Roth MB. Suspended animation-like state protects mice from lethal hypoxia. Shock. 2007;27:370-372.  Back to cited text no. 146
Whiteman M, Cheung NS, Zhu YZ, et al. Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun. 2005;326:794-798.  Back to cited text no. 147
Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J. 2004;18:1165-1167.  Back to cited text no. 148
Beere HM, Wolf BB, Cain K, et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2000;2:469-475.  Back to cited text no. 149
Dou Y, Wang Z, Chen G. The role of hydrogen sulfide in stroke. Med Gas Res. 2016;6:79-84.  Back to cited text no. 150
Wu D, Zheng N, Qi K, et al. Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential. Med Gas Res. 2015;5:1.  Back to cited text no. 151
Bouillaud F, Blachier F. Mitochondria and sulfide: a very old story of poisoning, feeding, and signaling? Antioxid Redox Signal. 2011;15:379-391.  Back to cited text no. 152
Guo W, Kan J, Cheng Z, et al. Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction. Oxid Med Cell Longev. 2012;2012:878052.  Back to cited text no. 153
Cheung NS, Peng ZF, Chen MJ, Moore PK, Whiteman M. Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons. Neuropharmacology. 2007;53:505-514.  Back to cited text no. 154
García-Bereguiaín MA, Samhan-Arias AK, Martín-Romero FJ, Gutiérrez-Merino C. Hydrogen sulfide raises cytosolic calcium in neurons through activation of L-type Ca2+ channels. Antioxid Redox Signal. 2008;10:31-42.  Back to cited text no. 155
Qu K, Chen CP, Halliwell B, Moore PK, Wong PT. Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke. 2006;37:889-893.  Back to cited text no. 156
Guidotti TL. Hydrogen sulfide intoxication. Handb Clin Neurol. 2015;131:111-133.  Back to cited text no. 157
Ding Y, Li X, Chen C, et al. A rapid evaluation of acute hydrogen sulfide poisoning in blood based on DNA-Cu/Ag nanocluster fluorescence probe. Sci Rep. 2017;7:9638.  Back to cited text no. 158


  [Figure 1]

  [Table 1], [Table 2]

This article has been cited by
1 Novel Mechanisms and Therapeutic Targets for Ischemic Stroke: A Focus on Gut Microbiota
Zeyu Bao, Zeyu Zhang, Guoyang Zhou, Anke Zhang, Anwen Shao, Feng Zhou
Frontiers in Cellular Neuroscience. 2022; 16
[Pubmed] | [DOI]
2 Molecular Hydrogen Neuroprotection in Post-Ischemic Neurodegeneration in the Form of Alzheimer’s Disease Proteinopathy: Underlying Mechanisms and Potential for Clinical Implementation—Fantasy or Reality?
Ryszard Pluta, Slawomir Januszewski, Stanislaw J. Czuczwar
International Journal of Molecular Sciences. 2022; 23(12): 6591
[Pubmed] | [DOI]
3 GAS6/Axl Signaling Modulates Blood-Brain Barrier Function Following Intravenous Thrombolysis in Acute Ischemic Stroke
Zhen-Ni Guo, Jie Liu, Junlei Chang, Peng Zhang, Hang Jin, Xin Sun, Yi Yang
Frontiers in Immunology. 2021; 12
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  Pathological Mec...Advances in Rese...Future Perspecti...
  In this article
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded168    
    Comments [Add]    
    Cited by others 3    

Recommend this journal