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Rodkin, S.; Nwosu, C.; Sannikov, A.; Raevskaya, M.; Tushev, A.; Vasilieva, I.; Gasanov, M. The Neuroprotective Effect of Hydrogen Sulfide. Encyclopedia. Available online: (accessed on 29 November 2023).
Rodkin S, Nwosu C, Sannikov A, Raevskaya M, Tushev A, Vasilieva I, et al. The Neuroprotective Effect of Hydrogen Sulfide. Encyclopedia. Available at: Accessed November 29, 2023.
Rodkin, Stanislav, Chizaram Nwosu, Alexander Sannikov, Margarita Raevskaya, Alexander Tushev, Inna Vasilieva, Mitkhat Gasanov. "The Neuroprotective Effect of Hydrogen Sulfide" Encyclopedia, (accessed November 29, 2023).
Rodkin, S., Nwosu, C., Sannikov, A., Raevskaya, M., Tushev, A., Vasilieva, I., & Gasanov, M.(2023, July 13). The Neuroprotective Effect of Hydrogen Sulfide. In Encyclopedia.
Rodkin, Stanislav, et al. "The Neuroprotective Effect of Hydrogen Sulfide." Encyclopedia. Web. 13 July, 2023.
The Neuroprotective Effect of Hydrogen Sulfide

Hydrogen sulfide (H2S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. H2S has great neuroprotective potential. H2S reduces oxidative stress, lipid peroxidation, and neuroinflammation; inhibits processes associated with apoptosis, autophagy, ferroptosis and pyroptosis; prevents the destruction of the blood-brain barrier; increases the expression of neurotrophic factors; and models the activity of Ca2+ channels in neurotrauma. In addition, H2S activates neuroprotective signaling pathways in psychiatric and neurodegenerative diseases. However, high levels of H2S can cause cytotoxic effects. Thus, the development of H2S-associated neuroprotectors seems to be especially relevant.

hydrogen sulfide neurotrauma apoptosis autophagy ferroptosis pyroptosis neuron glial cells cognitive impairment encephalopathy depression anxiety disorders epilepsy neurodegenerative diseases

1. Introduction

Neurotrauma is one of the leading causes of disability and death worldwide. It takes third position after cardiovascular and oncological diseases. Moreover, due to neurotrauma, the highest mortality and proportion of disability is observed among the young population. This situation is complicated due to the lack of effective clinical neuroprotective drugs that can protect neurons and glial cells from traumatic injury [1][2]. In addition, the heterogeneity of neurotrauma creates additional difficulties in their study and difficulties in developing and selecting a competent treatment strategy [3]. In addition, central (CNS) and peripheral nervous system (PNS) injuries often lead to various mental disorders [4][5][6][7][8] and neurodegenerative diseases [9][10][11][12][13], which are accompanied by increased cell death of the nervous tissue [14][15][16][17][18][19]. It is worth noting that nerve cells are very sensitive to various influences, including microwave radiation, which can cause neurodegenerative diseases [20]. This confirms the presence of complex intermolecular interactions in the nervous tissue. To solve these problems, it is necessary to search for promising molecular targets and study the intracellular signaling processes associated with them [21].
Gasotransmitters are important signaling gaseous molecules that perform various functions in the body under normal and pathological conditions [22]. They play an important role in the processes of cell survival and death [23]. Although many signaling mechanisms of cytoprotection and cytotoxicity of these messengers are poorly understood and often contradictory, the S-gasotransmitter H2S remains of great interest to researchers, especially in conditions of traumatic damage to the nervous system [24][25][26], and mental [27] and neurodegenerative diseases [28].
H2S is produced endogenously in many tissues and is involved in various cellular processes: neurotransmission, apoptosis, inflammation, oxidative stress, angiogenesis, etc. [22]. Many scientific data indicate that H2S can act both as a neuroprotective agent and as a factor responsible for neurodegeneration [25][29][30][31]. Its role in neurotrauma is also ambiguous: some researchers point to its pronounced neuroprotective effect [29][32][33][34][35][36], while others associate it with cell death [37][38][39][40]. Of particular interest are the H2S-dependent signaling mechanisms of survival and death of nerve cells in mental disorders [4] and neurodegenerative diseases [41], which often develop with neurotrauma [4][5][6][7][8][9][10][11][12][13].

2. Classification and Molecular Mechanisms of Neurotrauma

Neurotrauma is damage to various structures of the CNS and PNS caused by external forces. It includes isolated and combined traumatic brain injury (TBI); isolated and combined spinal cord injury (SCI); and multiple limb injury with isolated or combined damage to bones, ligaments, blood vessels, and peripheral nerves [42]. Currently, it is known that neurotrauma can lead to various mental and neurodegenerative diseases. This can be based on both molecular mechanisms and direct mechanical damage to anatomically important structures of the CNS and PNS.
TBI and SCI in young and middle-aged men is ahead of cardiovascular and oncological diseases. Along with this, injuries of the PNS are a major public health problem [1][2][43]. With mechanical damage in the nervous tissue, various pathological processes develop, leading to the death of neurons. The treatment of these neuropathological processes is a major public health problem worldwide. However, effective clinical neuroprotective drugs have not yet been found. Their search requires deep and comprehensive studies of the molecular mechanisms of neurodegeneration and neuroprotection in these pathological processes [2].
TBI is a type of damage where the skull suffers from mechanical effects, as well as intracranial formations—the brain, meninges, blood vessels, cranial nerves. TBI is a heterogeneous pathological condition [25][44][45][46]. The destruction of nervous tissue in TBI is due to primary and secondary mechanisms of brain damage. Primary damage is caused by the direct impact of mechanical energy on the substance of the brain. In the area of primary brain damage, necrosis of brain tissue, death of neurons and glial cells, axonal ruptures and vascular thrombosis occur [25][44][45][46][47]. As a result, a focus is formed, protected by a penumbra—a zone of moderate ischemia. Cell death in the penumbra region leads to the expansion of the zone of the necrotic focus of TBI [48][49].
Secondary brain damage develops in response to primary mechanical damage, which triggers a cascade of molecular cellular events: oxidative phosphorylation in the mitochondria is disrupted, intracellular Ca2+ concentration increases, free oxygen radicals and vasoactive metabolites of arachidonic acid are released, the mechanisms of the complement cascade and lipid peroxidation are activated, and so on [50]. A sharp activation of the metabolic processes in neurons leads to ATP pool depletion and a disruption of the functions of Ca2+ channels. As a result, there is an increase in the permeability of the cell membranes to Ca2+ ions and the release of Ca2+ from intracellular depots, which leads to the depolarization of neurons and the release of glutamate, which activates N-methyl-D-aspartic acid (NMDA) receptors (NMDARs). Intracellular overload of Ca2+ occurs, which triggers a whole cascade of reactions associated with the activation of phospholipases, proteases and nucleases, the lysis of structural proteins, the expression of pro-apoptotic genes, the release of cell death factors from mitochondria, hyper synthesis of nitric oxide, and oxidative stress [51][52]. Hence, leading to the apoptotic death of neurons and glial cells [44].
Another major traumatic injury to the central nervous system is SCI. This is characterized by compression, or partial or complete rupture of the spinal cord. This group of neurotraumas is characterized by high disability and mortality and is practically untreatable. [53][54]. Spinal cord injury can be characterized by the destruction of several, many, or all of the nerve fibers that pass through the injury site. Recovery after this type of neurotrauma is complicated by the extremely weak regenerative capabilities of the spinal cord and is usually possible only with mild damage; with slight death of nerve cells and slight destruction of spinal nerve fibers [55]. This type of injury is accompanied by primary and secondary injuries similar to TBI [56].
Furthermore, injuries to the PNS are of great danger, and often lead to a deterioration in the quality of life up to severe disability or death [57]. Peripheral nerve damage is the result of the destruction of nerves that extend from the spinal cord and brain to various parts of the body and are located outside of the CNS [58]. These nerves can be damaged as a result of various factors, such as trauma, disease, inflammation, etc. Of particular danger are injuries to peripheral nerves, often accompanied by their complete rupture, that is, axotomy (AT), which initiates a complex cascade of signaling and metabolic processes aimed at the death or survival of the neuron [59][60].
AT is characterized by three main molecular-cellular events: Wallerian degradation of the severed axon, death of the damaged neuron, or its regeneration with the regrowth of the axon and the restoration of nerve connections. The peculiarity of PNS neurons is their ability to regenerate a damaged axon, while CNS neurons degenerate and die as a result of AT [61]. About 30% of PNS motor and sensory neurons survive AT by restoring nerve connections. An important factor associated with the survival of nerve cells in AT is the distance from the site of the axon rupture to the soma. Generally, the larger it is, the higher the chances of neuron regeneration [62][63].
H2S plays an important role in pathological conditions and may also be involved in processes associated with inflammation [64][65], oxidative stress synthesis [32][34][66], apoptosis [39][40], and autophagy [25][47], etc.

3. Metabolism and Functions of H2S

3.1. Biosynthesis of H2S and Its Deposition

The third gasotransmitter, after nitric oxide (NO) and carbon monoxide (CO), is H2S. Its discovery as a signaling molecule dates back to 1996, when the endogenous formation of H2S in the brain tissue was established with the help of the enzyme cystathionine-β-synthase and its possible role in neuromodulation was assumed. In aqueous solutions, hydrogen sulfide dissociates into H+, HS and S2−. Under physiological conditions, approximately 20% of this gas exists in the form of H2S, about 80% in the form of HS and only traces in the form of S2− [67][68].
H2S mainly exists as gaseous molecules or sodium bisulfide (NaHS). H2S can bind to hemoglobin to form sulfhemoglobin. In addition, proteins containing the iron–sulfur complex and sulfane, which includes hydrosulfides/persulfides, are commonly recognized forms of H2S accumulation in the body [31].
The main substrate for the production of H2S in humans and animals is L-cysteine, as well as its disulfide form—cysteine. The synthesis of hydrogen sulfide in the body occurs under the influence of the enzymes cystathionine-β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) (Figure 1), together with cysteine aminotransferase (CAT) [24][25][67][68].
Figure 1. Biosynthesis of H2S in the body. Cystathionine-β-synthase (CBS) catalyzes the condensation of homocysteine (Hcy) with serine to form cystathionine, which cleaves cystathionine-γ-lyase (CSE). This results in the synthesis of H2S. CBS, CSE and 3-mercaptopyruvate sulfurtransferase (3-MST) catalyze the conversion of cysteine to H2S.
CBS is predominantly expressed in the brain, liver, kidneys, and pancreas. CBS catalyzes the condensation of homocysteine (Hcy) with serine to form cystathionine. Subsequently, cystathionine undergoes proteolysis by the enzyme CSE. This leads to the formation of cysteine, which is a precursor of glutathione. It should be noted that in addition to the canonical pathway, CBS is involved in desulfurization reactions that lead to the formation of endogenous H2S. The formation of H2S may be affected by a thiol-cysteine reaction catalyzed by CBS with the release of s-thiolate. Cysteine may also undergo hydrolysis by CSE to form H2S, as well as pyruvate and ammonia. Disruption of the mechanisms of regulation of CBS is associated with a change in the levels of Hcy and/or H2S and, inevitably, leads to various pathological conditions (Figure 1) [69][70].

3.2. Catabolism of H2S

The catabolism of H2S has been studied much less than its synthesis in the body. Currently, three pathways of H2S catabolism are mainly known: oxidation, methylation and exhalation. The oxidation of H2S mainly occurs in hepatocytes. Here, H2S is oxidized by mitochondrial enzymes to sulfate with the intermediates persulfide (RSSH), sulfite (SO32−), and thiosulfate (S2O32−) [71][72].
As a result, most of the H2S is excreted in the urine in the form of sulfate. It has been shown that the increase in sulfide oxidation in the kidneys, heart and liver upon administration of exogenous H2S is due to an increase in quinone oxidoreductase (SQR) (Figure 2). However, this effect was not observed in the brain tissue, which indicates a defect in the oxidation of sulfides in the nervous tissue of the brain [73].
Figure 2. H2S catabolism pathways in the body: oxidation, methylation and exhalation. TSMT, thiol-S-methyl transferase; SQR, quinone oxidoreductase; SDO, sulfur deoxygenase; SO, sulfite oxidase.
Free H2S exists in low concentration in the blood and decays rapidly. Therefore, it will probably not all be transported to the liver for disposal. The question of H2S catabolism in the brain via alternative pathways independent of the liver and kidneys remains open [31].
The methylation of H2S occurs primarily in the cytoplasm in contrast to the oxidative catabolic pathway of this gasotransmitter. First, H2S is methylated to methane thiol, and then it is methylated to a non-toxic dimethyl sulfide by a thiol-S-methyl transferase (TSMT) (Figure 2). The methylation of sulfides has been found to be a significantly slower process than oxidation [74][75]. H2S can be excreted from the body through lung tissue (Figure 2) [31][76].

3.3. Various Biological Effects of Endogenous H2S

The main physiological effects of H2S are neuromodulation, regulation of vascular tone and oxidative stress, anti-inflammatory action, angiogenesis, and energy generation. However, these effects do not exhaust the diversity of the biological actions of H2S. Presently, the list of functions performed by this gaseous signaling agent is constantly expanding (Figure 3) [77].
Figure 3. The participation of H2S in normal and pathological conditions in the brain, heart, blood vessels, gastrointestinal tract, liver, kidneys, and lungs.
Just like NO, H2S is a new generation neurotransmitter that has also been shown to have pronounced neuroprotective effects. In physiological conditions, H2S has a role in learning and memory processes. It facilitates long-term potentiation in the hippocampus by activating NMDARs associated with Ca2+ channels [78][79]. Disturbances in the endogenous production and metabolism of H2S have been observed in neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s disease (PD) [80][81]

4. Endogenous and Exogenous H2S in Neurotrauma

4.1. Endogenous H2S Levels in Neurotrauma

Recently, several experiments have been developed to study and detect changes in the concentration of H2S in neurotrauma in both animal and human models. The concentration of H2S has been shown to be a dynamic system. The level of the endogenous expression of H2S and CBS in the blood and brain tends to decrease after neurotrauma. Zhang M and colleagues demonstrated that CBS expression was suppressed in the cerebral cortex and hippocampus of mice in TBI. Furthermore, at first it gradually decreased, reaching the minimal values, and then increased. H2S demonstrated dynamic changes in TBI, in parallel with the expression of the key enzyme of its synthesis [82].

4.2. Exogenous H2S: Between Neuroprotection and Neurodegeneration

It is known that H2S is involved in the processes of neuroprotection and neurodegeneration in neurotrauma. The administration of H2S donors can protect neurons and prevent the development of hemodynamic disorders in TBI [82]. Increasing the concentration of H2S reduces cerebral edema, improves motor activity, and reduces apoptosis and autophagy in an animal model of TBI [83]. According to Jiang and co-authors, H2S leads to the activation of antioxidant enzymes, reducing the oxidative damage to nervous tissue cells in TBI [84]. The authors of another study indicate that H2S reduces mitochondrial dysfunction and autophagy in TBI (Figure 4) [85].
Figure 4. The role of H2S in neuroprotection and neurodegeneration in neurotrauma. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation.
Increasing the concentration of H2S by using a ferrofluid hydrogel (FFH) with iron tetrasulfide (Fe3S4) significantly reduces activated microglial/macrophage levels and the expression of pro-inflammatory factors, and increases the rate of directional growth of axons in animal models of SCI [86]. The use of H2S-releasing silk fibroin hydrogel resulted in a decrease in the level of neuronal pyroptosis induced by TBI [87]. NaHS has been reported to reduce the area of spinal cord infarction in the ischemic-reperfusion model of injury [88]
In a mouse model of sciatic nerve damage, H2S was shown to significantly reduce neuropathic pain [89]. In addition, CSE and MST have been found to be present in normal nerves, and axotomy activates CSE in Schwann cells [73]. Inhibition of H2S production has been reported to improve the growth of regenerating axons and remyelination processes in peripheral nerve injuries (Figure 4) [90].

5. The Role of H2S in Cell Death in Neurotrauma

5.1. Participation of H2S in Oxidative Stress

Recently, the main H2S-dependent biological effects in various neurotraumas are considered in the context of the regulation of oxidative stress. It is known that, at 37 °C and a pH of 7.4, more than 80% of H2S molecules dissolve in surface waters and dissociate into the ions H+, HS- and S2−. HS is a powerful one-electron chemical reagent that effectively traps reactive oxygen species (ROS). Hydrosulfide anions are able to quench ROS by transferring a hydrogen atom or a single electron. The rate of this reaction is directly limited by diffusion. In this case, the reaction of hydrosulfide anions with molecular oxygen proceeds faster in the presence of divalent metal ions. H2S effectively interacts with hypochlorous acid (HClO), hydrogen peroxide (H2O2), lipid hydroperoxides and peroxynitrite (ONOO), neutralizing their oxidative potential [91]. In addition, H2S itself is a reducing agent that can directly react and extinguish the superoxide anion (O2), NO and its free radical products, as well as other ROS (Figure 5). 

Figure 5. The role of H2S in oxidative stress in neurotrauma. H2S can directly react with and quench ROS and NO. In addition, H2S can increase the level of intracellular reduced glutathione (GSH), which is an antioxidant. However, H2S can activate γ-glutamylcysteine synthase (γ-GSC), which limits GSH synthesis. H2S is involved in the activation of a number of antioxidant defense enzymes: γ-glutamylcysteine synthase (γ-GSC), thioredoxin (Trx-1), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and p66Shc.
In addition, H2S can react with NO to form nitroxide (HNO), which is able to bind to the thiol groups of proteins, leading to the formation of disulfide bonds. HNO can modify GSH with the formation of GSH disulfide and sulfinamide, which can increase oxidative stress and inflammatory processes [92].
H2S increases thioredoxin (Trx-1), which is a small (12 kDa) molecule containing the characteristic Cys–Gly–Pro–Cys motif, and the oxidation–reduction of Trx-1 occurs from two of its cysteine residues. Trx-1 is a 12 kDa oxidoreductase enzyme containing a dithiol-disulfide active site that acts as an antioxidant, facilitating the reduction of other proteins by cysteine-thiol-disulfide [66].
H2S can bind to the copper (Cu) catalytic center of superoxide dismutase (SOD), which leads to an increase in the rate of absorption of superoxide anions [93]. Recent studies have also shown that H2S can attenuate oxidative stress by increasing the activity of catalase (CAT) and glutathione peroxidase (GPx) (Figure 5).

5.2. Modulation of the H2S Activity of NMDARs and Intracellular Ca2+ Homeostasis

H2S has been found to modulate NMDAR activity. Protein kinase A (PKA) is known to regulate NMDAR activity. Studies have shown that H2S can increase levels of cAMP, which, as a secondary messenger, activates PKA. As a result, the activity of the NMDAR increases. However, H2S can activate NMDARs in an independent way. Since NMDARs are extremely sensitive to oxidation and reduction reactions, the biological effects of H2S on these receptors may be due to the reduction of disulfide bonds [78]. H2S can directly interact with the cysteine residues of receptor subunits, modifying them by S-sulfhydration [79].
H2S can increase cytosolic Ca2+ in neurons by activating slow Ca2+ L-type channels. Ca2+ L-type channels are one of the main members of the family of potential-controlled calcium channels. The discovery of these channels occurs in response to a strong depolarization of the membrane and causes a prolonged current of Ca2+. Ca2+ L-type channels are expressed in many tissues, including the nervous system [94]. It is known that these Ca2+ channels are involved in the pathogenesis of various injuries of the central nervous system and the PNS [95][96][97]. Thus, it has been shown that H2S can increase the Ca2+ current in astrocytes, microglia and neurons through the activation of Ca2+ L-type channels [98][99]

5.3. Anti- and Pro-Inflammatory Effects of H2S

Neuro inflammation is an inflammatory response in the nervous tissue characterized by the activation of glial cells, the involvement of neutrophils and macrophages, and the increased synthesis of cytokines, chemokines, free radicals and secondary messengers. The neuroinflammatory response is characterized by a growing front of molecular cellular events underlying secondary damage to nervous tissue [100][101]. A number of studies have shown that H2S plays an important role in inflammatory processes in various pathological conditions, including neurotrauma. The use of ATB-346 (2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester), a new H2S-releasing derivative of naproxen, in TBI, significantly reduced the inflammatory response, due to the inhibition of oxidative stress, nuclear NF-κB (factor kappa-light-chain-enhancer of activated B cells), leukocyte adhesion to the endothelium, tumor necrosis factor (TNF), and interleukin-1 β (IL-1 β) [64].
The family NF-κB is known to consist of transcription factors that play a complex role in immunity and inflammation. NF-κB regulates inflammation through nuclear translocation followed by the expression of pro-inflammatory factors [102]. H2S can modulate the activity of NF-κB activity through trans-sulfonation mechanisms, resulting in the inhibition of the nuclear translocation of NF-κB and a reduced inflammatory response [103][104].

5.4. The Effect of H2S on the Level of Neurotrophic Factors

It is known that H2S is able to modulate the level of neurotrophic factors in normal and pathological conditions [26][105][106]. Thus, in a mouse TBI model, the administration of an H2S donor restored GDNF and NGF levels in damaged neural tissue, preserving their neuroprotective effects [64]. The use of a mitochondria-targeted H2S donor in middle cerebral artery occlusion has been reported to increase BDNF and NGF expression, reducing ischemic neuronal damage [26]. The administration of NaHS, a donor of H2S, increased BDNF levels, probably through activation of the transcription factor cAMP response element-binding protein (CREB), which regulates the gene for this neurotrophic factor in brain damage [107].

5.5. Effects of H2S on the Blood-Brain Barrier and Cerebral Edema

Damage to the BBB is the most important pathological substrate of neurotrauma. It was found that H2S can participate in the restoration of the functional and anatomical integrity of the BBB [108][109], as well as reduce cerebral edema [25][110]. Thus, in a rat TBI model, it was shown that the use of NaHS, the classic H2S donor, reduced the excessive permeability of the BBB by activating the mitochondrial adenosine triphosphate-sensitive potassium channels and reducing oxidative stress. Positive H2S-dependent effects may be associated with the inhibition of PKC-α, β I, β II and δ and the activation of PKC-ε, as well as increased levels of Claudin-5, Occludin and ZO-1 [111].

5.6. The Role of H2S in Remyelination Processes

Remyelination is an important aspect of the recovery of damaged neurons in injuries of the brain [112], spinal cord [113], and peripheral nerves [114]. The processes associated with demyelination develop as a result of secondary damage, leading to a dysfunction of the neuronal network, neurodegeneration, and ultimately, to the death of neurons [113]. It is known that H2S can participate in this process [90].
It has been shown that the production of H2S in Schwann cells can lead to destruction of the myelin sheath and the recruitment of macrophages. H2S positively influences the dedifferentiation and proliferation of Schwann cells in Wallerian degeneration by regulating lysosomal-associated membrane protein 1 (LAMP1), p75 neurotrophin receptor (p75 NTR), c-Jun, and p-ERK1/2. The authors of the study suggest that inhibition of CSE expression may be a potential target in the treatment of pathological processes associated with demyelination [90].

5.7. H2S-Associated Anti- and Pro-Apoptotic Signaling Mechanisms

H2S can modulate the apoptosis of neurons and glial cells in neurotrauma. It can act as an anti- and pro-oxidant, as described above, and can regulate the levels of anti- and pro-apoptotic groups of proteins in various traumatic injuries of the nervous system [29][30][31][83]. H2S can directly interact with proteins through S-sulfhydration or persulfhydration of cysteine residues on proteins [115], and bind to metalloproteins, modulating their activity and function [116]. In addition, H2S can realize its activity through the activation and inhibition of various signaling pathways [25][83].
In a recent study, it was shown that H2S can inhibit the expression of the p53 protein in damaged neurons, exerting a neuroprotective effect in TBI. Moreover, as the authors suggest, this H2S-dependent effect was mediated through the pathway p53/glutaminase 2. The use of an H2S donor showed a significant decrease in TUNEL-positive neuronal and glial cells [29]. However, in other studies, H2S caused an increase in p53 expression and the initiation of apoptosis [39][40]. Another major pro-apoptotic protein, caspase-3, is also a target for H2S. Caspase-3 plays a central role in the cascade of caspases, proteolytic enzymes that sequentially activate each other and underlying proteases [117][118]. H2S has been shown to reduce the expression of caspase-3 in damaged neurons and their apoptosis in TBI [29][47]. H2S reduced levels of this proapoptotic enzyme in spinal cord injury models (Figure 6) [35][119]
Figure 7. The role of H2S in apoptosis in neurotrauma. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; Casp1, caspase-1; Casp3, caspase-3; NOX, NADPH-oxidase; Bcl-2, B-cell lymphoma 2; Bax, bcl-2-like protein 4; Akt, protein kinase B; p53, tumor protein p53; Nfr2, nuclear factor erythroid 2–related factor 2; p65, RelA; RPS3, ribosomal protein S3; lncRNA CasC7, long non-coding RNA CasC7. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation; dotted line—alternative regulation.

5.8. H2S-Associated Mechanisms of Autophagy

Autophagy plays an important role in the survival and death of neurons in brain injuries [120]. H2S has been shown to regulate autophagy-dependent cell death after TBI [25][47]. One of the mechanisms for blocking autophagic neuronal death in neurotrauma may be the H2S-dependent modulation of the PI3K/Akt/Nrf2 pathway and a reduction in oxidative stress [121]. It is known that PI3K/Akt/Nrf2 is a central mechanism involved in autophagy (Figure 7) [122][123].
Figure 7. The role of H2S in the regulation of autophagy in neurotrauma. miR-30c, micro-RNA 30c; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; Nfr2, nuclear factor erythroid 2–related factor 2; Beclin, the mammalian orthologue of yeast Atg6; LC3, Microtubule-associated protein 1A/1B-light chain 3. Arrows with a sharp end—positive regulation; arrows with a blunt end—negative regulation.

5.9. H2S-Associated Mechanisms of Ferroptosis

H2S plays an important role in ferroptosis. This gasotransmitter can inhibit the process of ferroptosis by increasing the level of antioxidant enzymes, such as GSH, and via ROS uptake [124]. There are practically no data on the functions of H2S in the ferroptosis of neurons and glial cells in nervous tissues. For example, H2S protects the retinal-blood-brain barrier through the activation of the NRF2/KEAP1 signaling pathway, and via AMPK to p62 phosphorylation [125]. H2S is reported to protect BV2 microglial cells by reducing lactate dehydrogenase levels (LDH), oxidative stress, lipid peroxidation, and Fe2+ accumulation [126].

5.10. H2S-Associated Mechanisms of Pyroptosis

Pyroptosis is a type of programmed necrotic cell death that occurs as a result of caspase-1 activation and the disruption of the integrity of the plasma membrane. A feature of this cell death is the active release of IL-1β and IL-18, dependent on caspase-1, which determines the development of an inflammatory reaction [127]. To date, it has been proven that pyroptosis plays an important role in the pathogenesis of injuries of the brain and spinal cord [128]. It has been shown that H2S may be a key regulator of the processes associated with pyroptosis [129].

6. The Role of H2S in Mental Disorders and Neurodegenerative Diseases

6.1. Cognitive Impairment

Endogenous H2S may reduce cognitive impairment through the reduction of endoplasmic reticulum stress and the inhibition of caspase-12 and C/EBP homologous protein (CHOP) levels [27]. It has been shown in a rat model of subarachnoid hemorrhage that H2S can reduce cognitive deficits by inhibiting the neuroinflammation induced by the TLR4/NF-κB signaling pathway that activates microglial cells (Figure 8) [130].
Figure 8. Possible H2S-dependent signaling mechanisms that regulate cell death in the nervous tissue in cognitive impairment and encephalopathy. H2S, hydrogen sulfide; CHOP, C/EBP homologous protein; Casp12, caspase-12; TRL4, toll like receptor 4; NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species; PSD-9, postsynaptic density protein 95; Bax, bcl-2-like protein 4; NMDAR, N-methyl-D-aspartate receptor; IL-6, interleukin-6; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; Syn1, synapsin 1; LDHA, lactate dehydrogenase A; mTOR, mammalian target of rapamycin; PDK, pyruvate dehydrogenase kinase 1; SOD, superoxide dismutase; GSH, glutathione; Aco, aconitase; CS, citrate synthase; Sirt1, NAD-dependent deacetylase sirtuin-1; CK, creatine kinase; NF-ĸB p65, RelA; PD, pyruvate dehydrogenase; Bcl-2, B-cell lymphoma 2; HO-2, heme oxygenase 2; M2-PK, pyruvate kinase M2; CPR78, cuticular protein RR-2 motif 78; Nrf2, nuclear factor erythroid 2–related factor 2; ARE, antioxidant response element.
NaHS, the classic H2S donor, had a beneficial effect on the memory of TBI-surviving rats [4]. In a mouse model of surgical trauma accompanied by neuroinflammation, H2S improved orientation in the Morris water maze. At the same time, the neuroprotective effect of H2S was due to a decrease in the level of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in blood serum and in hippocampal cells, which is a key structure of learning and memory [131].

6.2. Encephalopathy

H2S can significantly attenuate oxidative stress and apoptosis in encephalopathy through activation of the Nrf2/ARE signaling pathway [132]. However, a high content of H2S can lead to a decrease in the activity of citrate synthase (CS) and aconitase (Aco) in the mitochondria of neurons of the cerebral cortex, as well as creatine kinase (CK) in this brain structure, the striatum, and the hippocampus in encephalopathy.

6.3. Depression and Anxiety Disorders

Studies have shown that the administration of NaHS for a week had an antidepressant and anxiolytic effect on mice and rats in various test procedures: forced swimming, tail hanging, and plus maze [133]. In a model of sleep deprivation in rats, H2S attenuated depressive and anxiety disorder through the increased expression of Sirt1 in the hippocampus and decreased levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and CC motif chemokine ligand 2 (CCL2). At the same time, H2S increased the expression of IL-4 and IL-10, which belong to the anti-inflammatory group of cytokines. The use of the Sirt1 inhibitor leveled the neuroprotective effects of H2S [134].

6.4. Epilepsy

In a mouse model of electrically stimulated epileptic seizures, it has been shown that acute and recurrent seizures lead to a decrease in plasma H2S levels. The authors of the study suggest that H2S can be considered as a new candidate for the role of a biomarker of severe epileptic seizures. The level of thiocyanate, which is a product of cyanide metabolism via the trans-sulfonation pathway involving H2S, was also strongly reduced in the brain and plasma after convulsions. It is noted that the level of GSH did not change. The study yielded important data on the expression of a number of proteins. An increase in the anti-apoptotic protein optic atrophy 1 (OPA1) was observed, as well as mitochondrial fission factor (Mff), mitofusin 2 (MFN2), and dynamin-1-like protein (Drp1) after epileptic seizures (Figure 9) [135].
Figure 10. Possible H2S-dependent signaling mechanisms that regulate cell death in nervous tissue in depression, anxiety disorders, epilepsy, and chronic pain. H2S, hydrogen sulfide; AMPAR, AMPA-type glutamate receptor; IL-4, interleukin-4; IL-6, interleukin-6; IL-1β, interleukin-1β; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α; HO-2, heme oxygenase 2; PI3K, phosphatidylinositol 3-kinase; AKT, RAC-alpha serine/threonine-protein kinase; Sirt1, NAD-dependent deacetylase sirtuin-1; mTORC1, mammalian target of rapamycin complex 1; H3K9ac, acetylated histone H3 lysine 9; GPX4, Glutathione peroxidase 4; Kir6.2, major subunit of the ATP-sensitive K+ channel; SUR1, subunit of the ATP-sensitive K+ channel; GRP78, glucose-regulated protein 78; GSH, glutathione; PSD-9, postsynaptic density protein 95; NQO1, NAD(P)H quinone dehydrogenase 1; OPA1, optic atrophy 1; Beclin, mammalian orthologue of yeast Atg6; Mff, mitochondrial fission factor; ROS, reactive oxygen species; Sirt6, NAD-dependent deacetylase sirtuin-6; p-Akt, phosphorylated RAC-alpha serine/threonine-protein kinase; NOS2, inducible nitric oxide synthase; SLC7A11, solute carrier family 7 member 11; CCL2, C-C motif ligand 2; Fe2+, iron ion; Casp12, caspase-12; NMDAR, N-methyl-D-aspartate receptor; GSTA1, glutathione S-transferase A1; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B; c-fos, gene encoding c-fos protein; Notch1, Notch homolog 1; ACRP30, Adipocyte complement-related protein of 30 kDa; MFN2, Mitofusin-2; Syp, synaptophysin; Drp1, dynamin-related protein; CHOP, C\EBP homologous protein; PKC, protein kinase C; P62, sequestosome 1; GSTM1, glutathione s-transferase Mu 1; GABABR1\GABABR2, gamma-aminobutyric acid receptor subunits, GABABR1 and GABABR2.

7. Neurodegenerative Diseases

7.1. Alzheimer’s Disease

Studies have shown that there is a significant decrease in the level of H2S in the brain of patients suffering from AD [28]. Violation of H2S-homeostasis towards a decrease in the level of H2S is also observed in neurotrauma [82], which indicates the general mechanisms of dysfunction of the H2S-synthesizing system in these pathological conditions. H2S and its metabolites have been proposed as markers of cognitive impairment and vascular dysfunction in AD [80].
H2S is reported to inhibit the hyperphosphorylation of Tau by sulfhydration glycogen synthase kinase 3β (GSK3β), improving the motor and cognitive impairment caused by AD [41]. In a triple transgenic mouse model of AD (3×Tg-AD) demonstrating both Aβ and Tau disorders, the treatment for three months with H2S significantly protected learning and memory in 3×Tg-AD mice. At the same time, a decrease in amyloid β-plaques in the cortex and hippocampus was observed. These neuroprotective effects were due to the H2S-dependent downregulation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases, and p38, which play a key role in phosphorylation, Tau, inflammatory response, oxidative stress, and Ca2+-excitotoxicity (Figure 10) [136].
Figure 10. Possible H2S-dependent signaling mechanisms that regulate cell death in nervous tissue in neurodegenerative diseases. BACE1, beta-site amyloid precursor protein cleaving enzyme 1; p38 MAPK, p38 mitogen-activated protein kinase; Tau, microtubule-associated protein tau; GSK3β, glycogen synthase kinase-3 beta; JNK, c-Jun N-terminal kinase; Aβ, amyloid beta; Casp3, caspase-3; TNF-α, tumor necrosis factor-α; Akt, RAC-alpha serine/threonine-protein kinase; IL-6, interleukin-6; Bax, bcl-2-like protein 4; Bcl-2, B-cell lymphoma 2; PSD-95, postsynaptic density protein 95; Sirt1, NAD-dependent deacetylase sirtuin-1; TORC1, target of rapamycin kinase complex 1; CREB, cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; Nrf2, nuclear factor erythroid 2–related factor 2; ARE, antioxidant response element; HO-1, heme oxygenase 1; TrkB, tropomyosin receptor kinase B; Glu, glutamic acid; WE, Warburg effect; 5-HT, serotonin; miR-133a-5p, microRNA 133a-5p; KATP channel, ATP-sensitive K+ channel; PS1, presenilin-1; p65 NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; miR-155, microRNA 155; ROS, reactive oxygen species; NO, nitric oxide; MDA, malonic dialdehyde; NMDAR, N-methyl-D-aspartate receptor; ROCK2, Rho associated coiled-coil containing protein kinase 2.

7.2. Parkinson’s Disease

Abnormal levels of H2S and its metabolites have been identified in many studies in PD. Thus, it was shown that the level of endogenous H2S significantly decreased in the substantia nigra (SN) in PD, and the use of H2S donors contributed to the neuroprotective effect and reduced the death of dopaminergic neurons in this pathological condition [137]. The protective effect of H2S has been shown in various PD models in vitro and in vivo [138].
It was shown that the use of the H2S donor ACS84, a derivative of the compound L-Dopa, reduced motor dysfunction in mice with induced PD by reducing neuronal loss in the SN, via Nrf-2 activation, and through the increased expression of a number of antioxidant enzymes [139].

8. Therapeutic Approaches Using H2S as a Neuroprotector

Many experimental animal studies have shown that H2S has a beneficial effect on the survival of neurons and glial cells in various pathological conditions, including neurotrauma, and psychiatric and neurodegenerative diseases. However, there is no H2S-associated neuroprotector that has undergone clinical trials, yet.
The complexity of the development of this drug lies in the fact that it is necessary to understand the molecular signaling mechanisms associated with H2S well, which are realized under the conditions of a particular pathological condition. This is not the end of the problem. The therapeutic effect of H2S largely depends on its concentration: a level of H2S close to the physiological level exhibits a neuroprotective effect, and a high level of H2S can lead to cytotoxicity. Therefore, this drug should release H2S at the required concentration for a long time and have a neurocumulative effect in order to accumulate precisely in the nervous tissue and not release H2S in non-target organs. Moreover, if there are already good developments on the first point, then the situation is more complicated regarding the second [140].
However, the situation with slow H2S donors is also ambiguous. For example, GYY4137 is reported to be ineffective due to the low release of H2S, requiring high concentrations. In this connection, new, long-acting H2S donors based on GYY4137, such as AP67 and AP105, have been developed. They exhibit high biological activity [141]. FW1256 could be a promising H2S donor; it has demonstrated a good anti-inflammatory effect in a number of studies [142].

9. Conclusions

Injuries of the central and peripheral nervous system and associated neurodegenerative diseases and mental disorders are one of the main causes of disability and death worldwide after cardiovascular and oncological diseases. H2S can be considered as a potential molecular target for neuroprotective effects. Definitely, the positive role of H2S, manifested in the reduction of oxidative stress, inflammation, demyelination processes, excitotoxicity, apoptosis, autophagy, ferroptosis, and pyroptosis, prevail over its negative effects in the nervous tissue during traumatic damage to the CNS and PNS. In addition, the use of H2S donors effectively reduces the symptoms of mental disorders, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy, chronic pain, and also inhibits the progression of neurodegenerative diseases.


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