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H2S alleviated TBI-induced motor and spatial memory deficits and brain edema. (A) A wire-grip test was performed to analyze the motor function at 0 to 7d after TBI (n = 5). (B) A Rota-rod test was performed to analyze the motor function at 0 to 7d and 14d after TBI (n = 5). (C) A Morris water maze test was performed to test spatial memory ability on days 8 to 15 (n = 5). (D) A spatial probe test was performed to test spatial memory ability on days 16 (n = 5). (E) The pathological changes was analyzed by H&E staining. (F) The brain water content was measured at 24 h after TBI (n = 5). #P<0.05 vs. sham group.* P<0.05, vs. TBI and TBI+ vehicle groups. #P<0.05 vs. sham group.
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Several reports suggest that hydrogen sulfide (H2S) exerts multiple biological and physiological effects on the pathogenesis of traumatic brain injury (TBI). However, the exact molecular mechanism involved in this effect is not yet fully known. In this study, we found that H2S alleviated TBI-induced motor and spatial memory deficits, brain patholog...
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... with the sham group, TBI lead to a significant decline in motor performance at 0 to 7 days post-injury. NaHS, an H2S donor, treatment significantly improve the motor function on days 0 to 7 after TBI compared to TBI and TBI+ vehicle groups ( Figure 1A, 1B). ...
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... with the sham group, rats from TBI and TBI+ vehicle groups showed increased latencies to find the hidden platform. We observed a significant decrease in the latencies in the TBI+ NaHS group ( Figure 1C). The data of a spatial probe test also showed that H2S improved the spatial memory ability of TBI rats ( Figure 1D). ...
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... observed a significant decrease in the latencies in the TBI+ NaHS group ( Figure 1C). The data of a spatial probe test also showed that H2S improved the spatial memory ability of TBI rats ( Figure 1D). ...
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... determine the effect of H2S on TBI-induced cerebral injury, we analyzed brain pathology and brain edema. As shown in Figure 1E, compared with the sham group on day 7, rats from TBI and TBI+ vehicle groups showed serious pathological changes. Treatment with NaHS significantly improved the pathological changes. ...
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... with NaHS significantly improved the pathological changes. In addition, TBI led to a significant increase in the percentage of brain water content compared to the sham group ( Figure 1F). Treatment with NaHS markedly reduced the percentage of brain water content. ...
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... with the sham group, TBI lead to a significant decline in motor performance at 0 to 7 days post-injury. NaHS, an H2S donor, treatment significantly improve the motor function on days 0 to 7 after TBI compared to TBI and TBI+ vehicle groups ( Figure 1A, 1B). ...
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... with the sham group, rats from TBI and TBI+ vehicle groups showed increased latencies to find the hidden platform. We observed a significant decrease in the latencies in the TBI+ NaHS group ( Figure 1C). The data of a spatial probe test also showed that H2S improved the spatial memory ability of TBI rats ( Figure 1D). ...
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... observed a significant decrease in the latencies in the TBI+ NaHS group ( Figure 1C). The data of a spatial probe test also showed that H2S improved the spatial memory ability of TBI rats ( Figure 1D). ...
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... determine the effect of H2S on TBI-induced cerebral injury, we analyzed brain pathology and brain edema. As shown in Figure 1E, compared with the sham group on day 7, rats from TBI and TBI+ vehicle groups showed serious pathological changes. Treatment with NaHS significantly improved the pathological changes. ...
Citations
... In particular, Pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) inhibitors, such as NSC74429, have shown promise in protecting against the damaging effects of oxidative stress triggered by hydrogen peroxide and excitotoxicity induced by glutamate [94]. Furthermore, hydrogen sulfide (H 2 S), a newly recognized gaseous neurotransmitter, has demonstrated neuroprotective effects by reducing oxidative stress associated with glutamate, potentially through the p53/glutaminase 2 pathway [95]. Excitotoxicity is considered an important secondary injury mechanism following a TBI, involving impaired neuronal calcium regulation and excessive glutamate release, resulting in dendrite damage. ...
A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI’s impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment.
... To date, it is known that H 2 S can regulate p53 levels. However, its role in this process is ambiguous: some authors point to its neuroprotective effect due to a decrease in the level of p53 [13], while others demonstrate a cytotoxic effect through the activation of p53 and triggering apoptosis [14,15]. The role of H 2 S in the expression and localization of p53 in neurons and glial cells in TBI and axotomy is barely studied, which makes this research topic particularly relevant and promising both from a practical point of view and from a fundamental standpoint. ...
... Presently, it is known that H2S can regulate pro-apoptotic proteins, including p53, in various pathological conditions. The regulation of p53 expression through H2S-dependen signaling pathways has been studied in various experimental models using H2S donor and inhibitors of the enzymes responsible for the synthesis of this gasotransmitter [13][14][15] However, the mechanisms of H2S-dependent regulation of p53 in neurons and glial cell in traumatic brain injury and axotomy are barely studied. ...
... How ever, such studies are few and often contradictory. For example, a recent study demon strated the neuroprotective effect of H2S associated with the inhibition of p53 expression in damaged neurons [13]. At the same time, other authors report that H2S induces p5 expression and activates apoptotic signaling [14,15]. ...
Citation: Rodkin, S.; Nwosu, C.; Raevskaya, M.; Khanukaev, M.; Bekova, K.; Vasilieva, I.; Vishnyak, D.; Tolmacheva, A.; Efremova, E.; Gasanov, M.; et al. The Role of Hydrogen Sulfide in the Localization and Expression of p53 and Cell Death in the Nervous Tissue in Traumatic Brain Injury and Axotomy. Int. J. Mol. Sci. 2023, 24, 15708. https://doi.
Abstract: Traumatic brain injury (TBI) is one of the leading causes of disability and death worldwide. It is characterized by various molecular-cellular events, with the main ones being apoptosis and damage to axons. To date, there are no clinically effective neuroprotective drugs. In this study, we examined the role of hydrogen sulfide (H 2 S) in the localization and expression of the key pro-apoptotic protein p53, as well as cell death in the nervous tissue in TBI and axotomy. We used a fast donor (sodium sulphide, Na 2 S) H 2 S and a classic inhibitor (aminooxyacetic acid, AOAA) of cystathionine β-synthase (CBS), which is a key enzyme in H 2 S synthesis. These studies were carried out on three models of neurotrauma in vertebrates and invertebrates. As a result, it was found that Na 2 S exhibits a pronounced neuroprotective effect that reduces the number of TUNEL-positive neurons and glial cells in TBI and apoptotic glia in axotomy. This effect could be realized through the Na 2 S-dependent decrease in the level of p53 in the cells of the nervous tissue of vertebrates and invertebrates, which we observed in our study. We also observed the opposite effect when using AOAA, which indicates the important role of CBS in the regulation of p53 expression and death of neurons and glial cells in TBI and axotomy.
... H 2 S的神经 生物学效应以及内源性释放调节机制使其被定义为一 种抗继发性脑损伤的神经保护因子 [298] . 比如, 脑内H 2 S 常在神经元兴奋时释放, 通过诱导星形胶质细胞Ca 2+ 波从细胞外间隙摄取更多的谷氨酸, 从而抵消谷氨酸 介导的神经元兴奋性毒性 [299] . H 2 S可激活各种离子通 道 [300] , 随后通过扩张脑血管 [293] , 维持血脑屏障通透性 和改善线粒体功能 [159,300] 等发挥其对TBI的保护功能, S-巯基化修饰离子通道蛋白可能是核心机制 [301] . ...
... The critical role of H 2 S in inhibiting ferroptosis and promoting function recovery against TBI has been reported in many previous studies Kimura et al. 2006;Sun et al. 2021). However, the underlying mechanism remains unclear. ...
... The above results in this research have demonstrated the critical role of H 2 S in desensitizing cells from ferroptosis after TBI, consistent with many previous studies Sun et al. 2021;Wang et al. 2022a, b, c, d). It should be noted that ferroptosis is one of the cell death types induced by TBI (Gao et al. 2023). ...
... Although previous studies have reported that H 2 S could exert neuroprotective effects by reducing ferroptosis post-TBI (Kimura et al. 2006;Sun et al. 2021), this study first Fig.9 The schematic representation of neuroprotective effects of NaHS treatment against TBI-induced ferroptosis. ...
Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H 2 S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H 2 S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H 2 S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H 2 S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H 2 S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H 2 S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H 2 S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H 2 S against TBI.
Graphical Abstract
TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.
... H 2 S 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 proapoptotic groups of proteins in various traumatic injuries of the nervous system [29][30][31]133]. H 2 S can directly interact with proteins through S-sulfhydration or persulfhydration of cysteine residues on proteins [190], and bind to metalloproteins, modulating their activity and function [191]. ...
... The use of an H 2 S donor showed a significant decrease in TUNEL-positive neuronal and glial cells [29]. However, in other studies, H 2 S 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 H 2 S. Caspase-3 plays a central role in the cascade of caspases, proteolytic enzymes that sequentially activate each other and underlying proteases [201,202]. H 2 S has been shown to reduce the expression of caspase-3 in damaged neurons and their apoptosis in TBI [29,50]. H 2 S reduced levels of this proapoptotic enzyme in spinal cord injury models (Figure 7) [35,140]. ...
Injuries of the central (CNS) and peripheral nervous system (PNS) are a serious problem of the modern healthcare system. The situation is complicated by the lack of clinically effective neuroprotective drugs that can protect damaged neurons and glial cells from death. In addition, people who have undergone neurotrauma often develop mental disorders and neurodegenerative diseases that worsen the quality of life up to severe disability and death. Hydrogen sulfide (H2S) is a gaseous signaling molecule that performs various cellular functions in normal and pathological conditions. However, the role of H2S in neurotrauma and mental disorders remains unexplored and sometimes controversial. In this large-scale review study, we examined the various biological effects of H2S associated with survival and cell death in trauma to the brain, spinal cord, and PNS, and the signaling mechanisms underlying the pathogenesis of mental illnesses, such as cognitive impairment, encephalopathy, depression and anxiety disorders, epilepsy and chronic pain. We also studied the role of H2S in the pathogenesis of neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, we reviewed the current state of the art study of H2S donors as neuroprotectors and the possibility of their therapeutic uses in medicine. Our study showed that 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. However, so far, all H2S modulators are at the stage of preclinical trials. Nevertheless, many of them show a high neuroprotective effect in various animal models of neurotrauma and related disorders. Despite the fact that our review is very extensive and detailed, it is well structured right down to the conclusions, which will allow researchers to quickly find the proper information they are interested in.
... MPST in neurons that survive after TBI . Later studies linked protection by H 2 S to regulation of glutamate-mediated oxidative stress via the p53/glutaminase-2 pathway (Sun et al., 2021). ...
The gaseous neurotransmitter hydrogen sulfide (H2 S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signaling events. Unlike conventional neurotransmitters, H2 S cannot be stored in vesicles due to its gaseous nature. Instead, it is either locally synthesized or released from endogenous stores. Sulfhydration affords both specific and general neuroprotective effects and is critically diminished in several neurodegenerative disorders. Conversely, some forms of neurodegenerative disease are linked to excessive cellular H2 S. Here, we review the signaling roles of H2 S across the spectrum of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, Down syndrome, traumatic brain injury, the ataxias, and amyotrophic lateral sclerosis, as well as neurodegeneration generally associated with aging.
... While all of these changes would be considered likely beneficial to brain health in the setting of TBI, it is unclear whether any of these occur as a direct result of H 2 S action or if this simply reflects the profile of a healthier brain by virtue of other upstream effects of H 2 S. Interestingly, Zhang et al. have shown that increased expression of 3-MST in neurons occurs predominantly in those neurons that survive after TBI [140], implicating a regulated and direct protective role of endogenous H 2 S after TBI. More recently, H 2 S-mediated protection in TBI in rats has been linked to the modulation of glutamate-mediated oxidative stress via the p53/glutaminase2 pathway [141]. In addition, the Centurion laboratory recently reported that subchronic treatment with NaHS protected rats from hemodynamic and sympathetic nervous system impairments after TBI and also restored CSE and CBS expression in the brain [142]. ...
The gaseous signaling molecule hydrogen sulfide (H2S) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H2S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions. Although toxic and even fatal at very high concentrations, emerging evidence has also revealed a pronounced neuroprotective role for lower doses of endogenously generated or exogenously administered H2S. Unlike traditional neurotransmitters, H2S is a gas and, therefore, is unable to be stored in vesicles for targeted delivery. Instead, it exerts its physiologic effects through the persulfidation/sulfhydration of target proteins on reactive cysteine residues. Here, we review the latest discoveries on the neuroprotective roles of H2S in Alzheimer’s disease (AD) and traumatic brain injury, which is one the greatest risk factors for AD.
... Moreover, it can interact with them directly through Ssulfhydration or persulfhydration of cysteine residues and through activation or inhibition of signaling mechanisms. It has been shown that H 2 S can either activate or inhibit the expression of p53 [61,62], caspase-3, Bax, and a number of other proteins involved in apoptosis [56]. However, the subtle H 2 S-dependent mechanisms of regulation of anti-and pro-apoptotic proteins remain poorly understood. ...
Cardiovascular, rheumatic, kidney, and neurodegenerative diseases and mental disorders are a common cause of deterioration in the quality of life up to severe disability and death worldwide. Many pathological conditions, including this group of diseases, are based on increased cell death through apoptosis. It is known that this process is associated with signaling pathways controlled by a group of gaseous signaling molecules called gasotransmitters. They are unique messengers that can control the process of apoptosis at different stages of its implementation. However, their role in the regulation of apoptotic signaling in these pathological conditions is often controversial and not completely clear. This review analyzes the role of nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S), and sulfur dioxide (SO2) in apoptotic cell death in cardiovascular, rheumatic, kidney, and neurodegenerative diseases. The signaling processes involved in apoptosis in schizophrenia, bipolar, depressive, and anxiety disorders are also considered. The role of gasotransmitters in apoptosis in these diseases is largely determined by cell specificity and concentration. NO has the greatest dualism; scales are more prone to apoptosis. At the same time, CO, H2S, and SO2 are more involved in cytoprotective processes.
... Indeed, modulation of H 2 S signaling has been shown to induce beneficial effects after brain injury including TBI, ischemic brain injury and subarachnoid hemorrhage ( Table 3). Most of the studies mainly use the administration of NaHS, a fast-releasing inorganic donor [11,148,[153][154][155][156][157][158][159][160][161][162][163][164], whereas slow-releasing agents such as ATB 346 [165], ADT [166], GYY-4137 [167], and AP39 [168] has been less studied. Besides, the effects of H 2 S donors in brain injury models are mainly assessed in short-term consequences. ...
The systemic cardiovascular effects of major trauma, especially neurotrauma, contribute to death and permanent disability in trauma patients and treatments are needed to improve outcomes. In some trauma patients, dysfunction of the autonomic nervous system produces a state of adrenergic overstimulation, causing either a sustained elevation in catecholamines (sympathetic storm) or oscillating bursts of paroxysmal sympathetic hyperactivity. Trauma can also activate innate immune responses that release cytokines and damage-associated molecular patterns into the circulation. This combination of altered autonomic nervous system function and widespread systemic inflammation produces secondary cardiovascular injury, including hypertension, damage to cardiac tissue, vascular endothelial dysfunction, coagulopathy and multiorgan failure. The gasotransmitters gases nitric oxide (NO) and hydrogen sulfide (H2S) are small gaseous molecules with potent effects on vascular tone regulation. Exogenous NO (inhaled) has potential therapeutic benefit in cardio-cerebrovascular diseases, but limited data suggests potential efficacy in traumatic brain injury (TBI). H2S is a modulator of NO signaling and autonomic nervous system function that has also been used as a drug for cardio-cerebrovascular diseases. The inhaled gases NO and H2S are potential treatments to restore cardio-cerebrovascular function in the post-trauma period.
... GLU is largely secreted in ischemic brain tissues, and neurons actively respond to this neurotransmitter (Datusalia et al., 2018). It has been reported that hydrogen sulfide protected against traumatic brain injury through modulation of the GLU-mediated oxidative stress (Sun et al. 2021). Hydrogen sulfide is a neuro-regulator that accelerates the generation of hippocampal long-term potentiation by modulating the activity of the NMDA receptor (NMDAR) (Kimura 2013). ...
Neurologic deterioration after massive cerebral infarct should be identified at an early stage for medical and surgical treatments. We investigated the effect of hydrogen sulfide on the excitotoxity of PC12 cells exposed to oxygen–glucose deprivation (OGD) and its effect on the apoptosis of brain tissues in rats with middle cerebral artery occlusion (MCAO). Rats with MCAO were treated with SAM, a cystathionine beta-synthase (CBS) activator, or AOAA, a CBS inhibitor. Hydrogen sulfide content in the brain tissues of infarcted patients or rats with MCAO was decreased, whereas glutamate (GLU) content was increased. In addition, SAM reduced reactive oxygen species content, lactate dehydrogenase release, and apoptosis levels in the brain tissues of rats with MCAO. The PC12 cells that were exposed to OGD were also treated with 20 mM GLU and later treated with SAM or AOAA. In PC12 cells, SAM reduced the apoptosis caused by GLU after OGD. The protective effects of hydrogen sulfide was elicited through the sulfur-sulfhydrylation modification of NMDAR and the induction of ERK/MAPK signaling. Our results showed that hydrogen sulfide exerts a protective effect on the PC12 cells and the rats with MCAO, which might represent a possible therapeutic agent against massive cerebral infarct.
