Review Article | Open Access
Yong-Peng Yu, Xiang-Lin Chi, Li-Jun Liu, "A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury", The Scientific World Journal, vol. 2014, Article ID 432318, 9 pages, 2014. https://doi.org/10.1155/2014/432318
A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury
Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH.
Nitric oxide (NO) and carbon monoxide (CO) are established physiologic messenger molecules, and the former serving as an endothelial cell-derived relaxing factor (EDRF) has an important role in the regulation of blood pressure . Even though hydrogen sulfide (H2S) has long been known as a noxious and toxic gas, recent accumulated evidence suggests that H2S, as an important endogenous vasodilator and neuromodulator [2, 3], has been implicated in similar functions . A physiologic role for H2S in regulating blood pressure, its potent neuroprotective , and anti-inflammatory effects support a hypothesis that H2S might act as an effective agent that may have therapeutic potential against brain damage induced by oxidative stress, inflammation, hypoxic vasoconstriction, and other factors. Brain damage mainly induced by cerebral vasospasm is a potentially incapacitating or lethal complication in patients with aneurysmal SAH. Thus, the development of effective preventative and therapeutic interventions is an urgent and significant need. The objective of this paper is to present an overview of the pathogenesis of brain injury after SAH and the multiple physiologic functions of H2S in the vascular system, based on which a hypothesis is providing that H2S might be an effective therapy agent for brain injury after SAH.
2. Distribution and Level of H2S in Vascular Tissues
There are three known enzymes that produce H2S endogenously in mammalian tissue: cystathionine-synthase (CBS), gamma lyase (CGL or cystathionine gamma-lyase, CSE), and 3-mercaptopyruvate sulfur transferase (3MST). There are three major fates of H2S in the body. First, most of the H2S produced in the body is oxidized in the mitochondria to an end product of sulfate. The remaining H2S either is methylated by thiol S-methyltransferase (TSMT) to methanethiol and dimethyl sulfide or binds to methemoglobin to form sulfhemoglobin. In most tissues, CBS and CSE, which are responsible for catalyzing the production of H2S, are both pyridoxal-5-phosphate-dependent enzymes that utilize cysteine and homocysteine as substrates to liberate ammonium, pyruvate, and H2S . It was originally believed that CBS was responsible for H2S production in the brain through the activation of the Ca2+/calmodulin pathway. H2S is produced by 3MST from l-cysteine and alpha-ketoglutarate through the metabolism with cysteine aminotransferase (CAT) .
H2S production was observed in ileum, portal vein, and thoracic aorta homogenates when L-Cys and PLP were administered. Moreover, the application of aminooxyacetate (CBS inhibitor) inhibited H2S production in ileum but failed to affect generation of H2S in portal vein and thoracic aorta, suggesting the lack of CBS in vascular tissues [8, 9]. Many studies have been focused on this issue [3, 10–13]. Endogenous H2S has been paid more and more attention to since its physiological discovery. It is expected that physiological concentration of H2S may vary extensively from synthesizing enzymes in different tissues. It was reported that endogenous concentration of H2S in rat, human, and bovine brains ranged within 50–160 μM [14–16], whereas its serum concentration was about to be 50 μM. Previous study showed that H2S does not circulate in the plasma at high enough concentration to be detectable in blood and plasma from a variety of animals, including trout, mouse, Wistar rat, Dawley rat, pig, and cow . H2S concentration in brain and liver homogenates was measured 14 ± 3 nM and 17 ± 3 nM, respectively .
3. Multiple Physiologic Functions and Beneficial Effects of H2S in Biological Systems
The biological effects of H2S on vascular system have been studied for more than a decade. It was first reported that H2S concentration dependently relaxed norepinephrine precontracted portal vein and thoracic aorta, and this relaxation effect was reversible upon removal of chemicals . This vasodilatory effect was later found to be present not only in thoracic aorta, but also in other types of vascular tissues including mesenteric arteries, pulmonary artery, and tail artery. H2S induced vasorelaxation is mainly brought about by the opening of KATP channels [17, 18]. Other signaling mechanisms for the vasorelaxant effect of H2S may involve depletion of intracellular ATP levels in aortic rings  and intracellular acidosis . KATP channels are likely not to be involved in H2S induced vasoconstriction . However, many studies were performed to attempt to unveil the underlying mechanism of H2S induced constrictive effects. Firstly, H2S may react with NO to form a compound, which by itself has no effect on vascular contractility. NO, as a potent physiological vasodilator, quenched by H2S, which might underlie H2S induced vascular constriction response [19, 22]. Moreover, H2S exerted inhibitory effects on endothelial nitric oxide synthase (eNOS) activity . H2S was found to downregulate cAMP levels in vascular smooth muscle cells (SMC) . H2S exerts antihypertensive effects to different extents in different hypertensive models. The antihypertensive role of H2S is confirmed. Slow H2S-releasing compounds and therefore might be as potential therapeutics for hypertension treatment in the future. The data mentioned above suggests that the evidence for H2S’s effects on vascular smooth muscle tone is contradictory.
The mechanisms by which H2S affects injured cells are complicated. Interestingly, in some studies, H2S induced proinflammatory effects which indicates that the background of these immunomodulatory influences still remains elusive . H2S has several effects on mitochondria of cardiac cells such as the reversible inhibition of cytochrome C oxidase, which leads to preservation of mitochondrial structure and function after ischemia/reperfusion. Inhibition of mitochondrial respiration in the injured myocytes results in attenuated generation of reactive oxygen species (ROS) and may alter the function of the affected cell . H2S decreases lipid peroxidation by scavenging hydrogen peroxide and superoxide in a model of isoproterenol induced myocardial injury. Besides these mechanisms, H2S also acts as a direct scavenger neutralizing cytotoxic reactive species like peroxynitrite.
The physiological actions of H2S make this gas ideally suited to protect the heart, brain, liver, kidney, and lungs against injury during ischemia/reperfusion (I/R). In recent years, the cytoprotective effects of endogenous and exogenous H2S have been investigated in models of in vitro and in vivo ischemic injury . Previous study showed that either endogenous or exogenous increases in H2S at the time of reperfusion limit the extent of myocardial infarction, which was accompanied by a decrease in myocardial inflammation and mitochondrial function preservation . Regulation and cytoprotective, physiological, and chemical roles of H2S in biological systems including ischemic injury of cardiac-cerebral vascular disease have been investigated in many studies [23–30].
The vasodilatory effect of H2S, which might be a potential candidate to be considered as EDRF and was later found to be present in widespread arteries including thoracic aorta, mesenteric arteries, pulmonary, and other types of vascular tissues , was particularly involved at the microcirculation level [31, 32]. Based on the accumulated data, several signaling pathways including cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), NO/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) [33, 34], and calcium/calmodulin (CaM)  were involved in the vasoregulatory effect of H2S. Previous study also suggested that hypoxia and H2S shared a common and unique pathway in the excitation-contraction process. The inhibition of H2S synthesis can inhibit both hypoxic vasoconstriction and hypoxic vasodilation .
This role of H2S on smooth muscle is likely to be a general effect. Besides the recently established vasoregulatory role of H2S, its anti-inflammatory effect in different systems has been investigated. Recent studies have demonstrated that H2S may in fact limit inflammation and free radical damage , while another study indicated that H2S might exert an important proinflammatory role in regulating the severity of pancreatitis and associated lung injury . Previous data suggested that ROS were implicated not only in the control of vascular tone in blood, but also in the H2S-induced regulatory function of vascular tissues [33, 38]. These findings raise the possibility that pharmacologic enhancement of H2S formation could be an alternative approach for repairing neuron damage induced by vasospasm, ischemia, oxidative stress, inflammation, and other factors, while previous study has demonstrated that H2S treatment improved endothelium-dependent coronary microvascular relaxation, providing biochemical myocardial protection via attenuation of caspase-independent apoptosis and autophagy in the experimental model . It suggested that the evidence for H2S’s effects on autophagy might be contradictory.
4. Causes and Mechanisms of Brain Injury after Subarachnoid Hemorrhage
Accumulated data indicate that not only delayed ischemic injury , which had been considered the most important cause of poor outcome after SAH, but also early brain injury has become the vital determinant of the intensity of later developing neurological complications . Delayed cerebral vasospasm that develops 3–7 days after SAH had traditionally been considered the most important determinant of delayed ischemic injury. In recent years, increasing evidence suggests that several mechanisms, including ionic and physiological, biochemical, molecular, persistent vascular changes, cell death, oxidative stress, and inflammatory cascade activation, were involved in the pathogenesis of early brain injury after SAH [42–44]. Previous papers show that many experimental studies as well as autopsies performed on the brains of patients after SAH demonstrated extensive ischemic damage. Many factors including elevation of intracranial pressure (ICP), release of vasoactive substances during erythrocyte lysis, platelet aggregation, lipid peroxidation, unopposed sympathetic activity, and alterations in the nitric oxide/nitric oxide synthase (NO/NOS) pathways may contribute to this brain injury .
Though cerebral vasospasm probably plays some part in brain injury after SAH, neurologic injury may not be entirely explained by ischemia. The relationship between cerebral vasospasm and neurologic outcome might be associated with other coexisting causative factors such as microvascular dysfunction and complex neuronal-glial interactions. Previous study suggested that cerebral infarction contributed to poor outcome by vasospasm-independent effects after SAH [44, 46]. Cortical spreading depression (CSD) as one of the interesting mechanisms in brain damage after SAH has gained increasing attention [47, 48]. It has been previously reported that leukocyte-endothelial cell interactions, which played a significant role in the pathophysiology of cerebral vasospasm, could explain the clinical variability and time course of this disease . Therefore, timely therapeutic targeting of the inflammatory response may prevent vasospasm-related brain damage and improve outcomes in patients with SAH.
Autophagy, being a self-degradative process, which plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, and eliminating intracellular pathogens [50, 51], is important for balancing sources of energy at critical times in development and in response to nutrient stress. The autophagy pathway has been reported to be involved in several central nervous system diseases such as cerebral ischemia , hypoxia-ischemia induced brain injury, and traumatic brain injury . In the experimental SAH model, it is suggested that autophagy activation could participate in the pathogenesis of early brain injury induced by SAH. That is to say, activation of the autophagy pathway may play a potential role to attenuate the development of brain damage in SAH .
5. Involvement of H2S in Vascular Relaxation
H2S, known as a poisonous and toxic gas of the rotten egg, is endogenously produced from the metabolism of l-cysteine by constitutively expressed enzymes, including CBS and CSE [54, 55]. H2S produced by CSE can enhance outward flux of K+ via opening KATP channels, resulting in hyperpolarization of membrane potential and vascular smooth muscle relaxation [17, 56]. The vascular effects of H2S are suggested to be partially mediated by a functional endothelium . It is also suggested to regulate smooth muscle tone in coordination with NO . Previous study reported that CSE gene knockout mice displayed significant hypertension and decreased endothelium-dependent vasorelaxation, being accompanied by reduction of H2S levels in many tissues, including serum, heart, and aorta . Intravenous delivery of NaHS, an H2S donor, can transiently decrease systolic blood pressure of mice, suggesting that H2S plays a vital role in regulating physiologic vasodilation and blood pressure.
The effect of H2S on regulating vascular smooth muscle tone and blood pressure implies that it might involve in regulating cerebral blood flow cerebral vasospasm after SAH and there is a possibility of its potential therapeutic effect on prevention and reversal of cerebral vasospasm. While the evidence on H2S associated with cerebral vasospasm after SAH is limited, more studies should be performed from the basic research in the future.
6. The Effect of NO in Pathophysiology, Reversal of Delayed Cerebral Vasospasm
NO, as the most well-known EDRF, is produced by eNOS in the intima and by neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) in the adventitia of cerebral vessels and smooth muscle cells [59, 60]. Other substances which display properties in common with the characteristics of EDRF include CO  and H2S . H2S, NO, and nitrite are formed in vivo and are of vital importance in the tissue response to hypoxia. These signaling molecules are involved in a multitude of processes including the regulation of vascular tone, cellular metabolic function, and cytoprotection .
NO can directly activate soluble guanylcyclase (sGC) to catalyze the conversion of GTP to cyclic GMP in smooth muscle cells. Increased levels of cyclic GMP lead to prevention of Ca2+-dependent activation of myosin light-chain kinase . Activation of Ca2+-dependent KATP channels [65, 66] has been suggested to be involved in NO-induced vascular smooth muscle relaxation. In addition to causing vasodilation, decreasing vascular resistance, and lowering blood pressure, NO derived from endothelial cells can also inhibit platelet aggregation and adhesion and reduce smooth muscle proliferation .
In animals subjected to SAH, oxyhemoglobin (oxyHb) gradually released from blood clots in the subarachnoid space via erythrocyte lysis is a powerful scavenger of NO . Together with vasoconstricting factors such as endothelin-1 (ET-1), cyclooxygenase (COX) products, and ROS , the decreased bioavailability of NO derived from endothelium, neurons, and nitrergic nerve would lead to cerebral vasospasm after SAH. Excessive production of NO plays a role under pathological conditions such as inflammation and cerebral ischemia, leading to generation of peroxynitrite and other highly toxic compounds. This may account partly for the delayed ischemic neurological deficit after subarachnoid hemorrhage. Also, previous studies have demonstrated that iNOS inhibition might yield therapeutic methods to alleviate ischemic brain injury . On the other hand, preconditioning mediated by eNOS might have beneficial effects on reducing vasospasm and cerebral ischemia after SAH . Thus, based on these data, the key therapeutic target in cerebral vasospasm after SAH would be exogenous administration of NO donors, inhibition of PDE and BOXes, and prevention of oxyHb neurotoxicity . In animal models, intravenous administration of nitroglycerin (NTG) or sodium nitroprusside (SNAP) with NO in the form of nitrates could prevent cerebral vasospasm effectively [73, 74]. Nitrite, which is reported as an endogenous NO donor in blood , may provide a way to overcome reduced NO production in the arterial wall after SAH . In a primate SAH model, intravenous continuous delivery of sodium nitrite for two weeks prevents development of vasospasm without changes in blood pressure, which demonstrates that nitrite could release NO locally in the subarachnoid space . However, further study on nitrite needs to be done to elucidate pharmacokinetics of sodium nitrite in humans and establish proper dosage and safety profile. Regional (intracarotid/intracerebral arterial) or local (intraventricular or intrathecal) delivery of NO donors is not clinically attractive because of increased risk of severe complications or surgical access .
7. The Parallels and Contrastive Effects between NO and H2S: Looking for Crosstalk
NO and H2S are ancient, prebiotic, and chemically reactive molecules, which living organisms have evolved to cope with and ultimately make use of for signaling purposes. The reactivity of NO and H2S is controlled partly by keeping their steady-state levels in vivo rather low (in the nanomolar to low micromolar range) by balancing consumption with production, by the NOS enzymes in the case of NO and by the enzymes CSE, CBS, or the tandem enzymes cysteine aminotransferase (CAT) and 3-mercaptopyruvate sulfur transferase (3-MST) in the case of H2S. Another common feature of these enzymatic pathways is that both have an amino acid as substrate: L-Arg is the substrate for NOS and L-Cys is a substrate for CSE and CBS . In the vertebrate circulation, NO and H2S diffuse away from their site of production and react specifically with their biological targets. NO may activate soluble guanylate cyclase present in adjacent smooth muscle cells and trigger vasorelaxation or react with ROS to form secondary reactive nitrogen oxide species (e.g., peroxynitrite). Conversely, H2S may activate potassium channels and, depending on whether the vessel is systemic or pulmonary/gill, may then trigger vasorelaxation or vasoconstriction, respectively, or even both at different time scales . Thus, whereas NO is strictly a vasodilator, H2S may mediate dilation and/or constriction. The prevailing view is that both NO and H2S have a limited radius of effects and have mainly paracrine/autocrine actions. NO, however, can be transported in the blood as plasma and erythrocyte nitrite and S-nitrosothiols, which are relatively stable oxidation products of NO metabolism. Such products may then be recycled back to NO at distant locations and therefore NO can be also regarded as an endocrine signaling molecule. Such endocrine function has not been demonstrated for H2S up to now . Furthermore, it is not yet clear to which extent H2S is capable of generating S-nitrosothiols or other related products. It appears conceivable that a possible crosstalk between the two pathways might involve some thiol-based biochemical compounds common to either pathway . On the other hand, H2S relaxations are reported to be independent of NO synthesis or cGMP , which suggests other downstream targets specific for H2S. The antithrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases . Previous study reported that H2S affects homeostasis which is mediated by H2S-evoked NO production . These hypotheses, while pointing to a possible delicate balance between these two pathways, need to be confirmed experimentally.
Clearly, understanding the crosstalk between these two pathways is a major challenge for future investigations. Whereas highly sensitive and specific reductive chemiluminescence has been essential to determine type, concentrations, and fate of NO metabolites, concerning H2S detection in vivo, intracellular H2S concentrations are not known due to the lack of a suitable, sensitive, and specific method to analyze its various forms currently. As it is the case for NO that can be regenerated from nitrite, there is no evidence that H2S metabolites can be transported in the blood, stored in tissues, and reactivated to generate H2S at present. It is possible therefore that our understanding on this aspect may change with the development of alternative methodologies in the future. There is a need for future research in this field to better understand the complexity of biological interaction between the H2S and NO/nitrite signaling pathways.
8. H2S: A Novel Neuroprotectant for Central Nervous System Diseases Based on Its Role in Physiology
Since 1996, when H2S was firstly reported, the role of H2S has been gradually revealed by various contributions worldwide . H2S has been generally recognized as an important signaling molecule in cardiovascular and nervous systems. The physiological effects of H2S has been confirmed by understanding the therapeutic implications of H2S in central nervous system (CNS) related diseases including neurodegenerative diseases, diabetes, and cancer, among others. In the CNS, H2S ameliorates ischemic injuries but leads to the aggravation of stroke. H2S concentration enhancement could induce cerebral infarct, while CBS or CSE inhibitors can reverse this effect on the brain. The role of H2S in neuron protection has been shown in glutamate-induced death with enhancement of cysteine and γ-glutamylcysteine concentrations, which leads to increasing concentrations of GSH [83–86].
Parkinson’s disease (PD) is a common neurodegenerative disease with various manifestations, among which is cognitive deficiency, namely, dementia, which is characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN). In a PD rat model induced by 6-hydroxydopamine (6-OHDA), the endogenous H2S level significantly decreased in the SN. However, H2S treatment can specifically inhibit accumulation of proinflammatory factors in the striatum and 6-OHDA-evoked NADPH oxidase activation, oxygen consumption, and microglial activation in the SN . Dementia is usually ascribed to changes in the nucleus basalis of Meynert and the cerebral cortex . H2S has also been suggested to attenuate vascular dementia injury via inhibition of apoptosis by regulating Bcl-2 and Bax expressions .
Alzheimer’s disease (AD) is the most common form of dementia, which is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid beta peptides (A-beta) . As mentioned above, endogenous H2S is predominantly produced in the brain from cysteine by CBS. In the brains of AD patients, lower levels of H2S are a strong risk factor for the development of AD [91, 92]. Localized increases in H2S could delay aggravation and exacerbation of symptoms in patients with AD [85, 93, 94]. In addition, patients with Down syndrome overproduce H2S due to high level of the urinary excretion of thiosulfate, suggesting a positive relationship between H2S concentration and the aggravation of this disease [94–96]. Accordingly, it has been demonstrated that H2S has protective effects against A-beta-induced cell injury by inhibiting inflammation, promoting cell growth, and preserving mitochondrial function . Moreover, H2S can protect neurons from oxidative stress, which is responsible for neuronal damage and degeneration in AD. H2S protects neurons against glutamate-mediated oxidative stress by enhancing the activities of γ-GCS and cystine transport, which results in increasing glutathione levels . Neurotoxicity of elevated Hcy is associated with inhibition of endogenous H2S generation. It has been suggested that H2S could reduce neurotoxicity induced by Hcy and that enhancement of H2S synthesis may be a useful therapeutic strategy against Hcy-induced AD . These lines of evidences suggest that H2S is a promising therapeutic target for treating neurodegenerative diseases.
9. Hypothesis and Theoretical Aspects Fundamental to This Hypothesis
At present, the mainstay treatment of brain injury after SAH is neurocritical care management aimed at reducing secondary brain injury, oral nimodipine, hemodynamic therapy, statin/magnesium/nicardipine therapy, cerebrospinal fluid (CSF) drainage, and endovascular techniques to improve cerebral vasospasm. Most of these treatments are aimed at one or two physiological and pathological mechanisms of brain injury after SAH. Then a therapy or therapies focused on multiple mechanisms may prevent the brain injury and improve the long-term outcome of SAH better. In fact, the possible roles and target of endogenous H2S in pathophysiological regulation of SAH have not been investigated. In light of the multiple physiologic roles and beneficial effects of H2S in mammalian tissue mentioned above, our hypothesis is that H2S might act as an effective agent which might provide a novel approach to the treatment of brain injury after SAH. This hypothesis is based on the following facts: it is suggested that vascular contractility is regulated by endogenous and exogenous H2S at physiologically relevant concentrations . Furthermore, some studies reported that vasorelaxation response elicited by H2S was greater in small mesenteric arteries as compared to that in larger vascular tissues such as aorta . H2S is an endogenous substance that is also produced, reaching an endogenous level of 50–160 μM. Cerebral vascular smooth muscle cells would be exposed to significant amounts of H2S [58, 101]. Previous study indicated that exogenous H2S, generated as sodium sulfide, could limit the inflammatory response to acute myocardial I/R injury in an animal model .
It has been known that the mechanism underlying the brain injury after SAH is interlaced with multiple causative and/or pathogenic factors, including free radicals reactions, inflammatory processes, apoptosis, an imbalance between vasoconstrictor and vasodilator substances (endothelium derived substances, NO, endothelin, arachidonic acid metabolites, etc.), an upheaval of factors which regulate vascular tone, and endothelial proliferation . As mentioned above, autophagy could participate in the pathogenesis of brain injury induced by SAH, which will provide novel ideas for pursuing therapeutic agents for SAH-induced brain injury. The success of these current therapies in reducing incidence of cerebral vasospasm without reduction in brain injury and improved quality of life indicates that treating vasospasm alone may not achieve favorable result. Therefore, therapies against SAH designed to direct towards inhibiting brain injury may prove more beneficial in preventing neurological deterioration.
In light of a wide range of physiological roles of H2S as mentioned above, it produces physiological and pathological functions in many organs and systems. Previous papers have reported that H2S could protect against reperfusion injury, lethal hypoxia, and exerted anti-inflammatory and antiapoptotic activities and oxidative stress effects  as well as effect of autophagy activation. Furthermore, as an endogenous gasotransmitter and a potential treatment, H2S has distinct advantages over pharmaceutical drugs: its tissue compatibility and high blood brain barrier permeability are stronger than many other antioxidants and it is an endogenous substance. We speculate that H2S could be a potentially effective approach to the treatment of brain injury including vasospasm after SAH. With our existing knowledge about the beneficial effects of H2S, the future of H2S as a potential therapy against brain injury after SAH is deemed to be promising and exciting.
11. Looking Forward: Challenges for Translation of the Toxic Molecule H2S and Its Therapeutic Application
Investigation of the role of H2S is still in its infancy. H2S has both scientific and technological values. The latter tends to dominate because of its financial value and direct applicability. The scientific investigation of H2S is also important for the elucidation of its base fundamental roles. Certainly, problems and challenges will arise and the limitations of experimental materials will constrain further research in the field of H2S. A sustained and controlled H2S-releasing donor that functions both in vitro and in vivo has not been found yet. With an increased understanding of the various H2S mechanisms in the body, further study of H2S becomes more difficult and complicated. H2S is known as a third gaseous signaling molecule, which means that it plays the role of a messenger. The concentration of H2S has been proven to have relevance in particular diseases; for instance, it is overproduced in sepsis and found at inadequate levels in AD . Therefore, the mechanism controlling the actual concentration of H2S in certain tissues may become the ultimate problem for H2S related research. It should be emphasized that a relevant relationship does not mean a relationship of causation. By regulating the H2S concentration in particular tissues, symptoms of a specific disease can be controlled, which implies that the origin of the disease has not been addressed. That is to say, the regulation of H2S can only provide transient protection from certain diseases, such as hypertension. The challenges of the sustained and controlled release of H2S-releasing drugs were mentioned above. Another difficulty in H2S related research comes from the multiple functions of H2S, which cause a shortage of specific effects which are dose-, time-, and tissue-dependent.
The pathophysiology of cerebral vasospasm after SAH is complicated and needs to be further clarified. The role of NO in the regulation of cerebral blood flow, pathogenesis, and treatment of cerebral vasospasm and delayed ischemic neurological deficit after SAH is mostly investigated. Studies on other EDRFs such as H2S associated with cerebral vasospasm are limited and may provide potential targets for possible development of preventive and therapeutic measures on regulation of cerebral blood flow and brain injury after SAH including cerebral vasospasm. Interaction among these factors also needs to be investigated. The inflammatory response accompanying SAH may represent a crucial pathway in the pathogenesis of cerebral vasospasm and delayed ischemic neurological deficit [106, 107]. Experimental and clinical research is required to elucidate the role of EDRFs such as H2S in regulation of cerebral blood flow and cerebral vasospasm, the interventional methods for prevention and reversal of vasospasm, and protection from neurological ischemic deficits. For patients with different diseases, H2S may need to be administered as different drugs. Therefore, a focus on the general effects of H2S, such as on brain injury after SAH, is rational.
Conflict of Interests
The authors declare that there is no conflict of interests, financial or otherwise.
- J. F. Ndisang, H. E. N. Tabien, and R. Wang, “Carbon monoxide and hypertension,” Journal of Hypertension, vol. 22, no. 6, pp. 1057–1074, 2004.
- Y.-F. Li, C.-S. Xiao, and R.-T. Hui, “Calcium sulfide (CaS), a donor of hydrogen sulfide (H2S): a new antihypertensive drug?” Medical Hypotheses, vol. 73, no. 3, pp. 445–447, 2009.
- C. Szabõ, “Hydrogen sulphide and its therapeutic potential,” Nature Reviews Drug Discovery, vol. 6, no. 11, pp. 917–935, 2007.
- S. Fiorucci, E. Antonelli, E. Distrutti et al., “Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs,” Gastroenterology, vol. 129, no. 4, pp. 1210–1224, 2005.
- Y. Kimura, R. Dargusch, D. Schubert, and H. Kimura, “Hydrogen sulfide protects HT22 neuronal cells from oxidative stress,” Antioxidants and Redox Signaling, vol. 8, no. 3-4, pp. 661–670, 2006.
- C. K. Nicholson and J. W. Calvert, “Hydrogen sulfide and ischemia-reperfusion injury,” Pharmacological Research, vol. 62, no. 4, pp. 289–297, 2010.
- N. Shibuya, M. Tanaka, M. Yoshida et al., “3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain,” Antioxidants and Redox Signaling, vol. 11, no. 4, pp. 703–714, 2009.
- R. Hosoki, N. Matsuki, and H. Kimura, “The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide,” Biochemical and Biophysical Research Communications, vol. 237, no. 3, pp. 527–531, 1997.
- P. Chen, R. Poddar, E. V. Tipa et al., “Homocysteine metabolism in cardiovascular cells and tissues: implications for hyperhomocysteinemia and cardiovascular disease,” Advances in Enzyme Regulation, vol. 39, pp. 93–109, 1999.
- L. Li and P. K. Moore, “Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air?” Trends in Pharmacological Sciences, vol. 29, no. 2, pp. 84–90, 2008.
- N. L. Whitfield, E. L. Kreimier, F. C. Verdial, N. Skovgaard, and K. R. Olson, “Reappraisal of H2S/sulfide concentration in vertebrate blood and its potential significance in ischemic preconditioning and vascular signaling,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 294, no. 6, pp. R1930–R1937, 2008.
- J. Furne, A. Saeed, and M. D. Levitt, “Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 295, no. 5, pp. R1479–R1485, 2008.
- M. D. Levitt, M. S. Abdel-Rehim, and J. Furne, “Free and acid-labile hydrogen sulfide concentrations in mouse tissues: anomalously high free hydrogen sulfide in aortic tissue,” Antioxidants and Redox Signaling, vol. 15, no. 2, pp. 373–378, 2011.
- K. Abe and H. Kimura, “The possible role of hydrogen sulfide as an endogenous neuromodulator,” Journal of Neuroscience, vol. 16, no. 3, pp. 1066–1071, 1996.
- J. C. Savage and D. H. Gould, “Determination of sulfide in brain tissue and rumen fluid by ion-interaction reversed-phase high-performance liquid chromatography,” Journal of Chromatography—Biomedical Applications, vol. 526, no. 2, pp. 540–545, 1990.
- R. Wang, “The gasotransmitter role of hydrogen sulfide,” Antioxidants and Redox Signaling, vol. 5, no. 4, pp. 493–501, 2003.
- Y. Cheng, J. F. Ndisang, G. Tang, K. Cao, and R. Wang, “Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 287, no. 5, pp. H2316–H2323, 2004.
- S. Kubo, I. Doe, Y. Kurokawa, H. Nishikawa, and A. Kawabata, “Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension,” Toxicology, vol. 232, no. 1-2, pp. 138–146, 2007.
- L. Kiss, E. A. Deitch, and C. Szabó, “Hydrogen sulfide decreases adenosine triphosphate levels in aortic rings and leads to vasorelaxation via metabolic inhibition,” Life Sciences, vol. 83, no. 17-18, pp. 589–594, 2008.
- S. W. Lee, Y. Cheng, P. K. Moore, and J.-S. Bian, “Hydrogen sulphide regulates intracellular pH in vascular smooth muscle cells,” Biochemical and Biophysical Research Communications, vol. 358, pp. 1142–1147, 2007.
- J. L. Jia, Y.-H. Liu, E. S. W. Khin, and J.-S. Bian, “Vasoconstrictive effect of hydrogen sulfide involves downregulation of cAMP in vascular smooth muscle cells,” The American Journal of Physiology—Cell Physiology, vol. 295, no. 5, pp. C1261–C1270, 2008.
- L. Li, P. Rose, and P. K. Moore, “Hydrogen sulfide and cell signaling,” Annual Review of Pharmacology and Toxicology, vol. 51, pp. 169–187, 2011.
- D. Popov, “An outlook on vascular hydrogen sulphide effects, signalling, and therapeutic potential,” Archives of Physiology and Biochemistry, vol. 119, pp. 189–194, 2013.
- A. Stein and S. M. Bailey, “Redox biology of hydrogen sulfide: implications for physiology, pathophysiology, and pharmacology,” Redox Biology, vol. 1, pp. 32–39, 2013.
- P. M. Snijder, R. A. de Boer, E. M. Bos et al., “Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism,” PLoS ONE, vol. 8, Article ID e63291, 2013.
- H. Kimura, “Production and physiological effects of hydrogen sulfide,” Antioxidants & Redox Signaling, vol. 20, no. 5, pp. 783–793, 2013.
- J. T. Du, W. Li, J. Y. Yang, C. S. Tang, Q. Li, and H. F. Jin, “Hydrogen sulfide is endogenously generated in rat skeletal muscle and exerts a protective effect against oxidative stress,” Chinese Medical Journal, vol. 126, pp. 930–936, 2013.
- E. M. Bos, R. Wang, P. M. Snijder et al., “Cystathionine γ-lyase protects against renal ischemia/reperfusion by modulating oxidative stress,” Journal of the American Society of Nephrology, vol. 24, pp. 759–770, 2013.
- J. Yin, C. Tu, J. Zhao et al., “Exogenous hydrogen sulfide protects against global cerebral ischemia/reperfusion injury via its anti-oxidative, anti-inflammatory and anti-apoptotic effects in rats,” Brain Research, vol. 1491, pp. 188–196, 2013.
- J. Zhou, P. F. Wu, F. Wang, and J. G. Chen, “Targeting gaseous molecules to protect against cerebral ischaemic injury: mechanisms and prospects,” Clinical and Experimental Pharmacology and Physiology, vol. 39, pp. 566–576, 2012.
- J. Han, Z. W. Chen, and G. W. He, “Acetylcholine and sodium hydrosulfide-induced endothelium-dependent relaxation and hyperpolarization in cerebral vessels of global cerebral ischemia-reperfusion rat,” Journal of Pharmacological Sciences, vol. 121, pp. 318–326, 2013.
- R. D. Di Villa Bianca, R. Sorrentino, C. Coletta et al., “Hydrogen sulfide-induced dual vascular effect involves arachidonic acid cascade in rat mesenteric arterial bed,” Journal of Pharmacology and Experimental Therapeutics, vol. 337, no. 1, pp. 59–64, 2011.
- S. Muzaffar, N. Shukla, M. Bond et al., “Exogenous hydrogen sulfide inhibits superoxide formation, NOX-1 expression and Rac1 activity in human vascular smooth muscle cells,” Journal of Vascular Research, vol. 45, no. 6, pp. 521–528, 2008.
- M. Bucci, A. Papapetropoulos, V. Vellecco et al., “Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 10, pp. 1998–2004, 2010.
- C. C. Bauer, J. P. Boyle, K. E. Porter, and C. Peers, “Modulation of Ca2+ signalling in human vascular endothelial cells by hydrogen sulfide,” Atherosclerosis, vol. 209, no. 2, pp. 374–380, 2010.
- K. R. Olson, R. A. Dombkowski, M. J. Russell et al., “Hydrogen sulfide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation,” Journal of Experimental Biology, vol. 209, no. 20, pp. 4011–4023, 2006.
- M. Bhatia, F. L. Wong, D. Fu, H. Y. Lau, S. M. Moochhala, and P. K. Moore, “Role of hydrogen sulfide in acute pancreatitis and associated lung injury,” The FASEB Journal, vol. 19, no. 6, pp. 623–625, 2005.
- Y.-H. Liu and J.-S. Bian, “Bicarbonate-dependent effect of hydrogen sulfide on vascular contractility in rat aortic rings,” The American Journal of Physiology—Cell Physiology, vol. 299, no. 4, pp. C866–C872, 2010.
- R. M. Osipov, M. P. Robich, J. Feng et al., “Effect of hydrogen sulfide on myocardial protection in the setting of cardioplegia and cardiopulmonary bypass,” Interactive Cardiovascular and Thoracic Surgery, vol. 10, no. 4, pp. 506–512, 2010.
- R. M. Pluta, J. Hansen-Schwartz, J. Dreier et al., “Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought,” Neurological Research, vol. 31, no. 2, pp. 151–158, 2009.
- A. Alaraj, F. T. Charbel, and S. Amin-Hanjani, “Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage,” Neurological Research, vol. 31, no. 6, pp. 651–659, 2009.
- V. Friedrich, R. Flores, A. Muller, and F. A. Sehba, “Escape of intraluminal platelets into brain parenchyma after subarachnoid hemorrhage,” Neuroscience, vol. 165, no. 3, pp. 968–975, 2010.
- F. A. Sehba, R. M. Pluta, and J. H. Zhang, “Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury,” Molecular Neurobiology, vol. 43, no. 1, pp. 27–40, 2011.
- A. Spallone, M. Acqui, F. S. Pastore, and B. Guidetti, “Relationship between leukocytosis and ischemic complications following aneurysmal subarachnoid hemorrhage,” Surgical Neurology, vol. 27, no. 3, pp. 253–258, 1987.
- F. A. Sehba and J. B. Bederson, “Nitric oxide in early brain injury after subarachnoid hemorrhage,” Acta neurochirurgica. Supplement, vol. 110, no. 1, pp. 99–103, 2011.
- M. D. I. Vergouwen, D. Ilodigwe, and R. L. MacDonald, “Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects,” Stroke, vol. 42, no. 4, pp. 924–929, 2011.
- B. Bosche, R. Graf, R.-I. Ernestus et al., “Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex,” Annals of Neurology, vol. 67, no. 5, pp. 607–617, 2010.
- J. P. Dreier, S. Major, A. Manning et al., “Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage,” Brain, vol. 132, no. 7, pp. 1866–1881, 2009.
- G. Pradilla, K. L. Chaichana, S. Hoang, J. Huang, and R. J. Tamargo, “Inflammation and cerebral vasospasm after subarachnoid hemorrhage,” Neurosurgery Clinics of North America, vol. 21, no. 2, pp. 365–379, 2010.
- D. Glick, S. Barth, and K. F. Macleod, “Autophagy: cellular and molecular mechanisms,” Journal of Pathology, vol. 221, no. 1, pp. 3–12, 2010.
- Z. Wang, X.-Y. Shi, J. Yin, G. Zuo, J. Zhang, and G. Chen, “Role of autophagy in early brain injury after experimental subarachnoid hemorrhage,” Journal of Molecular Neuroscience, vol. 46, no. 1, pp. 192–202, 2012.
- C. Liu, Y. Gao, J. Barrett, and B. Hu, “Autophagy and protein aggregation after brain ischemia,” Journal of Neurochemistry, vol. 115, no. 1, pp. 68–78, 2010.
- Y. B. Zhang, S. X. Li, X. P. Chen et al., “Autophagy is activated andmight protect neurons fromdegeneration after traumatic brain injury,” Neuroscience Bulletin, vol. 24, pp. 143–149, 2008.
- F. Wagner, P. Asfar, E. Calzia, P. Radermacher, and C. Szabó, “Bench-to-bedside review: hydrogen sulfide–the third gaseous transmitter: applications for critical care,” Critical Care, vol. 13, no. 3, p. 213, 2009.
- D. Mancardi, C. Penna, A. Merlino, P. Del Soldato, D. A. Wink, and P. Pagliaro, “Physiological and pharmacological features of the novel gasotransmitter: hydrogen sulfide,” Biochimica et Biophysica Acta, vol. 1787, no. 7, pp. 864–872, 2009.
- J. E. Dominy and M. H. Stipanuk, “New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant,” Nutrition Reviews, vol. 62, no. 9, pp. 348–353, 2004.
- W. Zhao and R. Wang, “H2S-induced vasorelaxation and underlying cellular and molecular mechanisms,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 283, no. 2, pp. H474–H480, 2002.
- G. Yang, L. Wu, B. Jiang et al., “H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase,” Science, vol. 322, no. 5901, pp. 587–590, 2008.
- N. Daneshtalab and J. S. Smeda, “Alterations in the modulation of cerebrovascular tone and blood flow by nitric oxide synthases in SHRsp with stroke,” Cardiovascular Research, vol. 86, no. 1, pp. 160–168, 2010.
- D. S. Bredt, “Endogenous nitric oxide synthesis: biological functions and pathophysiology,” Free Radical Research, vol. 31, no. 6, pp. 577–596, 1999.
- A. Kanu, J. Whitfield, and C. W. Leffler, “Carbon monoxide contributes to hypotension-induced cerebrovascular vasodilation in piglets,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 291, no. 5, pp. H2409–H2414, 2006.
- C. Zoccali, C. Catalano, and S. Rastelli, “Blood pressure control: hydrogen sulfide, a new gasotransmitter, takes stage,” Nephrology Dialysis Transplantation, vol. 24, no. 5, pp. 1394–1396, 2009.
- A. Fago, F. B. Jensen, B. Tota et al., “Integrating nitric oxide, nitrite and hydrogen sulfide signaling in the physiological adaptations to hypoxia: a comparative approach,” Comparative Biochemistry and Physiology—A Molecular and Integrative Physiology, vol. 162, no. 1, pp. 1–6, 2012.
- S. Moncada, R. M. J. Palmer, and E. A. Higgs, “Nitric oxide: physiology, pathophysiology, and pharmacology,” Pharmacological Reviews, vol. 43, no. 2, pp. 109–142, 1991.
- F. Plane, K. E. Wiley, J. Y. Jeremy, R. A. Cohen, and C. J. Garland, “Evidence that different mechanisms underlie smooth muscle relaxation to nitric oxide and nitric oxide donors in the rabbit isolated carotid artery,” British Journal of Pharmacology, vol. 123, no. 7, pp. 1351–1358, 1998.
- H. Kinoshita, T. Ishikawa, and Y. Hatano, “Role of K+ channels in augmented relaxations to sodium nitroprusside induced by mexiletine in rat aortas,” Anesthesiology, vol. 92, no. 3, pp. 813–820, 2000.
- N. Toda, K. Ayajiki, and T. Okamura, “Cerebral blood flow regulation by nitric oxide: recent advances,” Pharmacological Reviews, vol. 61, no. 1, pp. 62–97, 2009.
- W. Martin, G. M. Villani, D. Jothianandan, and R. F. Furchgott, “Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta,” Journal of Pharmacology and Experimental Therapeutics, vol. 232, no. 3, pp. 708–716, 1985.
- N. Toda and T. Okamura, “The pharmacology of nitric oxide in the peripheral nervous system of blood vessels,” Pharmacological Reviews, vol. 55, no. 2, pp. 271–324, 2003.
- C. Iadecola, F. Zhang, R. Casey, M. Nagayama, and M. Elizabeth Ross, “Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene,” Journal of Neuroscience, vol. 17, no. 23, pp. 9157–9164, 1997.
- A. K. Vellimana, E. Milner, T. D. Azad et al., “Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm,” Stroke, vol. 42, no. 3, pp. 776–782, 2011.
- R. M. Pluta, “Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH,” Neurological Research, vol. 28, no. 7, pp. 730–737, 2006.
- B.-L. Sun, S.-M. Zhang, Z.-L. Xia et al., “L-arginine improves cerebral blood perfusion and vasomotion of microvessels following subarachnoid hemorrhage in rats,” Clinical Hemorheology and Microcirculation, vol. 29, no. 3-4, pp. 391–400, 2003.
- Y. Ito, E. Isotani, Y. Mizuno, H. Azuma, and K. Hirakawa, “Effective improvement of the cerebral vasospasm after subarachnoid hemorrhage with low-dose nitroglycerin,” Journal of Cardiovascular Pharmacology, vol. 35, no. 1, pp. 45–50, 2000.
- K. Cosby, K. S. Partovi, J. H. Crawford et al., “Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation,” Nature Medicine, vol. 9, no. 12, pp. 1498–1505, 2003.
- R. M. Pluta, A. Dejam, G. Grimes, M. T. Gladwin, and E. H. Oldfield, “Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage,” Journal of the American Medical Association, vol. 293, no. 12, pp. 1477–1484, 2005.
- R. A. Dombkowski, M. J. Russell, A. A. Schulman, M. M. Doellman, and K. R. Olson, “Vertebrate phylogeny of hydrogen sulfide vasoactivity,” The American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 288, no. 1, pp. R243–R252, 2005.
- M. Whiteman, L. Li, I. Kostetski et al., “Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide,” Biochemical and Biophysical Research Communications, vol. 343, no. 1, pp. 303–310, 2006.
- K. R. Olson and N. L. Whitfield, “Hydrogen sulfide and oxygen sensing in the cardiovascular system,” Antioxidants and Redox Signaling, vol. 12, no. 10, pp. 1219–1234, 2010.
- L. Kram, E. Grambow, F. Mueller-Graf, H. Sorg, and B. Vollmar, “The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases,” Thrombosis Research, vol. 132, pp. e112–e117, 2013.
- A. . Moustafa and Y. Habara, “Hydrogen sulfide regulates Ca2+ homeostasis mediated by concomitantly produced nitric oxide via a novel synergistic pathway in exocrine pancreas,” Antioxidants & Redox Signaling, vol. 20, no. 5, pp. 747–758, 2013.
- Y.-H. Chen, W.-Z. Yao, B. Geng et al., “Endogenous hydrogen sulfide in patients with COPD,” Chest, vol. 128, no. 5, pp. 3205–3211, 2005.
- M. Ishigami, K. Hiraki, K. Umemura, Y. Ogasawara, K. Ishii, and H. Kimura, “A source of hydrogen sulfide and a mechanism of its release in the brain,” Antioxidants and Redox Signaling, vol. 11, no. 2, pp. 205–214, 2009.
- T. M. Cunha, D. Dal-Secco, W. A. Verri Jr. et al., “Dual role of hydrogen sulfide in mechanical inflammatory hypernociception,” European Journal of Pharmacology, vol. 590, no. 1–, pp. 127–135, 2008.
- Y.-Y. Liu, A. Sparatore, P. Del Soldato, and J.-S. Bian, “ACS84, a novel hydrogen sulfide-releasing compound, protects against amyloid β-induced cell cytotoxicity,” Neurochemistry International, vol. 58, no. 5, pp. 591–598, 2011.
- K. Qu, S. W. Lee, J. S. Bian, C.-M. Low, and P. T.-H. Wong, “Hydrogen sulfide: neurochemistry and neurobiology,” Neurochemistry International, vol. 52, no. 1, pp. 155–165, 2008.
- L.-F. Hu, M. Lu, C. X. Tiong, G. S. Dawe, G. Hu, and J.-S. Bian, “Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models,” Aging Cell, vol. 9, no. 2, pp. 135–146, 2010.
- A. D. Korczyn, “Vascular contribution to dementia in Parkinson's disease,” Neurodegenerative Diseases, vol. 7, no. 1–3, pp. 127–130, 2010.
- L.-M. Zhang, C.-X. Jiang, and D.-W. Liu, “Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats,” Neurochemical Research, vol. 34, no. 11, pp. 1984–1992, 2009.
- H. Hampel, “Amyloid-beta and cognition in aging and Alzheimer’s disease: molecular and neurophysiological mechanisms,” Journal of Alzheimer's Disease, vol. 33, pp. S79–S86, 2013.
- S. Seshadri, A. Beiser, J. Selhub et al., “Plasma homocysteine as a risk factor for dementia and Alzheimer's disease,” New England Journal of Medicine, vol. 346, no. 7, pp. 476–483, 2002.
- X.-Q. Tang, X.-T. Shen, Y.-E. Huang et al., “Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells,” Neuroscience Research, vol. 68, no. 3, pp. 241–249, 2010.
- M. Whiteman and P. G. Winyard, “Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising,” Expert Review of Clinical Pharmacology, vol. 4, no. 1, pp. 13–32, 2011.
- B. H. Tan, P. T.-H. Wong, and J.-S. Bian, “Hydrogen sulfide: a novel signaling molecule in the central nervous system,” Neurochemistry International, vol. 56, no. 1, pp. 3–10, 2010.
- M. Ufnal, M. Sikora, and M. Dudek, “Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms,” Acta Neurobiologiae Experimentalis, vol. 68, no. 3, pp. 382–388, 2008.
- M.-J. Wang, W.-J. Cai, N. Li, Y.-J. Ding, Y. Chen, and Y.-C. Zhu, “The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia,” Antioxidants and Redox Signaling, vol. 12, no. 9, pp. 1065–1077, 2010.
- Y.-Y. Liu and J.-S. Bian, “Hydrogen sulfide protects amyloid-β induced cell toxicity in microglia,” Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1189–1200, 2010.
- Y. Kimura and H. Kimura, “Hydrogen sulfide protects neurons from oxidative stress,” The FASEB Journal, vol. 18, no. 10, pp. 1165–1167, 2004.
- X.-Q. Tang, X.-T. Shen, Y.-E. Huang et al., “Inhibition of endogenous hydrogen sulfide generation is associated with homocysteine-induced neurotoxicity: role of ERK1/2 activation,” Journal of Molecular Neuroscience, vol. 45, no. 1, pp. 60–67, 2011.
- R. Wang, “Hydrogen sulfide: a new EDRF,” Kidney International, vol. 76, no. 7, pp. 700–704, 2009.
- L. Rochette and C. Vergely, “Hydrogen sulfide (H2S), an endogenous gas with odor of rotten eggs might be a cardiovascular function regulator,” Annales de Cardiologie et d'Angeiologie, vol. 57, no. 3, pp. 136–138, 2008.
- N. R. Sodha, R. T. Clements, J. Feng et al., “Hydrogen sulfide therapy attenuates the inflammatory response in a porcine model of myocardial ischemia/reperfusion injury,” Journal of Thoracic and Cardiovascular Surgery, vol. 138, no. 4, pp. 977–984, 2009.
- A. G. Kolias, J. Sen, and A. Belli, “Pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage: putative mechanisms and novel approaches,” Journal of Neuroscience Research, vol. 87, no. 1, pp. 1–11, 2009.
- Y.-P. Yu, Z.-G. Li, D.-Z. Wang, X. Zhan, and J.-H. Shao, “Hydrogen sulfide as an effective and specific novel therapy for acute carbon monoxide poisoning,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 6–9, 2011.
- Q.-H. Gong, X.-R. Shi, Z.-Y. Hong, L.-L. Pan, X.-H. Liu, and Y.-Z. Zhu, “A new hope for neurodegeneration: possible role of hydrogen sulfide,” Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 173–182, 2011.
- R. P. Ostrowski, A. R. Colohan, and J. H. Zhang, “Molecular mechanisms of early brain injury after subarachnoid hemorrhage,” Neurological Research, vol. 28, no. 4, pp. 399–414, 2006.
- A. S. Dumont, R. J. Dumont, M. M. Chow et al., “Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation,” Neurosurgery, vol. 53, no. 1, pp. 123–135, 2003.
Copyright © 2014 Yong-Peng Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.