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Therapeutic benefits of H2S in Alzheimer’s disease
Journal of Clinical Neuroscience xxx (2014) xxx–xxx
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Review
Therapeutic benefits of H2S in Alzheimer’s disease Hai-Jun Wei a,b, Xiang Li c, Xiao-Qing Tang a,b,⇑ a
Department of Physiology, Medical College, University of South China, 28 W Changsheng Road, Hengyang 421001, Hunan, PR China Institute of Neuroscience, Medical College, University of South China, Hengyang, Hunan, PR China c Department of Anesthesiology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, PR China b
a r t i c l e
i n f o
Article history: Received 31 August 2013 Accepted 1 January 2014 Available online xxxx Keywords: Alzheimer’s disease Hydrogen sulfide Antioxidation Anti-apoptosis Anti-inflammation b-amyloid
a b s t r a c t Hydrogen sulfide (H2S), an endogenously generated gaseous mediator, has been discovered to regulate a series of physiological and pathological processes in mammalian systems. In recent decades scientific interest has grown in the physiological and pathological implications of H2S, specifically its role in the central nervous system (CNS). H2S can work in the CNS as a neuromodulator to promote long-term potentiation and regulate intracellular calcium concentration and pH level in brain cells. H2S may protect the nervous system from oxidative stress, apoptosis, or degeneration. The aim of this review is to present the current understanding of H2S as a potential agent for the treatment of Alzheimer’s disease (AD). Dysregulation of H2S homeostasis is implicated in the pathological processes of AD. Substantial evidence from both in vivo and in vitro studies shows that H2S prevents neuronal impairment and attenuates cognitive dysfunction in the experimental model of AD. The mechanisms underlying the protective role of H2S in AD involve its antioxidant, anti-apoptotic, and anti-inflammatory effects. We conclude that H2S has potential therapeutic value for the treatment of AD. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction For hundreds of years, people have thought that hydrogen sulfide (H2S) is just a toxic gas with the smell of rotten eggs. However, recent studies have demonstrated that H2S regulates a series of physiological and pathological processes in mammals [1]. H2S is regarded as the third most abundant endogenous signaling gasotransmitter, following nitric oxide (NO) and carbon monoxide [1,2]. H2S is primarily generated from L-cysteine and homocysteine (Hcy) by two enzymes: cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE). CBS is mainly expressed in the central nervous system (CNS), while CSE is primarily expressed in the cardiovascular system [1,3,4]. Recently, it has been reported that the combined action of 3-mercaptopyruvate sulfurtransferase (3MST) and cysteine aminotransferase produce H2S from cysteine in brain [5]. The physiological functions of H2S in the CNS were first found in 1996 by Abe and Kimura [6]. They demonstrated that H2S selectively improves N-methyl-D-aspartate receptor mediated function and is beneficial for the induction of long-term potentiation [6]. Subsequently, more and more physiological and pathological functions of H2S in the CNS were discovered, and the neurobiology, neurochemistry, neurophysiology, neuropathology, and signaling properties of H2S have been focused on in a number of outstanding articles [1–4,7]. This article provides an overview of the therapeutic ⇑ Corresponding author. Tel.: +86 734 828 1389; fax: +86 734 828 1673. E-mail address: [email protected] (X.-Q. Tang).
benefits of H2S in Alzheimer’s disease (AD) and the underlying cellular and molecular mechanisms implicated.
2. Disturbance of endogenous H2S generation in AD AD is a progressive age-dependent neurodegenerative disease, affecting the cortex and hippocampus, and ultimately leading to cognitive dysfunction [8]. Neurofibrillary tangles and b-amyloid (Ab) plaques in the cortex and hippocampus are the hallmarks of AD [9,10]. In both familial and sporadic AD, Ab peptides, generated from amyloid precursor protein (APP) by b and c-secretases, are considered to be pivotal factors in the pathology of the disease [11]. Increasing evidence has demonstrated that H2S is relevant to AD pathogenesis. CBS is highly expressed in the brain and thus is believed to be the primary physiologic source of H2S in the CNS [1,3,4]. In 1996, Morrison et al. first discovered that brain levels of S-adenosylmethionine, a CBS activator, are significantly decreased in AD patients [12]. It has been reported that the total serum level of Hcy is accumulative and increased in AD patients as the result of the disruption of the transsulfuration pathway linking Hcy and glutathione (GSH), which is mediated by CBS and CSE [13]. The dysfunction of CBS in the transsulfuration pathway may lead to a decrease in H2S production in AD [14]. Moreover, our own research has shown that neurotoxicity of elevated Hcy is involved in inhibition of endogenous H2S production and
http://dx.doi.org/10.1016/j.jocn.2014.01.006 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
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down-regulation of expression and activity of CBS in PC12 cells [15]. Recently, Liu et al. reported that levels of H2S are decreased in AD patients and the change in H2S level may be related to the severity of AD [16]. Based on these findings, it is logical to suggest that the generation of endogenous H2S is disturbed in the AD brain, although more direct evidence is currently lacking. 3. Protective actions of H2S in AD Increasing evidence from both in vivo and in vitro studies suggest that H2S has potential therapeutic value for treatment of AD. 3.1. H2S protects against AD-related oxidative stress factors It has been demonstrated that the level of hypochlorous acid (HOCl) is elevated in the temporal and frontal cortex of AD brains [17,18]. Whiteman et al. reported that sodium hydrosulfide (NaHS, the donor of H2S) significantly inhibited HOCl-induced cytotoxicity, intracellular protein oxidation, and lipid peroxidation in SHSY5Y cells (human neuroblastoma cells) [19], which implies the potential neuroprotective effect of H2S against the pathological progression of AD. Our data reveal that NaHS ameliorates Ab-induced damage in PC12 cells through reducing the loss of mitochondrial membrane potential (Dwm) and attenuating the increase of intracellular reactive oxygen species (ROS) [20]. Moreover, in cultured PC12 cells, recent research on the relationship of H2S to b-site APP cleaving enzyme 1 (BACE-1) expression and Ab secretion discovered that H2S reduces BACE-1 mRNA and protein levels and Ab1–42 release [21]. Oxidative damage to lipids and proteins is an important early event in the pathogenesis of neurodegenerative diseases and malondialdehyde (MDA) and carbonyl proteins are regarded as useful oxidative markers in AD [22]. It has been demonstrated that H2S reduces MDA levels in human umbilical vein endothelial cells exposed to hydrogen peroxide [23] and destroys lipid hydroperoxides in oxidized low-density lipoprotein [24]. Schreier et al. demonstrated that H2S protect neuronal cells (SH-SY5Y) from the cytotoxic lipid oxidation product 4-hydroxynonenal (HNE) [25], which is markedly increased in the brains of patients with severe AD. Based on the above, H2S has a strong antioxidant capacity to resist AD-related oxidative stress factors such as HOCl, Ab, MDA, and 4-HNE, suggesting a promising role for H2S as a novel strategy to prevent AD. 3.2. H2S resists AD by inhibiting Hcy-induced oxidative stress Homocysteine (Hcy) is a thiol-containing amino acid derived from the metabolism of methionine. Both in vitro and in vivo studies have shown that Hcy is toxic to neuronal cells [26–32] and markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative injury [30]. Furthermore, Hcy changes hippocampus plasticity and synaptic transmission resulting in learning and memory deficits [33,34]. These unfavorable neuronal effects of Hcy are believed to be caused by the auto-oxidation of Hcy, which leads to cellular oxidative stress through the formation of ROS, including the superoxide anion and hydrogen peroxide [35,36]. Additional findings demonstrated that Hcy can induce lipid peroxidation and increase MDA and super oxide anion levels in rat brains [37,38]. These studies revealed that Hcy may be a marker of oxidative stress. Elevated plasma Hcy levels, known as hyperhomocysteinemia (HHcy), cause neurological abnormalities such as mental retardation, cerebral atrophy, and seizures [39,40]. Elevated brain Hcy has been reported in AD [41]. It is now established that elevated plasma Hcy is a strong, independent risk factor of AD [13,14,42–44]. Therefore, Hcy is regarded as a novel therapeutic
target for AD [14]. It has been shown that H2S partly prevents HHcy-associated renal damage through its antioxidant properties [45] and protects against Hcy-induced cytotoxicity and oxidative stress in vascular smooth muscle cells [46]. Interestingly, our studies showed that H2S protects PC12 cells against the increase in intracellular ROS induced by Hcy [47]. Additionally, we recently showed that ACS6, a novel H2S-releasing sildenafil, results in prevention of Hcy-caused neurotoxicity and overproduction of ROS by upregulating paraoxonase-1 [48]. Moreover, H2S significantly attenuates Hcy-induced oxidative stress, memory deficit, and neurodegeneration in mice [49]. In summary, H2S has protective effects against Hcy-induced oxidative stress and neurotoxicity. Therefore, it is logical to assume that H2S would be beneficial in the treatment of AD by inhibiting Hcy-induced oxidative stress. 3.3. H2S protects against AD in animal models Recently, Xuan et al. reported that pretreatment with NaHS ameliorates learning and memory deficits in an Ab1–40 rat model of AD [50]. Giuliani et al. found that H2S significantly protected against learning and memory impairment in three experimental models of AD, including the rat models of AD induced by brain injection of Ab1–40 or streptozotocin, and an AD mouse model harboring human transgenes APPSwe, PS1M146V and tauP301L (3 Tg-AD mice) [51]. Gong et al. reported that NaHS notably attenuates lipopolysaccharide (LPS)-induced neuroinflammation, neuronal ultrastructure impairment and cognitive defects [52], which suggest that H2S is a potential agent for the treatment of neuroinflammation-related diseases, such as AD. Taken together, these findings from in vivo studies show the potential therapeutic value of H2S for AD and lay the foundation for exploring a new H2S-modulated agent for preventing or delaying the development of AD. 3.4. H2S donors antagonize AD H2S can be produce non-enzymatically from polysulfides in garlic [53]. It is reported that garlic compounds containing S-allyl cysteine (SAC) attenuate Ab-induced apoptosis [54] and decrease Ab fibril production and defibrillate Ab preformed fibrils in vitro [55]. Moreover, garlic extracts have been demonstrated to exert anti-amyloidogenic, anti-inflammatory and anti-tangle effects in AD transgenic models harboring the Swedish double mutation [56]. S-propargyl-cysteine (SPRC), which is an SAC structural analog that can be used to adjust endogenous H2S levels [7,9], attenuates cognitive damage induced by LPS in rats [57]. Moreover, SPRC may inhibit Ab25–35-induced cognitive dysfunction and neuronal ultrastructure impairment in rats [58]. These findings indicate that appropriate treatments with H2S-modulating agents, such as SAC and SPRC, represent a potential approach to treat AD. 4. Mechanisms of the protective effects of H2S in AD
4.1. Antioxidation Oxidative stress has significant implication in the pathogenesis of AD. Studies have shown that NaHS is capable of improving reducing activity in neurons and protects them against oxidative impairment induced by hydrogen peroxide, glutamate, and hypochlorous acid, mainly through increasing GSH levels but not directly working as an antioxidant [19,59]. Increased levels of GSH are brought about by enhancing the transporters of cystine/L-cysteine, the redistribution of GSH to mitochondria, the activity of c-glutamylcysteine synthetase in neurons and the uptake of glutamate in astrocytes [59–61]. H2S also can protect an immortalized mouse hippocampal
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
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cell line (HT22) against oxidative glutamate toxicity through activation of adenosine triphosphate-dependent potassium and Cl channels, in addition to increasing the levels of GSH [62]. It has been demonstrated that H2S could be a vital protective element against carbonyl stress by inactivating/modulating the role of highly reactive a, b-unsaturated aldehydes such as HNE in the brain [25]. Moreover, it has been reported that anethole trithione hydroxide, a slow releasing H2S donor, is more efficacious in protecting retinal ganglion cells (RGC-5) against the toxic effects of glutamate in combination with buthionine sulfoxime, through scavenging ROS and stimulating GSH and glutathione-S-transferase [63]. Taken together, these studies effectively demonstrate the powerful antioxidative function of H2S for treatment of AD. 4.2. Anti-apoptosis There is increasing proof that H2S has anti-apoptotic actions. NaHS protects PC12 cells from apoptosis caused by Ab and Hcy [20,47]. Accumulation of formaldehyde is involved in the pathogenesis of AD [64–66]. Our data have demonstrated that NaHS significantly protects PC12 cells against formaldehyde-induced cytotoxicity and apoptosis [67]. Furthermore, our studies indicate that ACS6, an H2S-donating derivative of sildenafil, protects PC12 cells against Hcy-induced cytotoxicity and apoptosis [68]. Additionally, H2S can inhibit the damage of hippocampus neurons in vascular dementia through its anti-apoptotic action [69]. Based on these studies, we can conclude that the anti-apoptotic effect of H2S plays an important role in its protection against AD. Most data indicate that the anti-apoptotic effects of H2S are mainly due to the preservation of mitochondrial function. It is reported that NaHS significantly protects PC12 cells against formaldehyde-induced cytotoxicity and apoptosis through attenuating ROS accumulation, upregulating B cell lymphoma 2 (Bcl-2) levels, and down-regulating Bax expression [67]. ACS6 has been shown to protect PC12 cells against Hcy-induced cytotoxicity and apoptosis by inhibiting both loss of Dwm and accumulation of ROS, as well as modulating the expression of Bcl-2 [68]. 4.3. Anti-inflammation Neuroinflammation has been considered a key factor in the pathogenesis of neurodegeneration, including that seen in AD [70]. Thus, it is an effective therapeutic strategy to delay or stop the progress of neurodegenerative diseases by inhibiting the neurological inflammatory process. The data from Hu et al. demonstrate that NaHS reduces LPS-exerted production and release of NO and tumor necrosis factor (TNF)-a in primary cultured microglia and astrocytes and mouse immortalized BV2 microglial cells, suggesting that H2S has important implications in the treatment of neuroinflammationrelated diseases [71]. This anti-inflammatory effect of H2S in LPSstimulated microglia and astrocytes is due to inhibition of inducible nitric oxide synthase (iNOS) and p38 mitogen-activated protein kinase (MAPK) signaling pathways [71]. Lee et al. reported that inflammatory activation of microglia and astrocytes caused induction of nuclear factor-jB (NF-jB), release of the inflammatory mediators TNF-a, interleukin (IL)-6 and nitrite ions, and down-regulation of H2S synthesis; however, these effects are partially reversed by pretreatment of cells with NaHS, indicating that H2S is an endogenous anti-inflammatory and neuroprotective agent [72]. Interestingly, NaHS has been shown to significantly ameliorate Ab1–40-induced overexpression in IL-1b and TNF-a as well as the extensive astrogliosis and microgliosis in the hippocampus via the inhibition of p38 MAPK and p65 NF-jB activity [50]. H2S may also have indirect neuroprotective effects through its anti-inflammatory effect by inhibiting proinflammatory factors released during microglial activation and thereby reducing the inflammation
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associated neurotoxicity. It has been shown that the conditioned media from rotenone-treated microglia notably reduces the cell viability of SH-SY5Y neuronal cells; however, this action is weakened by the cotreatment of neuronal cells with NaHS and rotenone [73]. Lan and coworkers demonstrated that H2S produces an antiinflammatory effect in chemical hypoxia-stimulated PC12 cells through inhibiting the ROS-activated p38MAPK-iNOS pathway [74]. In addition, NaHS has been shown to attenuate LPS-induced cognitive defects and neuronal ultrastructure impairment in rats by repressing TNF-a and TNF receptor 1 production, as well as suppressing LPS-induced IjB-a degradation, and afterward NF-jB activation [52]. Taken together, these observations provide strong evidence for the powerful anti-inflammatory effect of H2S in the progress of neurodegenerative diseases, including AD. All the aforementioned findings also clearly indicate that suppressing the nuclear p38 MAPK and NF-jB signaling pathway is regarded as a possible mechanism underlying the anti-inflammatory role of H2S. Lee et al. demonstrated that pretreatment with three H2Sreleasing compounds, anethole trithione hydroxide, S-diclofenac, and S-aspirin, reduces the release of the proinflammatory mediators TNF-a, IL-6, and NO induced by microglial and astrocytic activation [73]. Moreover, studies have demonstrated that SPRC inhibits LPS and Ab25–35 induced cognitive dysfunction and neuronal ultrastructure impairment by inhibiting of TNF-a and TNF receptor 1 production, and IjB-a degradation and NF-jB p65 activation [57,58]. Therefore, H2S-releasing compounds have significant anti-inflammatory properties and may be candidates for treating neurodegenerative disorders that have a prominent neuroinflammatory component, such as AD [73]. 5. Conclusions H2S, considered the third most abundant gasotransmitter, following NO and carbon monoxide, is attracting widespread attention because it has a variety of physiological and pathological roles across multiple body systems [1,3,75]. The actions of H2S described in this review highlight its neuroprotective effects in AD. Sufficient evidence has accumulated in support of H2S acting as a potential therapeutic target for the treatment of AD. The mechanisms underlying the neuroprotective effect of H2S on AD involve its antioxidative, anti-apoptotic and anti-inflammatory effects. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by National Natural Science Foundation of China (81071005, 81202518, 81200985, 81200986, and 81371485), Natural Science Foundation of Hunan Province, China (11JJ3117, 12JJ9032) and the construct program of the key discipline in the Hunan province. References [1] Hu LF, Lu M, Hon Wong PT, et al. Hydrogen sulfide: neurophysiology and neuropathology. Antioxid Redox Signal 2011;15:405–19. [2] Qu K, Lee SW, Bian JS, et al. Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 2008;52:155–65. [3] Gadalla MM, Snyder SH. Hydrogen sulfide as a gasotransmitter. J Neurochem 2010;113:14–26. [4] Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids 2011;41:113–21. [5] Shibuya N, Tanaka M, Yoshida M, et al. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 2009;11:703–14.
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[6] Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 1996;16:1066–71. [7] Tan BH, Wong PT, Bian JS. Hydrogen sulfide: a novel signaling molecule in the central nervous system. Neurochem Int 2010;56:3–10. [8] Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci 2004;11:456–67. [9] Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005;120:545–55. [10] Samandouras G, Teddy PJ, Cadoux-Hudson T, et al. Amyloid in neurosurgical and neurological practice. J Clin Neurosci 2006;13:159–67. [11] Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 2010;13:812–8. [12] Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 1996;67:1328–31. [13] Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449–55. [14] Dwyer BE, Raina AK, Perry G, et al. Homocysteine and Alzheimer’s disease: a modifiable risk? Free Radic Biol Med 2004;36:1471–5. [15] Tang XQ, Shen XT, Huang YE, et al. Inhibition of endogenous hydrogen sulfide generation is associated with homocysteine-induced neurotoxicity: role of ERK1/2 activation. J Mol Neurosci 2011;45:60–7. [16] Liu XQ, Lio XQ, Jiang P, et al. Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof. Zhonghua Yi Xue Za Zhi 2008;88:2246–9. [17] Reynolds WF, Rhees J, Maciejewski D, et al. Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol 1999;155:31–41. [18] Green PS, Mendez AJ, Jacob JS, et al. Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease. J Neurochem 2004;90:724–33. [19] Whiteman M, Cheung NS, Zhu YZ, et al. Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun 2005;326:794–8. [20] Tang XQ, Yang CT, Chen J, et al. Effect of hydrogen sulphide on beta-amyloidinduced damage in PC12 cells. Clin Exp Pharmacol Physiol 2008;35:180–6. [21] Zhang H, Gao Y, Zhao F, et al. Hydrogen sulfide reduces mRNA and protein levels of b-site amyloid precursor protein cleaving enzyme 1 in PC12 cells. Neurochem Int 2011;58:169–75. [22] Greilberger J, Koidl C, Greilberger M, et al. Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer’s disease. Free Radic Res 2008;42:633–8. [23] Wen YD, Wang H, Kho SH, et al. Hydrogen sulfide protects HUVECs against hydrogen peroxide induced mitochondrial dysfunction and oxidative stress. PLoS One 2013;8:e53147. [24] Muellner MK, Schreier SM, Laggner H, et al. Hydrogen sulfide destroys lipid hydroperoxides in oxidized LDL. Biochem J 2009;420:277–81. [25] Schreier SM, Muellner MK, Steinkellner H, et al. Hydrogen sulfide scavenges the cytotoxic lipid oxidation product 4-HNE. Neurotox Res 2010;17:249–56. [26] Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997;94:5923–8. [27] Parsons RB, Waring RH, Ramsden DB, et al. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology 1998;19:599–603. [28] Kim JP, Koh JY, Choi DW. L-Homocysteate is a potent neurotoxin on cultured cortical neurons. Brain Res 1987;437:103–10. [29] Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920–6. [30] Ho PI, Ortiz D, Rogers E, et al. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res 2002;70:694–702. [31] Baydas G, Reiter RJ, Akbulut M, et al. Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and antiapoptotic protein levels. Neuroscience 2005;135:879–86. [32] Linnebank M, Lutz H, Jarre E, et al. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol Dis 2006;23:725–30. [33] Christie LA, Riedel G, Algaidi SA, et al. Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine. Neurosci Lett 2005;373:119–24. [34] Ataie A, Sabetkasaei M, Haghparast A, et al. Curcumin exerts neuroprotective effects against homocysteine intracerebroventricular injection-induced cognitive impairment and oxidative stress in rat brain. J Med Food 2010;13:821–6. [35] White AR, Huang X, Jobling MF, et al. Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 2001;76:1509–20. [36] Perna AF, Ingrosso D, De Santo NG. Homocysteine and oxidative stress. Amino Acids 2003;25:409–17. [37] Ataie A, Sabetkasaei M, Haghparast A, et al. An investigation of the neuroprotective effects of curcumin in a model of homocysteine – induced oxidative stress in the rat’s brain. Daru 2010;18:128–36.
[38] Ataie A, Sabetkasaei M, Haghparast A, et al. Neuroprotective effects of the polyphenolic antioxidant agent, curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat. Pharmacol Biochem Behav 2010;96:378–85. [39] Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and Bvitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med 2007;45:1590–606. [40] van den Berg M, van der Knaap MS, Boers GH, et al. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 1995;37:403–11. [41] Eto K, Asada T, Arima K, et al. Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem Biophys Res Commun 2002;293:1485–8. [42] Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr 2009;48:425–30. [43] Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346:476–83. [44] Miller JW. Homocysteine and Alzheimer’s disease. Nutr Rev 1999;57:126–9. [45] Sen U, Basu P, Abe OA, et al. Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure. Am J Physiol Renal Physiol 2009;297:F410–9. [46] Yan SK, Chang T, Wang H, et al. Effects of hydrogen sulfide on homocysteineinduced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 2006;351:485–91. [47] Tang XQ, Shen XT, Huang YE, et al. Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells. Neurosci Res 2010;68:241–9. [48] Tang XQ, Chen RQ, Dong L, et al. Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity. J Mol Neurosci 2013;50:70–7. [49] Kamat PK, Kalani A, Givvimani S, et al. Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebraladministered homocysteine in mice. Neuroscience 2013;252:302–19. [50] Xuan A, Long D, Li J, et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. J Neuroinflammation 2012;9:202. [51] Giuliani D, Ottani A, Zaffe D, et al. Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem 2013;104:82–91. [52] Gong QH, Wang Q, Pan LL, et al. Hydrogen sulfide attenuates lipopolysaccharide-induced cognitive impairment: a pro-inflammatory pathway in rats. Pharmacol Biochem Behav 2010;96:52–8. [53] Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U S A 2007;104:17977–82. [54] Peng Q, Buz’Zard AR, Lau BH. Neuroprotective effect of garlic compounds in amyloid-beta peptide-induced apoptosis in vitro. Med Sci Monit 2002;8:BR328–37. [55] Gupta VB, Rao KS. Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer’s beta-amyloid fibrils in vitro. Neurosci Lett 2007;429:75–80. [56] Chauhan NB. Effect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576. J Ethnopharmacol 2006;108:385–94. [57] Gong QH, Wang Q, Pan LL, et al. S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NFkappaB pathway in rats. Brain Behav Immun 2011;25:110–9. [58] Gong QH, Pan LL, Liu XH, et al. S-propargyl-cysteine (ZYZ-802), a sulphurcontaining amino acid, attenuates beta-amyloid-induced cognitive deficits and pro-inflammatory response: involvement of ERK1/2 and NF-kappaB pathway in rats. Amino Acids 2011;40:601–10. [59] Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J 2004;18:1165–7. [60] Kimura Y, Goto Y, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 2010;12:1–13. [61] Lu M, Hu LF, Hu G, et al. Hydrogen sulfide protects astrocytes against H(2)O(2)induced neural injury via enhancing glutamate uptake. Free Radic Biol Med 2008;45:1705–13. [62] Kimura Y, Dargusch R, Schubert D, et al. Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid Redox Signal 2006;8:661–70. [63] Majid AS, Majid AM, Yin ZQ, et al. Slow regulated release of H2S inhibits oxidative stress induced cell death by influencing certain key signaling molecules. Neurochem Res 2013;38:1375–93. [64] Yu PH. Involvement of cerebrovascular semicarbazide-sensitive amine oxidase in the pathogenesis of Alzheimer’s disease and vascular dementia. Med Hypotheses 2001;57:175–9. [65] Unzeta M, Solé M, Boada M, et al. Semicarbazide-sensitive amine oxidase (SSAO) and its possible contribution to vascular damage in Alzheimer’s disease. J Neural Transm 2007;114:857–62. [66] Jiang ZJ, Richardson JS, Yu PH. The contribution of cerebral vascular semicarbazide-sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol Appl Neurobiol 2008;34:194–204. [67] Tang XQ, Ren YK, Zhou CF, et al. Hydrogen sulfide prevents formaldehydeinduced neurotoxicity to PC12 cells by attenuation of mitochondrial dysfunction and pro-apoptotic potential. Neurochem Int 2012;61:16–24.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
H.-J. Wei et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx [68] Tang XQ, Chen RQ, Ren YK, et al. ACS6, a hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function. Med Gas Res 2011;1:20. [69] Zhang LM, Jiang CX, Liu DW. Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochem Res 2009;34:1984–92. [70] Amor S, Puentes F, Baker D, et al. Inflammation in neurodegenerative diseases. Immunology 2010;129:154–69. [71] Hu LF, Wong PT, Moore PK, et al. Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogenactivated protein kinase in microglia. J Neurochem 2007;100:1121–8.
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[72] Lee M, Schwab C, Yu S, et al. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol Aging 2009;30:1523–34. [73] Lee M, Sparatore A, Del Soldato P, et al. Hydrogen sulfide-releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation. Glia 2010;58:103–13. [74] Lan A, Xu W, Zhang H, et al. Inhibition of ROS-activated p38MAPK pathway is involved in the protective effect of H2S against chemical hypoxia-induced inflammation in PC12 cells. Neurochem Res 2013;38:1454–66. [75] Wang R. The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal 2003;5:493–501.
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Review
Therapeutic benefits of H2S in Alzheimer’s disease Hai-Jun Wei a,b, Xiang Li c, Xiao-Qing Tang a,b,⇑ a
Department of Physiology, Medical College, University of South China, 28 W Changsheng Road, Hengyang 421001, Hunan, PR China Institute of Neuroscience, Medical College, University of South China, Hengyang, Hunan, PR China c Department of Anesthesiology, The First Affiliated Hospital, University of South China, Hengyang, Hunan, PR China b
a r t i c l e
i n f o
Article history: Received 31 August 2013 Accepted 1 January 2014 Available online xxxx Keywords: Alzheimer’s disease Hydrogen sulfide Antioxidation Anti-apoptosis Anti-inflammation b-amyloid
a b s t r a c t Hydrogen sulfide (H2S), an endogenously generated gaseous mediator, has been discovered to regulate a series of physiological and pathological processes in mammalian systems. In recent decades scientific interest has grown in the physiological and pathological implications of H2S, specifically its role in the central nervous system (CNS). H2S can work in the CNS as a neuromodulator to promote long-term potentiation and regulate intracellular calcium concentration and pH level in brain cells. H2S may protect the nervous system from oxidative stress, apoptosis, or degeneration. The aim of this review is to present the current understanding of H2S as a potential agent for the treatment of Alzheimer’s disease (AD). Dysregulation of H2S homeostasis is implicated in the pathological processes of AD. Substantial evidence from both in vivo and in vitro studies shows that H2S prevents neuronal impairment and attenuates cognitive dysfunction in the experimental model of AD. The mechanisms underlying the protective role of H2S in AD involve its antioxidant, anti-apoptotic, and anti-inflammatory effects. We conclude that H2S has potential therapeutic value for the treatment of AD. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction For hundreds of years, people have thought that hydrogen sulfide (H2S) is just a toxic gas with the smell of rotten eggs. However, recent studies have demonstrated that H2S regulates a series of physiological and pathological processes in mammals [1]. H2S is regarded as the third most abundant endogenous signaling gasotransmitter, following nitric oxide (NO) and carbon monoxide [1,2]. H2S is primarily generated from L-cysteine and homocysteine (Hcy) by two enzymes: cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE). CBS is mainly expressed in the central nervous system (CNS), while CSE is primarily expressed in the cardiovascular system [1,3,4]. Recently, it has been reported that the combined action of 3-mercaptopyruvate sulfurtransferase (3MST) and cysteine aminotransferase produce H2S from cysteine in brain [5]. The physiological functions of H2S in the CNS were first found in 1996 by Abe and Kimura [6]. They demonstrated that H2S selectively improves N-methyl-D-aspartate receptor mediated function and is beneficial for the induction of long-term potentiation [6]. Subsequently, more and more physiological and pathological functions of H2S in the CNS were discovered, and the neurobiology, neurochemistry, neurophysiology, neuropathology, and signaling properties of H2S have been focused on in a number of outstanding articles [1–4,7]. This article provides an overview of the therapeutic ⇑ Corresponding author. Tel.: +86 734 828 1389; fax: +86 734 828 1673. E-mail address: [email protected] (X.-Q. Tang).
benefits of H2S in Alzheimer’s disease (AD) and the underlying cellular and molecular mechanisms implicated.
2. Disturbance of endogenous H2S generation in AD AD is a progressive age-dependent neurodegenerative disease, affecting the cortex and hippocampus, and ultimately leading to cognitive dysfunction [8]. Neurofibrillary tangles and b-amyloid (Ab) plaques in the cortex and hippocampus are the hallmarks of AD [9,10]. In both familial and sporadic AD, Ab peptides, generated from amyloid precursor protein (APP) by b and c-secretases, are considered to be pivotal factors in the pathology of the disease [11]. Increasing evidence has demonstrated that H2S is relevant to AD pathogenesis. CBS is highly expressed in the brain and thus is believed to be the primary physiologic source of H2S in the CNS [1,3,4]. In 1996, Morrison et al. first discovered that brain levels of S-adenosylmethionine, a CBS activator, are significantly decreased in AD patients [12]. It has been reported that the total serum level of Hcy is accumulative and increased in AD patients as the result of the disruption of the transsulfuration pathway linking Hcy and glutathione (GSH), which is mediated by CBS and CSE [13]. The dysfunction of CBS in the transsulfuration pathway may lead to a decrease in H2S production in AD [14]. Moreover, our own research has shown that neurotoxicity of elevated Hcy is involved in inhibition of endogenous H2S production and
http://dx.doi.org/10.1016/j.jocn.2014.01.006 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
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down-regulation of expression and activity of CBS in PC12 cells [15]. Recently, Liu et al. reported that levels of H2S are decreased in AD patients and the change in H2S level may be related to the severity of AD [16]. Based on these findings, it is logical to suggest that the generation of endogenous H2S is disturbed in the AD brain, although more direct evidence is currently lacking. 3. Protective actions of H2S in AD Increasing evidence from both in vivo and in vitro studies suggest that H2S has potential therapeutic value for treatment of AD. 3.1. H2S protects against AD-related oxidative stress factors It has been demonstrated that the level of hypochlorous acid (HOCl) is elevated in the temporal and frontal cortex of AD brains [17,18]. Whiteman et al. reported that sodium hydrosulfide (NaHS, the donor of H2S) significantly inhibited HOCl-induced cytotoxicity, intracellular protein oxidation, and lipid peroxidation in SHSY5Y cells (human neuroblastoma cells) [19], which implies the potential neuroprotective effect of H2S against the pathological progression of AD. Our data reveal that NaHS ameliorates Ab-induced damage in PC12 cells through reducing the loss of mitochondrial membrane potential (Dwm) and attenuating the increase of intracellular reactive oxygen species (ROS) [20]. Moreover, in cultured PC12 cells, recent research on the relationship of H2S to b-site APP cleaving enzyme 1 (BACE-1) expression and Ab secretion discovered that H2S reduces BACE-1 mRNA and protein levels and Ab1–42 release [21]. Oxidative damage to lipids and proteins is an important early event in the pathogenesis of neurodegenerative diseases and malondialdehyde (MDA) and carbonyl proteins are regarded as useful oxidative markers in AD [22]. It has been demonstrated that H2S reduces MDA levels in human umbilical vein endothelial cells exposed to hydrogen peroxide [23] and destroys lipid hydroperoxides in oxidized low-density lipoprotein [24]. Schreier et al. demonstrated that H2S protect neuronal cells (SH-SY5Y) from the cytotoxic lipid oxidation product 4-hydroxynonenal (HNE) [25], which is markedly increased in the brains of patients with severe AD. Based on the above, H2S has a strong antioxidant capacity to resist AD-related oxidative stress factors such as HOCl, Ab, MDA, and 4-HNE, suggesting a promising role for H2S as a novel strategy to prevent AD. 3.2. H2S resists AD by inhibiting Hcy-induced oxidative stress Homocysteine (Hcy) is a thiol-containing amino acid derived from the metabolism of methionine. Both in vitro and in vivo studies have shown that Hcy is toxic to neuronal cells [26–32] and markedly enhances the vulnerability of neuronal cells to excitotoxic and oxidative injury [30]. Furthermore, Hcy changes hippocampus plasticity and synaptic transmission resulting in learning and memory deficits [33,34]. These unfavorable neuronal effects of Hcy are believed to be caused by the auto-oxidation of Hcy, which leads to cellular oxidative stress through the formation of ROS, including the superoxide anion and hydrogen peroxide [35,36]. Additional findings demonstrated that Hcy can induce lipid peroxidation and increase MDA and super oxide anion levels in rat brains [37,38]. These studies revealed that Hcy may be a marker of oxidative stress. Elevated plasma Hcy levels, known as hyperhomocysteinemia (HHcy), cause neurological abnormalities such as mental retardation, cerebral atrophy, and seizures [39,40]. Elevated brain Hcy has been reported in AD [41]. It is now established that elevated plasma Hcy is a strong, independent risk factor of AD [13,14,42–44]. Therefore, Hcy is regarded as a novel therapeutic
target for AD [14]. It has been shown that H2S partly prevents HHcy-associated renal damage through its antioxidant properties [45] and protects against Hcy-induced cytotoxicity and oxidative stress in vascular smooth muscle cells [46]. Interestingly, our studies showed that H2S protects PC12 cells against the increase in intracellular ROS induced by Hcy [47]. Additionally, we recently showed that ACS6, a novel H2S-releasing sildenafil, results in prevention of Hcy-caused neurotoxicity and overproduction of ROS by upregulating paraoxonase-1 [48]. Moreover, H2S significantly attenuates Hcy-induced oxidative stress, memory deficit, and neurodegeneration in mice [49]. In summary, H2S has protective effects against Hcy-induced oxidative stress and neurotoxicity. Therefore, it is logical to assume that H2S would be beneficial in the treatment of AD by inhibiting Hcy-induced oxidative stress. 3.3. H2S protects against AD in animal models Recently, Xuan et al. reported that pretreatment with NaHS ameliorates learning and memory deficits in an Ab1–40 rat model of AD [50]. Giuliani et al. found that H2S significantly protected against learning and memory impairment in three experimental models of AD, including the rat models of AD induced by brain injection of Ab1–40 or streptozotocin, and an AD mouse model harboring human transgenes APPSwe, PS1M146V and tauP301L (3 Tg-AD mice) [51]. Gong et al. reported that NaHS notably attenuates lipopolysaccharide (LPS)-induced neuroinflammation, neuronal ultrastructure impairment and cognitive defects [52], which suggest that H2S is a potential agent for the treatment of neuroinflammation-related diseases, such as AD. Taken together, these findings from in vivo studies show the potential therapeutic value of H2S for AD and lay the foundation for exploring a new H2S-modulated agent for preventing or delaying the development of AD. 3.4. H2S donors antagonize AD H2S can be produce non-enzymatically from polysulfides in garlic [53]. It is reported that garlic compounds containing S-allyl cysteine (SAC) attenuate Ab-induced apoptosis [54] and decrease Ab fibril production and defibrillate Ab preformed fibrils in vitro [55]. Moreover, garlic extracts have been demonstrated to exert anti-amyloidogenic, anti-inflammatory and anti-tangle effects in AD transgenic models harboring the Swedish double mutation [56]. S-propargyl-cysteine (SPRC), which is an SAC structural analog that can be used to adjust endogenous H2S levels [7,9], attenuates cognitive damage induced by LPS in rats [57]. Moreover, SPRC may inhibit Ab25–35-induced cognitive dysfunction and neuronal ultrastructure impairment in rats [58]. These findings indicate that appropriate treatments with H2S-modulating agents, such as SAC and SPRC, represent a potential approach to treat AD. 4. Mechanisms of the protective effects of H2S in AD
4.1. Antioxidation Oxidative stress has significant implication in the pathogenesis of AD. Studies have shown that NaHS is capable of improving reducing activity in neurons and protects them against oxidative impairment induced by hydrogen peroxide, glutamate, and hypochlorous acid, mainly through increasing GSH levels but not directly working as an antioxidant [19,59]. Increased levels of GSH are brought about by enhancing the transporters of cystine/L-cysteine, the redistribution of GSH to mitochondria, the activity of c-glutamylcysteine synthetase in neurons and the uptake of glutamate in astrocytes [59–61]. H2S also can protect an immortalized mouse hippocampal
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cell line (HT22) against oxidative glutamate toxicity through activation of adenosine triphosphate-dependent potassium and Cl channels, in addition to increasing the levels of GSH [62]. It has been demonstrated that H2S could be a vital protective element against carbonyl stress by inactivating/modulating the role of highly reactive a, b-unsaturated aldehydes such as HNE in the brain [25]. Moreover, it has been reported that anethole trithione hydroxide, a slow releasing H2S donor, is more efficacious in protecting retinal ganglion cells (RGC-5) against the toxic effects of glutamate in combination with buthionine sulfoxime, through scavenging ROS and stimulating GSH and glutathione-S-transferase [63]. Taken together, these studies effectively demonstrate the powerful antioxidative function of H2S for treatment of AD. 4.2. Anti-apoptosis There is increasing proof that H2S has anti-apoptotic actions. NaHS protects PC12 cells from apoptosis caused by Ab and Hcy [20,47]. Accumulation of formaldehyde is involved in the pathogenesis of AD [64–66]. Our data have demonstrated that NaHS significantly protects PC12 cells against formaldehyde-induced cytotoxicity and apoptosis [67]. Furthermore, our studies indicate that ACS6, an H2S-donating derivative of sildenafil, protects PC12 cells against Hcy-induced cytotoxicity and apoptosis [68]. Additionally, H2S can inhibit the damage of hippocampus neurons in vascular dementia through its anti-apoptotic action [69]. Based on these studies, we can conclude that the anti-apoptotic effect of H2S plays an important role in its protection against AD. Most data indicate that the anti-apoptotic effects of H2S are mainly due to the preservation of mitochondrial function. It is reported that NaHS significantly protects PC12 cells against formaldehyde-induced cytotoxicity and apoptosis through attenuating ROS accumulation, upregulating B cell lymphoma 2 (Bcl-2) levels, and down-regulating Bax expression [67]. ACS6 has been shown to protect PC12 cells against Hcy-induced cytotoxicity and apoptosis by inhibiting both loss of Dwm and accumulation of ROS, as well as modulating the expression of Bcl-2 [68]. 4.3. Anti-inflammation Neuroinflammation has been considered a key factor in the pathogenesis of neurodegeneration, including that seen in AD [70]. Thus, it is an effective therapeutic strategy to delay or stop the progress of neurodegenerative diseases by inhibiting the neurological inflammatory process. The data from Hu et al. demonstrate that NaHS reduces LPS-exerted production and release of NO and tumor necrosis factor (TNF)-a in primary cultured microglia and astrocytes and mouse immortalized BV2 microglial cells, suggesting that H2S has important implications in the treatment of neuroinflammationrelated diseases [71]. This anti-inflammatory effect of H2S in LPSstimulated microglia and astrocytes is due to inhibition of inducible nitric oxide synthase (iNOS) and p38 mitogen-activated protein kinase (MAPK) signaling pathways [71]. Lee et al. reported that inflammatory activation of microglia and astrocytes caused induction of nuclear factor-jB (NF-jB), release of the inflammatory mediators TNF-a, interleukin (IL)-6 and nitrite ions, and down-regulation of H2S synthesis; however, these effects are partially reversed by pretreatment of cells with NaHS, indicating that H2S is an endogenous anti-inflammatory and neuroprotective agent [72]. Interestingly, NaHS has been shown to significantly ameliorate Ab1–40-induced overexpression in IL-1b and TNF-a as well as the extensive astrogliosis and microgliosis in the hippocampus via the inhibition of p38 MAPK and p65 NF-jB activity [50]. H2S may also have indirect neuroprotective effects through its anti-inflammatory effect by inhibiting proinflammatory factors released during microglial activation and thereby reducing the inflammation
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associated neurotoxicity. It has been shown that the conditioned media from rotenone-treated microglia notably reduces the cell viability of SH-SY5Y neuronal cells; however, this action is weakened by the cotreatment of neuronal cells with NaHS and rotenone [73]. Lan and coworkers demonstrated that H2S produces an antiinflammatory effect in chemical hypoxia-stimulated PC12 cells through inhibiting the ROS-activated p38MAPK-iNOS pathway [74]. In addition, NaHS has been shown to attenuate LPS-induced cognitive defects and neuronal ultrastructure impairment in rats by repressing TNF-a and TNF receptor 1 production, as well as suppressing LPS-induced IjB-a degradation, and afterward NF-jB activation [52]. Taken together, these observations provide strong evidence for the powerful anti-inflammatory effect of H2S in the progress of neurodegenerative diseases, including AD. All the aforementioned findings also clearly indicate that suppressing the nuclear p38 MAPK and NF-jB signaling pathway is regarded as a possible mechanism underlying the anti-inflammatory role of H2S. Lee et al. demonstrated that pretreatment with three H2Sreleasing compounds, anethole trithione hydroxide, S-diclofenac, and S-aspirin, reduces the release of the proinflammatory mediators TNF-a, IL-6, and NO induced by microglial and astrocytic activation [73]. Moreover, studies have demonstrated that SPRC inhibits LPS and Ab25–35 induced cognitive dysfunction and neuronal ultrastructure impairment by inhibiting of TNF-a and TNF receptor 1 production, and IjB-a degradation and NF-jB p65 activation [57,58]. Therefore, H2S-releasing compounds have significant anti-inflammatory properties and may be candidates for treating neurodegenerative disorders that have a prominent neuroinflammatory component, such as AD [73]. 5. Conclusions H2S, considered the third most abundant gasotransmitter, following NO and carbon monoxide, is attracting widespread attention because it has a variety of physiological and pathological roles across multiple body systems [1,3,75]. The actions of H2S described in this review highlight its neuroprotective effects in AD. Sufficient evidence has accumulated in support of H2S acting as a potential therapeutic target for the treatment of AD. The mechanisms underlying the neuroprotective effect of H2S on AD involve its antioxidative, anti-apoptotic and anti-inflammatory effects. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by National Natural Science Foundation of China (81071005, 81202518, 81200985, 81200986, and 81371485), Natural Science Foundation of Hunan Province, China (11JJ3117, 12JJ9032) and the construct program of the key discipline in the Hunan province. References [1] Hu LF, Lu M, Hon Wong PT, et al. Hydrogen sulfide: neurophysiology and neuropathology. Antioxid Redox Signal 2011;15:405–19. [2] Qu K, Lee SW, Bian JS, et al. Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 2008;52:155–65. [3] Gadalla MM, Snyder SH. Hydrogen sulfide as a gasotransmitter. J Neurochem 2010;113:14–26. [4] Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids 2011;41:113–21. [5] Shibuya N, Tanaka M, Yoshida M, et al. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 2009;11:703–14.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
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[6] Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 1996;16:1066–71. [7] Tan BH, Wong PT, Bian JS. Hydrogen sulfide: a novel signaling molecule in the central nervous system. Neurochem Int 2010;56:3–10. [8] Parihar MS, Hemnani T. Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci 2004;11:456–67. [9] Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005;120:545–55. [10] Samandouras G, Teddy PJ, Cadoux-Hudson T, et al. Amyloid in neurosurgical and neurological practice. J Clin Neurosci 2006;13:159–67. [11] Palop JJ, Mucke L. Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 2010;13:812–8. [12] Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 1996;67:1328–31. [13] Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449–55. [14] Dwyer BE, Raina AK, Perry G, et al. Homocysteine and Alzheimer’s disease: a modifiable risk? Free Radic Biol Med 2004;36:1471–5. [15] Tang XQ, Shen XT, Huang YE, et al. Inhibition of endogenous hydrogen sulfide generation is associated with homocysteine-induced neurotoxicity: role of ERK1/2 activation. J Mol Neurosci 2011;45:60–7. [16] Liu XQ, Lio XQ, Jiang P, et al. Plasma levels of endogenous hydrogen sulfide and homocysteine in patients with Alzheimer’s disease and vascular dementia and the significance thereof. Zhonghua Yi Xue Za Zhi 2008;88:2246–9. [17] Reynolds WF, Rhees J, Maciejewski D, et al. Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol 1999;155:31–41. [18] Green PS, Mendez AJ, Jacob JS, et al. Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease. J Neurochem 2004;90:724–33. [19] Whiteman M, Cheung NS, Zhu YZ, et al. Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun 2005;326:794–8. [20] Tang XQ, Yang CT, Chen J, et al. Effect of hydrogen sulphide on beta-amyloidinduced damage in PC12 cells. Clin Exp Pharmacol Physiol 2008;35:180–6. [21] Zhang H, Gao Y, Zhao F, et al. Hydrogen sulfide reduces mRNA and protein levels of b-site amyloid precursor protein cleaving enzyme 1 in PC12 cells. Neurochem Int 2011;58:169–75. [22] Greilberger J, Koidl C, Greilberger M, et al. Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer’s disease. Free Radic Res 2008;42:633–8. [23] Wen YD, Wang H, Kho SH, et al. Hydrogen sulfide protects HUVECs against hydrogen peroxide induced mitochondrial dysfunction and oxidative stress. PLoS One 2013;8:e53147. [24] Muellner MK, Schreier SM, Laggner H, et al. Hydrogen sulfide destroys lipid hydroperoxides in oxidized LDL. Biochem J 2009;420:277–81. [25] Schreier SM, Muellner MK, Steinkellner H, et al. Hydrogen sulfide scavenges the cytotoxic lipid oxidation product 4-HNE. Neurotox Res 2010;17:249–56. [26] Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 1997;94:5923–8. [27] Parsons RB, Waring RH, Ramsden DB, et al. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology 1998;19:599–603. [28] Kim JP, Koh JY, Choi DW. L-Homocysteate is a potent neurotoxin on cultured cortical neurons. Brain Res 1987;437:103–10. [29] Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920–6. [30] Ho PI, Ortiz D, Rogers E, et al. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res 2002;70:694–702. [31] Baydas G, Reiter RJ, Akbulut M, et al. Melatonin inhibits neural apoptosis induced by homocysteine in hippocampus of rats via inhibition of cytochrome c translocation and caspase-3 activation and by regulating pro- and antiapoptotic protein levels. Neuroscience 2005;135:879–86. [32] Linnebank M, Lutz H, Jarre E, et al. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells. Neurobiol Dis 2006;23:725–30. [33] Christie LA, Riedel G, Algaidi SA, et al. Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine. Neurosci Lett 2005;373:119–24. [34] Ataie A, Sabetkasaei M, Haghparast A, et al. Curcumin exerts neuroprotective effects against homocysteine intracerebroventricular injection-induced cognitive impairment and oxidative stress in rat brain. J Med Food 2010;13:821–6. [35] White AR, Huang X, Jobling MF, et al. Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer’s-type neurodegenerative pathways. J Neurochem 2001;76:1509–20. [36] Perna AF, Ingrosso D, De Santo NG. Homocysteine and oxidative stress. Amino Acids 2003;25:409–17. [37] Ataie A, Sabetkasaei M, Haghparast A, et al. An investigation of the neuroprotective effects of curcumin in a model of homocysteine – induced oxidative stress in the rat’s brain. Daru 2010;18:128–36.
[38] Ataie A, Sabetkasaei M, Haghparast A, et al. Neuroprotective effects of the polyphenolic antioxidant agent, curcumin, against homocysteine-induced cognitive impairment and oxidative stress in the rat. Pharmacol Biochem Behav 2010;96:378–85. [39] Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and Bvitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med 2007;45:1590–606. [40] van den Berg M, van der Knaap MS, Boers GH, et al. Hyperhomocysteinaemia; with reference to its neuroradiological aspects. Neuroradiology 1995;37:403–11. [41] Eto K, Asada T, Arima K, et al. Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem Biophys Res Commun 2002;293:1485–8. [42] Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr 2009;48:425–30. [43] Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346:476–83. [44] Miller JW. Homocysteine and Alzheimer’s disease. Nutr Rev 1999;57:126–9. [45] Sen U, Basu P, Abe OA, et al. Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure. Am J Physiol Renal Physiol 2009;297:F410–9. [46] Yan SK, Chang T, Wang H, et al. Effects of hydrogen sulfide on homocysteineinduced oxidative stress in vascular smooth muscle cells. Biochem Biophys Res Commun 2006;351:485–91. [47] Tang XQ, Shen XT, Huang YE, et al. Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells. Neurosci Res 2010;68:241–9. [48] Tang XQ, Chen RQ, Dong L, et al. Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity. J Mol Neurosci 2013;50:70–7. [49] Kamat PK, Kalani A, Givvimani S, et al. Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebraladministered homocysteine in mice. Neuroscience 2013;252:302–19. [50] Xuan A, Long D, Li J, et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. J Neuroinflammation 2012;9:202. [51] Giuliani D, Ottani A, Zaffe D, et al. Hydrogen sulfide slows down progression of experimental Alzheimer’s disease by targeting multiple pathophysiological mechanisms. Neurobiol Learn Mem 2013;104:82–91. [52] Gong QH, Wang Q, Pan LL, et al. Hydrogen sulfide attenuates lipopolysaccharide-induced cognitive impairment: a pro-inflammatory pathway in rats. Pharmacol Biochem Behav 2010;96:52–8. [53] Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U S A 2007;104:17977–82. [54] Peng Q, Buz’Zard AR, Lau BH. Neuroprotective effect of garlic compounds in amyloid-beta peptide-induced apoptosis in vitro. Med Sci Monit 2002;8:BR328–37. [55] Gupta VB, Rao KS. Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer’s beta-amyloid fibrils in vitro. Neurosci Lett 2007;429:75–80. [56] Chauhan NB. Effect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576. J Ethnopharmacol 2006;108:385–94. [57] Gong QH, Wang Q, Pan LL, et al. S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NFkappaB pathway in rats. Brain Behav Immun 2011;25:110–9. [58] Gong QH, Pan LL, Liu XH, et al. S-propargyl-cysteine (ZYZ-802), a sulphurcontaining amino acid, attenuates beta-amyloid-induced cognitive deficits and pro-inflammatory response: involvement of ERK1/2 and NF-kappaB pathway in rats. Amino Acids 2011;40:601–10. [59] Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J 2004;18:1165–7. [60] Kimura Y, Goto Y, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 2010;12:1–13. [61] Lu M, Hu LF, Hu G, et al. Hydrogen sulfide protects astrocytes against H(2)O(2)induced neural injury via enhancing glutamate uptake. Free Radic Biol Med 2008;45:1705–13. [62] Kimura Y, Dargusch R, Schubert D, et al. Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid Redox Signal 2006;8:661–70. [63] Majid AS, Majid AM, Yin ZQ, et al. Slow regulated release of H2S inhibits oxidative stress induced cell death by influencing certain key signaling molecules. Neurochem Res 2013;38:1375–93. [64] Yu PH. Involvement of cerebrovascular semicarbazide-sensitive amine oxidase in the pathogenesis of Alzheimer’s disease and vascular dementia. Med Hypotheses 2001;57:175–9. [65] Unzeta M, Solé M, Boada M, et al. Semicarbazide-sensitive amine oxidase (SSAO) and its possible contribution to vascular damage in Alzheimer’s disease. J Neural Transm 2007;114:857–62. [66] Jiang ZJ, Richardson JS, Yu PH. The contribution of cerebral vascular semicarbazide-sensitive amine oxidase to cerebral amyloid angiopathy in Alzheimer’s disease. Neuropathol Appl Neurobiol 2008;34:194–204. [67] Tang XQ, Ren YK, Zhou CF, et al. Hydrogen sulfide prevents formaldehydeinduced neurotoxicity to PC12 cells by attenuation of mitochondrial dysfunction and pro-apoptotic potential. Neurochem Int 2012;61:16–24.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006
H.-J. Wei et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx [68] Tang XQ, Chen RQ, Ren YK, et al. ACS6, a hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function. Med Gas Res 2011;1:20. [69] Zhang LM, Jiang CX, Liu DW. Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochem Res 2009;34:1984–92. [70] Amor S, Puentes F, Baker D, et al. Inflammation in neurodegenerative diseases. Immunology 2010;129:154–69. [71] Hu LF, Wong PT, Moore PK, et al. Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogenactivated protein kinase in microglia. J Neurochem 2007;100:1121–8.
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[72] Lee M, Schwab C, Yu S, et al. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol Aging 2009;30:1523–34. [73] Lee M, Sparatore A, Del Soldato P, et al. Hydrogen sulfide-releasing NSAIDs attenuate neuroinflammation induced by microglial and astrocytic activation. Glia 2010;58:103–13. [74] Lan A, Xu W, Zhang H, et al. Inhibition of ROS-activated p38MAPK pathway is involved in the protective effect of H2S against chemical hypoxia-induced inflammation in PC12 cells. Neurochem Res 2013;38:1454–66. [75] Wang R. The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal 2003;5:493–501.
Please cite this article in press as: Wei H-J et al. Therapeutic benefits of H2S in Alzheimer’s disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.006