s

ng Rn, PRHeng

Hydrogen suldeAntioxidationAnti-apoptosisAnti-inammation

endpathological processes in mammalian systems. In recent decades scientic

physiological and pathological implications of H2S, specically its role in theS).ellu

ulation of H2S homeostasis is implicated in the pathological processes of AD. Substantial evidence from

e thousmell ohat H2esses i

and is benecial for the induction of long-term potentiation [6].Subsequently, more and more physiological and pathological func-tions of H2S in the CNSwere discovered, and the neurobiology, neu-rochemistry, neurophysiology, neuropathology, and signalingproperties of H2S have been focused on in a number of outstandingarticles [14,7]. This article provides an overview of the therapeutic

brain andf H2S in th

decreased in AD patients [12]. It has been reported that the totalserum level of Hcy is accumulative and increased in AD patientsas the result of the disruption of the transsulfuration pathway link-ing Hcy and glutathione (GSH), which is mediated by CBS and CSE[13]. The dysfunction of CBS in the transsulfuration pathway maylead to a decrease in H2S production in AD [14]. Moreover, ourown research has shown that neurotoxicity of elevated Hcy isinvolved in inhibition of endogenous H2S production and

Corresponding author. Tel.: +86 734 828 1389; fax: +86 734 828 1673.E-mail address: tangxq01001@foxmail.com (X.-Q. Tang).

Journal of Clinical Neuroscience xxx (2014) xxxxxx

Contents lists availab

ca

.ein 1996 by Abe and Kimura [6]. They demonstrated that H2S selec-tively improves N-methyl-D-aspartate receptor mediated function

[1,3,4]. In 1996, Morrison et al. rst discovered that brain levelsof S-adenosylmethionine, a CBS activator, are signicantlyand cysteine aminotransferase produce H2S from cysteine in brain[5]. The physiological functions of H2S in the CNS were rst found

AD pathogenesis. CBS is highly expressed in thebelieved to be the primary physiologic source ohttp://dx.doi.org/10.1016/j.jocn.2014.01.0060967-5868/ 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Wei H-J et al. Therapeutic benets of H2S in Alzheimers disease. J Clin Neurosci (2014), http://dx.doi.org/1j.jocn.2014.01.006ant tothus ise CNSregarded as the third most abundant endogenous signaling gaso-transmitter, 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 cysta-thionine c-lyase (CSE). CBS is mainly expressed in the centralnervous system (CNS), while CSE is primarily expressed in the car-diovascular system [1,3,4]. Recently, it has been reported that thecombined action of 3-mercaptopyruvate sulfurtransferase (3MST)

AD is a progressive age-dependent neurodegenerative disease,affecting the cortex and hippocampus, and ultimately leading tocognitive dysfunction [8]. Neurobrillary tangles and b-amyloid(Ab) plaques in the cortex and hippocampus are the hallmarks ofAD [9,10]. In both familial and sporadic AD, Ab peptides, generatedfrom amyloid precursor protein (APP) by b and c-secretases, areconsidered to be pivotal factors in the pathology of the disease [11].

Increasing evidence has demonstrated that H2S is relevb-amyloid

1. Introduction

For hundreds of years, people havde (H2S) is just a toxic gas with therecent studies have demonstrated tphysiological and pathological procboth in vivo and in vitro studies shows that H2S prevents neuronal impairment and attenuates cognitivedysfunction in the experimental model of AD. The mechanisms underlying the protective role of H2S inAD involve its antioxidant, anti-apoptotic, and anti-inammatory effects. We conclude that H2S haspotential therapeutic value for the treatment of AD.

2014 Elsevier Ltd. All rights reserved.

ght that hydrogen sul-f rotten eggs. However,S regulates a series ofn mammals [1]. H2S is

benets of H2S in Alzheimers disease (AD) and the underlying cel-lular and molecular mechanisms implicated.

2. Disturbance of endogenous H2S generation in ADKeywords:Alzheimers disease

nervous system from oxidative stress, apoptosis, or degeneration. The aim of this review is to present thecurrent understanding of H2S as a potential agent for the treatment of Alzheimers disease (AD). Dysreg-Review

Therapeutic benets of H2S in Alzheimer

Hai-Jun Wei a,b, Xiang Li c, Xiao-Qing Tang a,b,aDepartment of Physiology, Medical College, University of South China, 28 W Changsheb Institute of Neuroscience, Medical College, University of South China, Hengyang, HunacDepartment of Anesthesiology, The First Afliated Hospital, University of South China,

a r t i c l e i n f o

Article history:Received 31 August 2013Accepted 1 January 2014Available online xxxx

a b s t r a c t

Hydrogen sulde (H2S), anseries of physiological andinterest has grown in thecentral nervous system (CNtiation and regulate intrac

Journal of Clini

journal homepage: wwwH2S can work in the CNS as a neuromodulator to promote long-term poten-lar calcium concentration and pH level in brain cells. H2S may protect thedisease

oad, Hengyang 421001, Hunan, PR ChinaChinayang, Hunan, PR China

ogenously generated gaseous mediator, has been discovered to regulate a

le at ScienceDirect

l Neuroscience

lsev ier .com/ locate/ jocn0.1016/

the superoxide anion and hydrogen peroxide [35,36]. Additional

attenuates Hcy-induced oxidative stress, memory decit, and neu-rodegeneration in mice [49]. In summary, H2S has protective

Therefore, it is logical to assume that H2S would be benecial in

al Nndings demonstrated that Hcy can induce lipid peroxidation andincrease MDA and super oxide anion levels in rat brains [37,38].These studies revealed that Hcymay be amarker of oxidative stress.

Elevated plasma Hcy levels, known as hyperhomocysteinemia(HHcy), cause neurological abnormalities such as mental retarda-tion, cerebral atrophy, and seizures [39,40]. Elevated brain Hcydown-regulation of expression and activity of CBS in PC12 cells[15]. Recently, Liu et al. reported that levels of H2S are decreasedin AD patients and the change in H2S level may be related to theseverity of AD [16]. Based on these ndings, it is logical to suggestthat 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 sug-gest 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 hydrosulde (NaHS,the donor of H2S) signicantly inhibited HOCl-induced cytotoxic-ity, intracellular protein oxidation, and lipid peroxidation in SH-SY5Y cells (human neuroblastoma cells) [19], which implies thepotential neuroprotective effect of H2S against the pathologicalprogression of AD.

Our data reveal that NaHS ameliorates Ab-induced damage inPC12 cells through reducing the loss of mitochondrial membranepotential (Dwm) and attenuating the increase of intracellular reac-tive oxygen species (ROS) [20]. Moreover, in cultured PC12 cells,recent research on the relationship of H2S to b-site APP cleavingenzyme 1 (BACE-1) expression and Ab secretion discovered thatH2S reduces BACE-1 mRNA and protein levels and Ab142 release[21]. Oxidative damage to lipids and proteins is an important earlyevent in the pathogenesis of neurodegenerative diseases and mal-ondialdehyde (MDA) and carbonyl proteins are regarded as usefuloxidative markers in AD [22]. It has been demonstrated that H2Sreduces MDA levels in human umbilical vein endothelial cellsexposed to hydrogen peroxide [23] and destroys lipid hydroperox-ides in oxidized low-density lipoprotein [24]. Schreier et al. demon-strated that H2S protect neuronal cells (SH-SY5Y) from the cytotoxiclipid oxidation product 4-hydroxynonenal (HNE) [25], which ismarkedly increased in the brains of patients with severe AD.

Based on the above, H2S has a strong antioxidant capacity toresist AD-related oxidative stress factors such as HOCl, Ab, MDA,and 4-HNE, suggesting a promising role for H2S as a novel strategyto prevent AD.

3.2. H2S resists AD by inhibiting Hcy-induced oxidative stress

Homocysteine (Hcy) is a thiol-containing amino acid derivedfrom themetabolism ofmethionine. Both in vitro and in vivo studieshave shown that Hcy is toxic to neuronal cells [2632] and mark-edly enhances the vulnerability of neuronal cells to excitotoxicand oxidative injury [30]. Furthermore, Hcy changes hippocampusplasticity and synaptic transmission resulting in learning andmem-ory decits [33,34]. These unfavorable neuronal effects of Hcy arebelieved to be caused by the auto-oxidation of Hcy, which leadsto cellular oxidative stress through the formation of ROS, including

2 H.-J. Wei et al. / Journal of Clinichas been reported in AD [41]. It is now established that elevatedplasma Hcy is a strong, independent risk factor of AD[13,14,4244]. Therefore, Hcy is regarded as a novel therapeutic

Please cite this article in press as: Wei H-J et al. Therapeutic benets of H2Sj.jocn.2014.01.006the treatment of AD by inhibiting Hcy-induced oxidative stress.

3.3. H2S protects against AD in animal models

Recently, Xuan et al. reported that pretreatmentwithNaHS ame-liorates learning and memory decits in an Ab140 rat model of AD[50]. Giuliani et al. found that H2S signicantly protected againstlearning and memory impairment in three experimental modelsof AD, including the rat models of AD induced by brain injection ofAb140 or streptozotocin, and an ADmousemodel harboring humantransgenes APPSwe, PS1M146V and tauP301L (3 Tg-AD mice) [51].Gong et al. reported that NaHS notably attenuates lipopolysaccha-ride (LPS)-induced neuroinammation, neuronal ultrastructureimpairment and cognitive defects [52], which suggest that H2S is apotential agent for the treatment of neuroinammation-related dis-eases, such as AD. Taken together, these ndings from in vivo studiesshow the potential therapeutic value of H2S for AD and lay the foun-dation for exploring a new H2S-modulated agent for preventing ordelaying the development of AD.

3.4. H2S donors antagonize AD

H2S can be produce non-enzymatically from polysuldes in gar-lic [53]. It is reported that garlic compounds containing S-allyl cys-teine (SAC) attenuate Ab-induced apoptosis [54] and decrease Abbril production and debrillate Ab preformed brils in vitro[55]. Moreover, garlic extracts have been demonstrated to exertanti-amyloidogenic, anti-inammatory and anti-tangle effects inAD transgenic models harboring the Swedish double mutation[56]. S-propargyl-cysteine (SPRC), which is an SAC structural ana-log that can be used to adjust endogenous H2S levels [7,9], attenu-ates cognitive damage induced by LPS in rats [57]. Moreover, SPRCmay inhibit Ab2535-induced cognitive dysfunction and neuronalultrastructure impairment in rats [58]. These ndings indicate thatappropriate treatments with H2S-modulating agents, such as SACand SPRC, represent a potential approach to treat AD.

4. Mechanisms of the protective effects of H2S in AD

4.1. Antioxidation

Oxidative stress has signicant implication in the pathogenesisof AD. Studies have shown that NaHS is capable of improving reduc-ing activity in neurons and protects them against oxidative impair-ment induced by hydrogen peroxide, glutamate, and hypochlorousacid, mainly through increasing GSH levels but not directly workingas an antioxidant [19,59]. Increased levels of GSH are brought aboutby enhancing the transporters of cystine/L-cysteine, the redistribu-effects against Hcy-induced oxidative stress and neurotoxicity.target for AD [14]. It has been shown that H2S partly preventsHHcy-associated renal damage through its antioxidant properties[45] and protects against Hcy-induced cytotoxicity and oxidativestress in vascular smooth muscle cells [46]. Interestingly, our stud-ies showed that H2S protects PC12 cells against the increase inintracellular ROS induced by Hcy [47]. Additionally, we recentlyshowed that ACS6, a novel H2S-releasing sildenal, results in pre-vention of Hcy-caused neurotoxicity and overproduction of ROSby upregulating paraoxonase-1 [48]. Moreover, H2S signicantly

euroscience xxx (2014) xxxxxxtion of GSH tomitochondria, the activity of c-glutamylcysteine syn-thetase in neurons and the uptake of glutamate in astrocytes[5961]. H2S also can protect an immortalized mouse hippocampal

in Alzheimers disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/

al Ncell line (HT22) against oxidative glutamate toxicity through activa-tion of adenosine triphosphate-dependent potassium and Cl chan-nels, in addition to increasing the levels of GSH [62]. It has beendemonstrated that H2S could be a vital protective element againstcarbonyl stress by inactivating/modulating the role of highly reac-tive 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 efcacious in protecting retinalganglion cells (RGC-5) against the toxic effects of glutamate in com-bination with buthionine sulfoxime, through scavenging ROS andstimulating GSH and glutathione-S-transferase [63]. Takentogether, these studies effectively demonstrate the powerful anti-oxidative 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 patho-genesis of AD [6466]. Our data have demonstrated that NaHS sig-nicantly protects PC12 cells against formaldehyde-inducedcytotoxicity and apoptosis [67]. Furthermore, our studies indicatethat ACS6, an H2S-donating derivative of sildenal, protects PC12cells against Hcy-induced cytotoxicity and apoptosis [68]. Addi-tionally, H2S can inhibit the damage of hippocampus neurons invascular dementia through its anti-apoptotic action [69]. Basedon these studies, we can conclude that the anti-apoptotic effectof H2S plays an important role in its protection against AD.

Most data indicate that the anti-apoptotic effects of H2S aremainly due to the preservation of mitochondrial function. It isreported that NaHS signicantly protects PC12 cells against form-aldehyde-induced cytotoxicity and apoptosis through attenuatingROS accumulation, upregulating B cell lymphoma 2 (Bcl-2) levels,and down-regulating Bax expression [67]. ACS6 has been shownto protect PC12 cells against Hcy-induced cytotoxicity and apopto-sis by inhibiting both loss of Dwm and accumulation of ROS, as wellas modulating the expression of Bcl-2 [68].

4.3. Anti-inammation

Neuroinammation has been considered a key factor in the path-ogenesis of neurodegeneration, including that seen in AD [70]. Thus,it is an effective therapeutic strategy to delay or stop the progress ofneurodegenerative diseases by inhibiting the neurological inam-matory process. The data from Hu et al. demonstrate that NaHSreduces LPS-exerted production and release of NO and tumor necro-sis factor (TNF)-a in primary cultured microglia and astrocytes andmouse immortalized BV2 microglial cells, suggesting that H2S hasimportant implications in the treatment of neuroinammation-related diseases [71]. This anti-inammatory effect of H2S in LPS-stimulatedmicroglia and astrocytes is due to inhibition of induciblenitric oxide synthase (iNOS) and p38 mitogen-activated proteinkinase (MAPK) signaling pathways [71]. Lee et al. reported thatinammatory activation of microglia and astrocytes caused induc-tion of nuclear factor-jB (NF-jB), release of the inammatorymedi-ators TNF-a, interleukin (IL)-6 and nitrite ions, and down-regulationof H2S synthesis; however, these effects are partially reversedby pretreatment of cells with NaHS, indicating that H2S is anendogenous anti-inammatory and neuroprotective agent [72].Interestingly, NaHS has been shown to signicantly ameliorateAb140-induced overexpression in IL-1b and TNF-a as well as theextensive astrogliosis and microgliosis in the hippocampus via theinhibition of p38 MAPK and p65 NF-jB activity [50]. H2S may also

H.-J. Wei et al. / Journal of Clinichave indirect neuroprotective effects through its anti-inammatoryeffect by inhibiting proinammatory factors released duringmicroglial activation and thereby reducing the inammation

Please cite this article in press as: Wei H-J et al. Therapeutic benets of H2Sj.jocn.2014.01.006associated neurotoxicity. It has been shown that the conditionedmedia from rotenone-treated microglia notably reduces the cellviability of SH-SY5Y neuronal cells; however, this action is weak-ened by the cotreatment of neuronal cells with NaHS and rotenone[73]. Lan and coworkers demonstrated that H2S produces an anti-inammatory effect in chemical hypoxia-stimulated PC12 cellsthrough inhibiting the ROS-activated p38MAPK-iNOS pathway[74]. In addition, NaHS has been shown to attenuate LPS-inducedcognitive defects and neuronal ultrastructure impairment in ratsby repressing TNF-a and TNF receptor 1 production, as well assuppressing LPS-induced IjB-a degradation, and afterward NF-jBactivation [52]. Taken together, these observations provide strongevidence for the powerful anti-inammatory effect of H2S in theprogress of neurodegenerative diseases, including AD. All the afore-mentioned ndings also clearly indicate that suppressing thenuclear p38 MAPK and NF-jB signaling pathway is regarded as apossible mechanism underlying the anti-inammatory role of H2S.

Lee et al. demonstrated that pretreatment with three H2S-releasing compounds, anethole trithione hydroxide, S-diclofenac,and S-aspirin, reduces the release of the proinammatory media-tors TNF-a, IL-6, and NO induced by microglial and astrocytic acti-vation [73]. Moreover, studies have demonstrated that SPRCinhibits LPS and Ab2535 induced cognitive dysfunction and neuro-nal ultrastructure impairment by inhibiting of TNF-a and TNFreceptor 1 production, and IjB-a degradation and NF-jB p65 acti-vation [57,58]. Therefore, H2S-releasing compounds have signi-cant anti-inammatory properties and may be candidates fortreating neurodegenerative disorders that have a prominent neuro-inammatory component, such as AD [73].

5. Conclusions

H2S, considered the third most abundant gasotransmitter, fol-lowingNO and carbonmonoxide, is attractingwidespread attentionbecause it has a variety of physiological andpathological roles acrossmultiple body systems [1,3,75]. The actions of H2S described in thisreview highlight its neuroprotective effects in AD. Sufcient evi-dence has accumulated in support of H2S acting as a potential ther-apeutic target for the treatment of AD. The mechanisms underlyingthe neuroprotective effect of H2S on AD involve its antioxidative,anti-apoptotic and anti-inammatory effects.

Conicts of Interest/Disclosures

The authors declare that they have no nancial or other con-icts of interest in relation to this research and its publication.

Acknowledgements

This study was supported by National Natural Science Founda-tion of China (81071005, 81202518, 81200985, 81200986, and81371485), Natural Science Foundation of Hunan Province, China(11JJ3117, 12JJ9032) and the construct program of the key disci-pline in the Hunan province.

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H.-J. Wei et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx 5Please cite this article in press as: Wei H-J et al. Therapeutic benets of H2Sj.jocn.2014.01.006in Alzheimers disease. J Clin Neurosci (2014), http://dx.doi.org/10.1016/

Therapeutic benefits of H2S in Alzheimers disease1 Introduction2 Disturbance of endogenous H2S generation in AD3 Protective actions of H2S in AD3.1 H2S protects against AD-related oxidative stress factors3.2 H2S resists AD by inhibiting Hcy-induced oxidative stress3.3 H2S protects against AD in animal models3.4 H2S donors antagonize AD

4 Mechanisms of the protective effects of H2S in AD4.1 Antioxidation4.2 Anti-apoptosis4.3 Anti-inflammation

5 ConclusionsConflicts of Interest/DisclosuresAcknowledgementsReferences