Journal of Clinical Neuroscience xxx (2014) xxxxxx

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Journal of Clinical Neuroscience

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Review

Therapeutic benets of H2S in Alzheimers 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 Afliated 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:
Alzheimers disease
Hydrogen sulde
Antioxidation
Anti-apoptosis
Anti-inammation
b-amyloid

a b s t r a c t
Hydrogen sulde (H2S), an endogenously generated gaseous mediator, has been discovered to regulate a
series of physiological and pathological processes in mammalian systems. In recent decades scientic
interest has grown in the physiological and pathological implications of H2S, specically 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 Alzheimers 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-inammatory effects. We conclude that H2S has
potential therapeutic value for the treatment of AD.
2014 Elsevier Ltd. All rights reserved.

1. Introduction
For hundreds of years, people have thought that hydrogen sulde (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 rst found
in 1996 by Abe and Kimura [6]. They demonstrated that H2S selectively improves N-methyl-D-aspartate receptor mediated function
and is benecial 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 [14,7]. This article provides an overview of the therapeutic
Corresponding author. Tel.: +86 734 828 1389; fax: +86 734 828 1673.
E-mail address: tangxq01001@foxmail.com (X.-Q. Tang).

benets of H2S in Alzheimers 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]. Neurobrillary 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. rst discovered that brain levels
of S-adenosylmethionine, a CBS activator, are signicantly
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/ 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/10.1016/
j.jocn.2014.01.006

H.-J. Wei et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

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 ndings, 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 hydrosulde (NaHS,
the donor of H2S) signicantly 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 Ab142 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 [2632] 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 decits [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
ndings 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
[13,14,4244]. 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 sildenal, results in prevention of Hcy-caused neurotoxicity and overproduction of ROS
by upregulating paraoxonase-1 [48]. Moreover, H2S signicantly
attenuates Hcy-induced oxidative stress, memory decit, 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 benecial 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 decits in an Ab140 rat model of AD
[50]. Giuliani et al. found that H2S signicantly protected against
learning and memory impairment in three experimental models
of AD, including the rat models of AD induced by brain injection of
Ab140 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 neuroinammation, neuronal ultrastructure
impairment and cognitive defects [52], which suggest that H2S is a
potential agent for the treatment of neuroinammation-related diseases, such as AD. Taken together, these ndings 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 polysuldes in garlic [53]. It is reported that garlic compounds containing S-allyl cysteine (SAC) attenuate Ab-induced apoptosis [54] and decrease Ab
bril production and debrillate Ab preformed brils in vitro
[55]. Moreover, garlic extracts have been demonstrated to exert
anti-amyloidogenic, anti-inammatory 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 Ab2535-induced cognitive dysfunction and neuronal
ultrastructure impairment in rats [58]. These ndings 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 signicant 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
[5961]. H2S also can protect an immortalized mouse hippocampal

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/10.1016/
j.jocn.2014.01.006

H.-J. Wei et al. / Journal of Clinical Neuroscience xxx (2014) xxxxxx

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 efcacious 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 [6466]. Our data have demonstrated that NaHS signicantly protects PC12 cells against formaldehyde-induced
cytotoxicity and apoptosis [67]. Furthermore, our studies indicate
that ACS6, an H2S-donating derivative of sildenal, 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 signicantly 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-inammation
Neuroinammation 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 inammatory 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 neuroinammationrelated diseases [71]. This anti-inammatory 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
inammatory activation of microglia and astrocytes caused induction of nuclear factor-jB (NF-jB), release of the inammatory 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-inammatory and neuroprotective agent [72].
Interestingly, NaHS has been shown to signicantly ameliorate
Ab140-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-inammatory
effect by inhibiting proinammatory factors released during
microglial activation and thereby reducing the inammation

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 antiinammatory 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-inammatory effect of H2S in the
progress of neurodegenerative diseases, including AD. All the aforementioned ndings also clearly indicate that suppressing the
nuclear p38 MAPK and NF-jB signaling pathway is regarded as a
possible mechanism underlying the anti-inammatory 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 proinammatory mediators TNF-a, IL-6, and NO induced by microglial and astrocytic activation [73]. Moreover, studies have demonstrated that SPRC
inhibits LPS and Ab2535 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 signicant anti-inammatory properties and may be candidates for
treating neurodegenerative disorders that have a prominent neuroinammatory 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. Sufcient 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-inammatory effects.
Conicts of Interest/Disclosures
The authors declare that they have no nancial or other conicts 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.
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j.jocn.2014.01.006

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