Therapeutic importance of hydrogen sulfide in age-associated neurodegenerative diseases

Abstract

Hydrogen sulfide (H₂S) is a gasotransmitter that acts as an antioxidant and exhibits a wide variety of cytoprotective and physiological functions in age-associated diseases. One of the major causes of age-related diseases is oxidative stress. In recent years, the importance of H₂S has become clear, although its antioxidant function has not yet been fully explored. The enzymes cystathionine β-synthase, cystathionine γ-lya-se, and 3-mercaptopyruvate sulfurtransferase are involved in the enzymatic production of H₂S. Previously, H₂S was considered a neuromodulator, given its role in long-term hippocampal potentiation, but it is now also recognized as an antioxidant in age-related neurodegeneration. Due to aerobic metabolism, the central nervous system is vulnerable to oxidative stress in brain aging, resulting in age-associated degenerative diseases. H₂S exerts its antioxidant effect by limiting free radical reactions through the activation of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase, which protect against the effects of aging by regulating apoptosis-related genes, including p53, Bax, and Bcl-2. This review explores the implications and mechanisms of H₂S as an antioxidant in age-associated neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Down syndrome.

Introduction

Hydrogen sulfide (H₂S) has organic outcomes in living organisms, especially with respect to cell signaling and post-transcriptional modifications. H₂S is the third gasotransmitter identified in mammalian cells (Gemici et al., 2015). H₂S has been recently shown to be produced by a number of tissues where it exerts biochemical and physiological effects (Rose et al., 2017). As an endogenous signaling molecule, H₂S has significant effects on the nervous system. Substantial evidence also exists that H₂S inhibits free radical reactions in aging and age-associated neurodegenerative diseases.

Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate (3MST) are important for H₂S production (Xie et al., 2016). The expression of H₂S is catalyzed by these enzymes. Parkinson’s disease (PD) is expressed in the murine brain and kidney, CSE in the liver and peripheral tissue, and 3MST in the brain, liver, kidney, and aorta (Kabil and Banerjee, 2014). The proper contribution of 3MST compared with CBS and CSE in the production of endogenous H₂S is currently under investigation (Singh and Banerjee, 2011). H₂S also acts as a modulator in age-associated neurodegenerative diseases of the CNS, including Alzheimer’s disease (AD), PD, Huntington disease (HD), and Down’s syndrome (DS). The thiol containing the toxic molecule homocysteine enhances the vulnerability of neural cells through excitotoxicity and an elevated level of plasma homocysteine (Cai et al., 2016). H₂S reduces the neurotoxicity of homocysteine by acting as a synaptic modulator (Seshadri et al., 2002). H₂S exerts its antioxidant function through superoxide super oxide dismutase (SOD), glutathione peroxidase (Gpx), and catalase (CAT) which combat free radicals (Dorrell et al., 2009). As H₂S is an antioxidant signaling molecule that interacts with other gasotransmitters, including nitric oxide (NO) and carbon monoxide, which increase or decrease the action of H₂S. In this review, we describe the potential causes of oxidative stress and the antioxidant function of H₂S in age-associated neurodegenerative diseases.

Database Search Strategy

We searched NCBI, Google scholar, and Medline for literatures regarding oxidative stress, H₂S, aging, reactive oxygen species, antioxidant and therapeutic importance of H₂S in neurodegenerative diseases published from inception to March 1, 2019 (Additional Table 1).

Additional Table 1.

Database search strategy

Serial No.	Article title	Eligibility criteria	Key words	Publicati on date	Database	Publishing language
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2	Hydrogen sulphide reduces insulin secretion from HIT-T15 cells by a KATP channel-dependent pathway	This review highlighted the role of H2S and KATP channel-dependent pathway	Ca+ channel, KATP channel, cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase	July 18, 2007	NCBI	English
3	Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells	This article demonstrates the genetic construction of neurodegenerative diseases	Alzheimer’s disease (AD), Huntington disease (HD), Parkinson’s disease, CAG repeats, pluripotent stem cells	June 28, 2012	NCBI	English
4	Evidence that hydrogen sulfide is a genotoxic agent	An article that describes about genomic instability or the cumulative mutations	H2S, DNA damage, NaHS, colorectal cancer	January, 2006	NCBI	English
5	Mitochondrial dysfunction in mouse trisomy 16 brain nephrology	Studies that have started to identify oxidative stress, mitochondrial dysfunction, neurodegenerative disease, Parkinson’s disease	Pyruvate dehydrogenase, Parkinson’s disease, Down syndrome	January 10, 2008	Google Scholar	English
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8	Potential biological chemistry of hydrogen sulfide (H2S) with the nitrogen oxides	This article tells about advanced glycation and lipoxidation end products (AGEs/ALEs) implicated in the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy	AS Angeli’s salt, cGMP, cyclic guanylate monophosphate, GSH; glutathione GSNO; glutathione S-nitrosothiol GSSG; oxidized glutathione, GSSH; glutathione persulfide, NOS; nitric oxide synthase, PLP; pyridoxal-5′-phosphate, SNP; sodium nitroprusside	February, 2013	Google scholar	English
9	Redox proteomics identification of oxidatively modified brain proteins in Alzheimer’s disease and mild cognitive impairment: insights into the progression of this dementing disorder	In this review, it has been discussed oxidatively modified hippocampal proteins in mild cognitive impairment: Insights into the development of Alzheimer’s disease	Cognitive impairment, AD, glutamate synthetase (GLUL)	May, 2006	NCBI	English
10	Amyloid β-peptide (1–42)-induced oxidative stress in Alzheimer’s disease: importance in disease pathogenesis and progression	This article discusses amyloid β-peptide (1–42)-induced uxidative stress in Alzheimer’s disease	Aβ, oxidative stress, AD, amyloid beta precursor, reactive oxygen species	August 16, 2013	NCBI	English
11	Cystathionine γ lyase–hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes	This study unravels CSE–H2S-mediated PPARγ activation might be a new therapeutic target for diabetes associated with obesity	Cystathionine γ lyase, hydrogen sulfide, phosphodiesterase, peroxisome, proliferator-activated receptor γ, sulfhydration, obesity	May, 2016	Google scholar	English
12	Induced pluripotent stem cells for disease modeling and drug discovery in neurodegenerative diseases	This article tells about induced pluripotent stem cells for disease modeling and drug discovery in neurodegenerative diseases	Pluripotent stem cell, drug target, drug screening	August 23, 2015	NCBI	English Pluripotent stem cell, drug target, drug screening
13	A new hope for a devastating disease: hydrogen sulfide in Parkinson’s disease	Protective effects can be described to mediate antioxidation, anti-inflammation, prosurvival activity and development of H2S in the treatment of PD	H2S, brain modulation, antioxidant effect, H2S donors	May, 2018	NCBI	English
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21	Glutathione metabolism in brain: metabolic interaction between astrocytes and neurons in the defense against reactive oxygen species	This research discusses glutathione metabolism in brain	Glutathione, Gpx, hydrogen peroxide, (H2O2)	December 25, 2001	NCBI	English
22	Hydrogen sulfide suppresses oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 generation from macrophages via the nuclear factor κB (NF-κB) pathway	This study suggested endogenous H2S inhibited ox-LDL-induced macrophage inflammation by suppressing NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter	H2S,NF-κB pathway, macrophages, phosphorylation	February 18, 2018	NCBI	English
23	Phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington’s disease	This article highlight advances cystag in Huntington’s disease (HD)	CAG repeats, oxidative stress, HD	October 28, 2005	NCBI	English
24	Carbon monoxide, hydrogen sulfide, and nitric oxide as signaling molecules in the gastrointestinal tract	Cystathionine β synthase, cyclic guanylyl cyclase, carbon monoxide, cystathionine ɤ lyase, H2S	Oxidative stress, antioxidant, neuropsychiatric disorder	August, 2014	Google Scholar	English
25	Redox modulations, antioxidants, and neuropsychiatric disorders	This study introduuce the complex topics of redox modulations and their role in the development of select neuropsychiatric disorders	Oxidative stress, antioxidant, neuropsychiatric disorder	June 14, 2015	NCBI	English
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31	Bioassay-comparison of the antioxidant efficacy of hydrogen sulfide and superoxide dismutase in isolated arteries and veins	This study addressed that H2S is a less effective vascular antioxidant than SOD. We propose that the previously described beneficial effects of H2S are unlikely to be related to its direct effect on superoxide	Hydrogen sulfide, super oxide dismutase (SOD)	December 12, 2013	NCBI	English
32	Hydrogen sulfide and cell signaling: team player or referee?	Current state of play of effects of hydrogen sulfide in plants	Glutathione, Hydrogen peroxide, Hydrogen sulfide, Nitric oxide, Signal transduction, Thiol modifications	Of hydrogen 2014	NCBI	English
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38	Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models	The role of H2S and its therapeutic potentials	Hydrogen sulfide, 6-OHDA, Rotenone, MPTP, Parkinson’s disease	2014	NCBI	English
39	Hydrogen sulfide upregulates glutamate–cysteine ligase catalytic subunit, glutamate– cysteine ligase modifier subunit, and glutathione and inhibits interleukin-1β secretion in monocytes exposed to high glucose levels	Beneficial effects of H2S-rich compounds in mitigating the pathogenesis of metabolic syndrome and atherosclerosis	Glutathione, glutamate, GCLC,GCLM	22 May, 2014	NCBI	English
40	Hydrogen sulfide-mechanisms of toxicity and development of an antidote	This study suggests sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning	H2S, cytochrome c oxidase	2016	NCBI	English
41	Enzymology of H2S biogenesis, decay and signaling	This review focuses on the enzymology of H2S homeostasis and discuss H2S-based signaling via persulfidation and thionitrous acid	H2S biogenesis, CBS, S-adenylyl cyclase	January 28, 2014	NCBI	English
42	H2S and its role in redox signaling	The chemical properties of H2S and its varied physiological effects are discussed	Redox, Thiol, Hydrogen sulfide	2016	NCBI	English
43	Sulfur as a signaling nutrient through hydrogen sulfide	This review provides an overview of sulfur metabolism	hydrogen sulfide, signaling, sufur metabolism, nutrition, su lfide oxidation	July, 2014	NCBI	English
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48	Hydrogen sulfide protects neurons from oxidative stress	This review highlights the involvement of AGEs in the development and progression of T2DM and their role in diabetic complications	T2DM, oxidative stress, AGEs	March 16, 2015	NCBI	English
49	Hydrogen sulfide chemical biology: pathophysiological roles and detection	This review examines different strategies for managing diabetic neuropathy which rely on exogenous antioxidants	DN, oxidative stress, antioxidant, hyperglycemia	2015	NCBI	English
50	Modeling neuropsychiatric and neurodegenerative diseases with induced pluripotent stem cells	The purpose of this study is to perform an updated meta-analysis to investigate the up-to-date pooling evidence based on published population-based cohort studies and assess the association between DM and the risk of PD.	Diabetes mellitus, PD	May 1, 2016	NCBI	English
51	Modeling Parkinson’s disease using patient-specific induced pluripotent stem cells	Novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review	Nitric oxide, oxidation, DNA oxidation	Jan, 2007	NCBI	English
52	Hydrogen sulfide and cell signaling	This article indicated that PD might exert protective effects against OSI through various interactions with PKC pathway	Glutathione, PD, PKCs, oxidative stress	2016	NCBI	English
53	Hydrogen sulfide attenuates chronic restrain stress- induced cognitive impairment by upreglulation of Sirt1 in hippocampus	H2S targets mitochondria at low micromolar concentrations via reversible inhibition of cytochrome c oxidase	CBS, CSE, 3MST, ATP, hydrogen sulfide	2008	NCBI	English
54	The hallmarks of aging	The regulation of expression of protooncogenes and apoptosis (programmed cell death), the development of diseases such as cancer and human immune deficiency may be affected by depleting or elevating cellular GSH level	NAC, GSH, oxidative stress, antioxidant	September 29, 2008	NCBI	English
55	The neuroprotection of hydrogen sulfide against MPTP-induced dopaminergic neuron degeneration involves uncoupling protein 2 rather than ATP-sensitive potassium channels	Free radical scavengers, or over expression of antioxidant enzymes in islets or transgenic mice can protect β cells from oxidative stres	Insulin, oxidative stress, apoptosis, beta cell death	October, 2010	NCBI	English
56	Slow regulated release of H2S inhibits oxidative stress induced cell death by influencing certain key signaling molecules	This review focuses on the relationship between oxidative stress and neuroinflammation in the development and progression of diabetic neuropathy	NF-κB, Oxidative stress, inflammation	February 27, 2014	NCBI	English
57	Biosynthesis and functions of glutathione, an essential biofactor	This review addresses recent findings on such lipohormetic mechanisms that are associated with lipid peroxidation in pancreatic beta cells. This articl	Beta cells, oxidative stress, lipid peroxidattion, type 2 diabetes	2017	NCBI	English
58	Hydrogen sulfide is produced by cystathionine γ-lyase at the steady-state low	This tells about the history of diabetes or the use of antidiabetes drugs was associated with Parkinson’s disease	a history of diabetes or the use of antidiabetes drugs was associated with Parkinson’s disease	May, 2011	Google Scholar	English
	intracellular Ca2+ concentrations
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61	In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage	This article present a new perspective on H2S production and storage in the brain	3-MST,CAT, hydrogen sulfide	April 2, 2002	NCBI	English
62	Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: implications for Alzheimer’s disease	This paper discuss about combined therapy involving antioxidants and check points for synaptic plasticity during early stages of the disease could become a viable therapeutic option for AD treatment	Cognitive decline, AD, oxidative stress, antioxidant	July 10, 2013	NCBI	English
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65	Antioxidant gene therapy against neuronal cell death	This study investigated oxidative stress in neuronal cell death associated with neurodegenerative disorders	AD, Aβ, BDNF, SOD	February 17, 2011	NCBI	English
66	Involvement of oxidative stress in Alzheimer disease	This study describes oxidatively modified macromolecules are present in biologic fluids from the patients with AD as well as cellular and animal AD models	Apoptosis, AD, NFTs, oxidative stress	July, 2006	NCBI	English
67	Neuronal oxidative stress precedes amyloid-β deposition in Down syndrome	This article leads to the expectation that oxidative damage should positively correlate with Aβ deposition	Alzheimer disease, Amyloid-β, Down syndrome, 8-hydroxyguanosine, Nitri c oxide, nitrotyrosine, Oxi dative damage	November 1, 2000	NCBI	English
68	Generation and characterization of human induced pluripotent stem cells	This research describes about detection of pluripotent cell markers, embryoid body differentiation, and teratoma differentiation are used to determine pluripotency in vitro and in vivo, respectively	iPSC cells, in vivo differentiation, in vitro differentiation	June 1, 2009	NCBI	English
69	Small molecules as therapeutic drugs for Alzheimer’s disease	In this article mitochondrial dysfunction has been implicated in aging and age-related neurodegenerative diseases are discussed	AD, mitochondria-targeted molecules, oxidative stress, PD, mitochondrial dynamics, aging	April, 2019	NCBI	English
70	Hydrogen sulfide as an oxygen sensor pathway in rats	This article describes pathophysiological responses and possible therapeutic uses	This article describes H2S interaction with gasotransmitters	November 30, 2013	NCBI	English
71	Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies	This article suggested an involvement of the peripheral IGF-I trophic system in ALS	ALS, IGF-I trophic system in ALS		NCBI	English
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73	Apoptosis inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins	Deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegance. These results suggest that chronic induction of wild- type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan	ALS, TDP-43, oxidative stress, aging	July 5, 2012	NCBI	English
74	Oxidative stress and down syndrome: A route toward Alzheimer-like dementia	The chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD	SOD1, ALS, antioxidant	2015	Google Scholar	English
75	The role of hydrogen sulfide in aging and age-related pathologies	mutant SOD1-induced destructive events favors recruitment of astrocytes to non-cell autonomous injury in ALS	ROS, Oxidative stress, hydrogen sulfide donor, NOS	January, 2108	NCBI	English
76	Homocysteine metabolism in children with Down syndrome: in vitro modulation	Oxidative stress and oxidative damage are a result of concurrent accumulation of mtDNA mutations and defective antioxidant enzymes in human aging.	ROS, Oxidative stress, hydrogen sulfide donor	2002	NCBI	English
77	Carbamoylation abrogates the antioxidant potential of hydrogen sulfide	These findings can significantly advance therapeutic approaches to the neurodegenerative diseases which are associated with oxidative stress, such as Parkinson’s disease	Hydrogen sulfide donor, PD, NaHS, PC12 cells	August 12, 2009	NCBI	English
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79	Brain phenotype of transgenic mice overexpressing cystathionine β-synthase	A key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes	Hsa21, DS, H2S	January 12, 2012	NCBI	English
80	Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease	This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD	Α-synuclein, PD, post-transcriptional modification, H2S, sulfhydration	January, 2018	NCBI	English
81	Intracellular oxidant activity, antioxidant enzyme defense system, and cell senescence in fibroblasts with trisomy 21	Deleterious role of oxidatively modified molecules in early cell senescence of T21F, thereby linking replicative and stress-induced senescence in cultured cells to premature aging in DS	SOD1, SOD2, trismy21, mRNA	February 19, 2015	NCBI	English
82	H2S biosynthesis and catabolism: new insights from molecular studies	Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H2S as playing a functional role in cell- signaling and post-translational modifications	H2S, biosynthesis, catabolism, molecular models	November 14, 2016	NCBI	English
83	Human-induced pluripotent stem cells: potential for neurodegenerative diseases	In this review, it has been discuss induced pluripotent stem cells (iPSCs). The ability to generate pluripotent stem cells from adult fully differentiated cells such as skin fibroblasts was a major advance in medicine in recent years	iPSC, aging, PD, RNA metabolism	May 13, 2014	NCBI	English
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85	Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down’s syndrome	An increased basal generation of superoxide in Ts16 neurons, probably caused by a deficient complex I of mitochondrial electron transport chain, which leads to an impaired mitochondrial energy metabolism and finally neuronal cell death	Trisomy 16, Down’s syndrome, Alzheimer’s disease, Reactive oxygen species, Superoxide anion NAD(P)H, autofluorescence, Hippocampal culture, Free radicals	January 15, 2000	NCBI	English
86	Special delivery from mitochondria to peroxisomes	Mitochondrial trafficking might play drawing upon knowledge of similar transactions between other organelles	Peroxisome, mitochondrial membrane, SOD1, SOD2	June, 2008	NCBI	English
87	Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions	TNF-α stimulates the transcription of CSE and the generated H2S sulfhydrates cysteine-38 of p65, enhancing its binding to the coactivator RPS3, thereby augmenting binding to the promoters of several antiapoptotic genes	NF-κB, TNF-α-induced cell death, H2S	January 13, 2012	Google Scholar	English
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89	3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain	H2S is produced by 3MST from cysteine and a-KG through metabolism by CAT, and that the produced H2S may immediately be stored as bound sulfane sulfur in the brain. These observations provide a new insight into the production and storage of H2S in the brain	H2S, 3-mercaptopyruvate, 3-MST, CBS, CSE, CAT	February 24, 2009	Google Scholar	English
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97	Hydrogen sulfide suppresses outward rectifier potassium currents in human pluripotent stem cell-derived cardiomyocytes	This study investigates electrophysiological responses of human pluripotent stem cells (hPSCs) derived cardiomyocytes towards H2S	hiPSCs, H2S, hESCs, action potential, electrophysiology	November 30, 2012	Google Scholar	English
98	An update on hydrogen sulfide and nitric oxide interactions in the cardiovascular system	This review discusses the current understanding of individual and interactive regulatory functions of H2S and NO in biosynthesis, angiogenesis, vascular one, cardioprotection, and posttranslational modification, indicating the importance of their cross-talk in the cardiovascular system	H2S, NO, posttranscriptional modifications, angiogenesis	September 9, 2018	Google Scholar	English
99	Hydrogen Sulfide and Cellular Redox Homeostasis	The antioxidant effect of H2S has been most extensively investigated and was thought as the major mechanism underlying the effects of H2S	H2S, mechanism, oxidative stress, reactive oxygen species, xanthine oxide	December 1, 2015	Google Scholar	English
100	Structural insights into pathogenic mutations in heme-dependent cystathionine-β-synthase	Cystathionine β-synthase represent the single most common cause of severe hereditary hyperhomocysteinemia	CBS, Homocysteine, Hemeprotein, Mutations	December, 2006	Google Scholar	English
101	In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets	Mutant htt-directed repression mechanism involving multiple specific components of the basal transcription apparatus	Htt, polyglutamine, CREB binding protein	December 29, 2005	Google Scholar	English
102	Hydrogen sulfide therapy in brain diseases: from bench to bedside	H2S produced in mitochondria, the major organelle that releases reactive oxygen species (ROS) causing toxic effects and ultimately leading to cell death, also may directly suppress oxidative stress through scavenging ROS	Mitochondrial oxidation, H2S, ROS, and neuronal function		NCBI	English
103	S sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair	In the presence of H2S, activated PARP-1 recruits XRCC1 and DNA ligase III to DNA breaks to mediate DNA damage repair, and cells are protected from senescence	H2S, CSE, DNA damage, poly-ADP ribose	2014	NCBI	English
104	Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats	A gaseous transmitter fulfilling a physiological role in regulating cardiovascular function. The mechanisms underlying the vascular relaxant effect of H2S are incompletely understood, although opening of ATP-sensitive K+ (KATP) channels in vascular smooth muscle cells may play an important role	Potassium channel, H2S, NaHS, CSE	January 1, 2007	NCBI	English

Oxidative Stress and Aging

Aging is the common result of oxidative stress. Reactive oxygen species (ROS) accumulation by mitochondria is mostly found in aged tissue (Viña et al., 2013). High levels of 8-Oxo-2′-deoxyguanosine, which result in oxidative harm, are commonly found in mtDNA (Hipkiss, 2006). According to the free radical theory of aging, discovered by Harman in 1954, aggregation of protein, lipid, and DNA molecules in mitochondria are responsible for cellular senescence (Miquel et al., 1980). Protein oxidation due to excessive oxidative stress is triggered by several signaling pathways, including transforming growth factor-β signaling, the DNA damage response, and mitogen activated protein kinase 2K3 (MAPK2K3) signaling, which is responsible for increased regulation of the cell cycle inhibitor, p53 (Muñoz-Espín and Serrano, 2014).

On the other hand, ongoing research has demonstrated that thiol and thiol-related enzymes, including Gpx, are linked with the progression of aging (Muñoz-Espín and Serrano, 2014). Gpx deficiency leads to increased levels of oxidative stress. Although the balance of ROS plays a vital role in enhancing or suppressing cellular fates such as proliferation and differentiation, the increased level of oxidative stress is considered a major mediator of aging (Ben-Porath and Weinberg, 2005). Moreover, protein aggregation has also been linked with aging. In particular, the aggregated protein, lipofuscin, is a hallmark of aging. Transitional metals bind lipofuscin to produce more ROS through the Fenton reaction (Ben-Porath and Weinberg, 2005). Under pathophysiological conditions, the aggregation of oxidized protein is irreversible. Proteins may appear as inclusion bodies, lysosomes, aggresomes, or plaques, and may affect normal cellular metabolism (Chin et al., 2008).

Taken together, these data suggest that oxidative stress is the root cause of aging that increases with age-related diseases. The contribution of ROS in protein oxidation is still unclear and will require further investigation.

Oxidative Stress and Mitochondrial Dysfunction in Neurodegeneration

Neurodegeneration is very common in elderly people. Oxidative stress is one of the major causes of these neurodegenerative diseases in aging (Ganguly et al., 2017). The molecular link between oxidative stress and neurodegeneration can vary disease to disease like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease (HD), and Down’s syndrome (DS). For example, ROS-rseponsive transcription factors can alter the expression of genes encoding such toxic proteins or the enzymes involved in the synthesis, processing, and degradation of such proteins which causes mitochondrial dysfunctions (Ganguly et al., 2017). In some conditions, the mutant gene produces an abnormal product that is not readily cleared by the protein degradation machinery, leading to its accumulation, and a similar thing can happen if the protein is posttranscriptionally modified because of redox status and the activity of kinases (Ciechanover and Kwon, 2015). In AD pathology, oxidative damage results in deposition of Aβ protein which triggers the neurodegeneration process (Dinda et al., 2019). In addition to this, oxidative damage causes decreased synthesis of adenosine tri phosphate (ATP), leading to mitochondrial membrane depolarization. In particular, extensive studies have been conducted using transgenic AD models, postmortem AD brain, cultured cells and isolated mitochondria through multiple mechanisms (Onyango et al., 2016). In transgenic AD mice and postmortem AD brain, progressive deposition of Aβ occurs in brain mitochondria (Onyango et al., 2016). Moreover, human induced pluripotent stem cell (hiPSC) models of AD have been generated from patients with amyloid precursor proteins (APP) mutations, including an E693 deletion which showed oxidative stress (Ross and Akimov, 2014). Oxidative stress is also responsible for accumulation of phosphorylated tau proteins within the neurons which might result in translation of a specific mRNA (Oliver and Reddy, 2019). In AD, increased phosphorylation of tau protein is the result of increased activities of glycogen synthase kinase 3 beta (GSK3β) and cluster of differentiation (CDK5) (Mondragón-Rodríguez et al., 2013). Moreover, significant accumulation of transitional metals such as Fe, Cu, and Zn causes impaired antioxidant defense (Butterfield et al., 2013).

Oxidative stresses also have their detrimental effects on PD and HD. The most common mitochondrial proteins PINK1 and PARK2 show dysfunctional properties (Rocha et al., 2018). PINK1 is normally on the inner mitochondrial membrane, but it migrates to the outer membrane to phosphorylate proteins due to oxidative stress when there is a reduction in mitochondrial membrane (Bose and Beal, 2019). Parkin protein is involved in mitochondrial homeostasis and the loss of parkin protein causes the loss of quality control of mitochondria and degeneration of dopaminergic neurons in mid brain (Cartelli et al., 2018). Neurons derived from a hiPSC of patients who harbor the α-synuclein mutation show increased sensitivity to environmental toxins such as rotenone, paraquat which leads to the inhibition of the myocyte enhancer factor 2C-peroxisome proliferator activated receptor-γ coactivator-α (MEF2C-PGC1α), which in turn contributes to mitochondrial dysfunctions (Bose and Beal, 2019). HD is the autosomal-dominant neurodegenerative disorder that is caused by abnormal expansion of polyglutamine (CAG) repeats in the huntingtin (HTT) (An et al., 2012). HD is considered as an ideal disorder model for exploring the effectiveness of iPSCs, because it is induced by a single gene, and there is a strong correlation between the length of the CAG repeat expansion and the onset of age disease (Cao et al., 2015). Cao et al. (2015) reported on the successful correction of the CAG repeat-expanded HTT allele in HD patient iPSCs. When evaluated with a series of experiments, HD consortium revealed that cells carrying the longer repeats were more vulnerable to cellular stresses and brain-derived neurotrophic factor deprivation, demonstrating the correlation of CAG repeat lengths with disease onset.

DS represents one of the best documented cases of a human disorder related to the redox imbalance that has been attributed by Cu, Zn-SOD1 and encoded by trisomic chromosome 21 (Rodríguez-Sureda et al., 2015). As an essential link to oxidative stress, mitochondrial dysfunctions are observed whenever redox imbalances occur. Bambrick and Fiskum (2008) reported a defective repair of oxidative damage to mitochondrial DNA (mtDNA) in fibroblasts from DS patients, while Schuchmann and Heinemann found mitochondria-associated anomalies in neurons from Ts16 mice. Superoxide formation was significantly increased in Ts16 neurons compared with control neurons (Schuchmann and Heinemann, 2000). A selective decrease in respiration was detected with the Complex I substrates malate and glutamate but not with the Complex II substrate succinate in isolated cortex mitochondria from Ts16 mice (Bambrick and Fiskum, 2008). Under oxidative stress condition, some markers like AGEs, dityrosine, and H₂S are found at increased levels in DS patients which are responsible for aging and neurodegeneration (Perluigi and Butterfield, 2012).

In a nutshell, oxidative stress has a progressive role in age-associated neurodegenerative diseases. H₂S might act as a therapeutic target for these neurodegenerative diseases from different perspectives.

Role of H₂S in the Regulation of Aging

H₂S plays various physiological roles in the human body by preventing oxidative damage or deterioration. Most age-associated diseases are a result of oxidative stress, whereas antioxidants increase longevity. Oxidative stress derivatives appear as ROS and RNS, such as super oxide (O₂^•–), hydrogen peroxide (H₂O₂), and NO (Zhu et al., 2007; Tyagi et al., 2009). H₂S has been shown to exhibit protective effects on mouse endothelial cells (bEnd3) against methionine-induced oxidative stress. According to the free radical theory, SOD converts O₂^•– to H₂O₂, which is then converted into H₂O and O₂ by CAT (Kimura et al., 2010). In the presence of reduced GSH, low concentration of H₂S broadly inhibits cellular damage by the reactive nitrogen species (RNS) derivative ONOO^– (Viña et al., 2013). H₂S also inhibits toxicity in human neuroblastoma SH-SY5Y cells through inhibition of ONOO^– (Viña et al., 2013).

The interrelationship between H₂S and aging is based on several factors, including genomic instability (Attene-Ramos et al., 2006). Genomic integrity and stability is affected by exogenous and endogenous treats where most damage occurs in the nuclear genome (López-Otín et al., 2013). Nuclear DNA damage are one of the causes of neurodegeneration, whereas H₂S attenuates DNA damage (López-Otín et al., 2013). In contrast to the nuclear genome, protection of mitochondrial DNA is not efficient and is heavily dependent on the machinery of nuclear DNA repair (Perridon et al., 2016). Mitochondrial DNA is more vulnerable to mutations due to the oxidative stress and the lack of protective histones on mitochondrial DNA (Perridon et al., 2016). Therefore, aging-associated mutations and deletions in the mitochondrial genome may also contribute to the aging process (Perridon et al., 2016). For instance, DNA is damaged by the treatment of fibroblasts with the H₂S donor, NaHS, resulting in apoptotic cell death in a Bax and cytochrome C-dependent manner (Kimura et al., 2010). Telomerase, a specialized DNA polymerase, is required to elongate telomers as the replicative DNA polymerase lacks his capacity (Hewitt et al., 2012). Dysfunctional telomeres are highly efficient in inducing apoptosis during aging (Hewitt et al., 2012). In addition to this, epigenetic alterations such as posttranslation of histones, alterations in DNA methylation pattern and chromatin remodeling, can regulate the accessibility of DNA and underlie the differential gene transcription observed between cell types during aging (López-Otín et al., 2013). S-sulfhydration, as well as extracellular regulated kinase (ERK1/2), prevents DNA damage. H₂S can activate poly ADP-ribose polymerase (PARP-1) and inhibit DNA damage in endothelial cells. PARP activation is mediated by the MEK/ERK pathway (Hancock and Whiteman, 2014). S-sulfhydrated MEK1 at cys341 induces ERK1/2 phosphorylation in the nucleus, which activates PARP-1 (Hancock and Whiteman, 2014). On the other hand, mutation of cys341 prevents the activation of PARP-1 (Zhao et al., 2014).

Experimental studies have reported that H₂S provides protection when chronic restraint stress-exposed rats are treated with NaHS. In particular, H₂S increased SOD activity and the level of GSH at an NaHS concentration of 30 or 100 μmol/kg, indicating the role of H₂S in oxidative stress (Li et al., 2017). Kimura (2014) also reported that the concentration of intracellular cysteine in the presence of H₂S exhibits an anti-aging function by inhibiting SIRT1, whereas SIRT1 has been identified in yeast as an NAD⁺-dependent histone deacetylase, which increases DNA stability. SIRT1 deficiency has been shown to hamper cognitive abilities and the antiaging role of SIRT1 is associated with the drug resveratrol (Figure 1B; Li et al., 2017).

Figure 1.

Biosynthesis of H₂S from enzymatic source and anti-aging function of H₂S.

(A) The synthetic procedure of H₂S. (B) Anti-aging effect of H₂S. This diagrammatic illustration reveals H₂S formation in mitochondria. Most prominently, three enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) are the main precursors for H₂S formation, where cytosol contains CBS and CSE and mitochondria contains 3MST. The origins of cytosolic H₂S formation are homocysteine, cysteine, and L-cysteine which are derived from proteins and cysteine. In mitochondria, H₂S is produced from 3 mercaptopyruvate (3-MP) and L-cysteine. H₂S exerts metabolic function through upregulation of silent information regulator 1 (SIRT1) and inhibiting free radical-induced oxidative stress. H₂S also inhibits cell aging through mediating super oxide dismutase/glutathione (SOD/GSH). Resveratrol, an anti-aging drug, initiates age-associated metabolic phenotypes by the inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE). H₂S enhances SIRT1 and inhibits PDE activity to provide anti-aging function. CAT: Cysteine acetyl transferase; DAO: diamine oxidase; H₂S: hydrogen sulfide; RNS: reactive nitrogen species; ROS: reactive oxygen species.

Enzymatic Contribution to the Biosynthesis of H₂S

The biosynthesis of H₂S is mediated by three enzymes: CSE, CBS, and 3MST. Cystathionine is the metabolite formed by CBS via the condensation of homocysteine (Kimura, 2015), while CSE converts L-cysteine and α-ketoglutarate (α-KG). H₂S is produced by the generation of pyruvate, ammonia, and L-cysteine. 3MST generates H₂S through the formation of pyruvate from 3-mercaptopyruvate (3MP), which undergoes cysteine and α-KG metabolism associated with cysteine amino transferase (Figure 1A).

Contribution of CBS

CBS has traditionally been introduced as the initial enzyme in the transsulfuration pathway (Régnier et al., 2012). As the physiological function of CBS is to eliminate homocysteine, CBS deficiency results in homocystinuria, which is characteristic of many metabolic diseases (Yamanishi et al., 2006). The catalytic function of CBS is mediated by 63-kDa subunits, which bind to the co-factor, heme, and pyridoxal 5′ phosphate (PLP). CBS individually binds to two substrates (homocysteine and serine) whose activity is mediated by S-adenosyl-L-methionine (SAM) (Mikami et al., 2013). Moreover, CBS can produce H₂S by three distinct pathways: (1) Converting cysteine and H₂O to form serine and H₂S; (2) condensation of cysteine and homocysteine to generate cystathionine and H₂S; and (3) condensation of two cysteine molecules to form lanthionine and H₂S (Singh and Banerjee, 2011). Under physiological conditions, CBS is cytosolic and H₂S acts as a neurotransmitter under high expression of CBS (Kabil et al., 2014b). CBS has also been shown to translocate to the nucleus and mitochondria (Teng et al., 2013).

Contribution of CSE

CSE mediates H₂S synthesis in smooth muscle cells through a PLP-dependent α, β-elimination reaction combined with cysteine. A high level of potentiation is observed during H₂S synthesis by CSE, particularly in the presence of PLP, while suppression is observed at 300 nM Ca²⁺. This indicates that when H₂S is generated by CSE in cells, the Ca²⁺ concentration is increased (Mikami et al., 2013). The binding site of CSE indicates the expression of CSE and explains the antiapoptotic function of H₂S (Sen et al., 2012) produced by CSE, which makes an addition to the cysteine residues of nuclear factor kappa-B (NF-κB), activating antiapoptotic genes (Sen et al., 2012). Moreover, in western blot analysis, CSE has been detected as an H₂S generator in the brain. Additionally, in a mouse model of HD, the level of CSE expression is low.

Contribution of 3MST and CAT

3MST and CAT also take part in H₂S synthesis in brain tissue (Gadalla and Snyder, 2010), which is recognized as the third source of H₂S production. 3MST also acts as alternative source to CBS for the synthesis of H₂S (Shibuya et al., 2009). 3MP is a substrate of 3MST and is produced through cysteine metabolism and α-KG by CAT. 3MST and CAT localize to the mitochondria and synaptosomes, where the molecular weight of α-KG is 3 kDa (Shibuya et al., 2009). 3MST is found in cerebral Purkinje cells, mitral cells, hippocampal pyramidal neurons, and astrocytes (Shibuya et al., 2009). For H₂S synthesis through the 3MST/CAT pathway, the mitochondrial cysteine concentration should be approximately 1 mM.

Under physiological conditions, CBS, CSE, and 3MST all play a vital role in H₂S synthesis and facilitate the protective function of H₂S in the CNS during aging and disease conditions.

Therapeutic Target and Cell Signaling of H₂S

In several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, sulfide molecule inhibits mitochondrial complex IV and induces apoptosis (Jiang et al., 2016). At 3–30 fold higher concentrations, sulfide becomes toxic by binding to and inhibiting cytochrome C oxidase in complex IV of the electron transport chain (Jiang et al., 2016). On the other hand, sulfide at low concentrations (0.01 to 1 μM) donates electrons to complex II of the mitochondrial electron transport chain which stimulates ATP production (Kabil et al., 2014a). In addition to this, the electrophysiological characteristics of H9 embryonic stem cells (hESCs) are affected by H₂S. At different concentrations, NaHS shows consistently altered hyper polarization (Wei et al., 2012). H₂S might be a therapeutic target for neurodegenerative diseases in hiPSC-derived cortical neurons.

S-sulfhydration is a common process of cellular proteins initiated by H₂S. With this process, H₂S maintains the altered regulation of cellular proteins and enzymes (Gadalla and Snyder, 2010). During S-sulfhydration, the –SSH group is synthesized by the association of thiol groups, where –SSH shows enhanced chemical reactivity (Li et al., 2011). Most importantly, S-sulfhydration of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) can determine cytokine-induced memory impairment in the brain under physiological conditions (Mir et al., 2014). A cysteine must be oxidized prior to modification with H₂S, as H₂S cannot directly react with reduced thiols (Paul and Snyder, 2015). Although the cytosol is a predominantly reducing environment, S-sulfhydration can occur under certain conditions when the generation of ROS occurs in response to physiological stimuli (Paul and Snyder, 2015). Du et al. (2014) observed that macrophage inflammation by oxidized lipoproteins via the sulfhydration of NF-κB p65 at cys38 controlled the phosphorylation of NF-κB p65 (Gade et al., 2013). Exogenous H₂S in microglial cells helps to increase Ca²⁺ influx through the plasma membrane (Abdulle et al., 2018). Elevated levels of Ca²⁺ are also necessary to activate microglial cells following lipopolysaccharide (LPS) challenge (Hoffmann et al., 2003), in which H₂S plays an active role. To increase GSH synthesis, H₂S also activates Cl- channels through K-ATP channels (Kabil et al., 2014a).

Antoxidative Regulatory Role of H₂S

H₂S exerts its antioxidant activity through the metabolism of GSH. Hamar et al. (2012) demonstrated that H₂S is a poor antioxidant compared with other antioxidative agents (Jain et al., 2014). H₂S increases the activity of cysteine and cysteine transporters to enhance the production of GSH. Additionally, oxidative stress is suppressed by H₂S when 3MST is combined with CAT (Kolluru et al., 2013). Cellular damage occurs in newborn rats as a result of GSH deficiency. In the absence of mitochondrial CAT, mitochondria depend on GSH for the removal of H₂O₂ (Figure 2; Meister, 1992). Moreover, in astrocytes, H₂S exerts its antioxidative effects against H₂O₂ by altering glutamate uptake. Several lines of evidence have shown that H₂S enhances the GSH biosynthetic enzyme, γ-glutamyl cysteine sulfurtransferase (Searcy et al., 1995). H₂S increases intracellular reduced glutathione (GSSH), where GSH is an important antioxidant and consists of glutamate, glycine, and cysteine. Among oxidized and reduced forms of cysteine, the reduced state is most prominent for GSH generation (Majid et al., 2013). When the ratio of GSH/GSSG decreases (Figure 2), oxidative stress increases and extracellular cysteine is reduced to produce GSH through the cysteine/glutamate antiport system (Kimura et al., 2010).

Figure 2.

Schematic representation of antioxidant regulatory role of H₂S.

Under oxidative stress, the source of ROS increases hydrogen peroxide (H₂O₂) and super oxide (O•₂^–). RNS increases peroxynitrite (NOOO^–). Simultaneously, glutathione (GSH) creates a redox cycle using nicotinamide adenine dinucleotide phosphate (NADPH) reducing agent associated with the enzyme, glutathione reductase (GR). On the other hand, peroxiredoxin (Prx) is a thiol based antioxidant, reacts with H₂O₂ at a very high rate to neutralize ROS from cell. Prx1, Prx2, and Prx4 are mostly found in nuclei rather than in cytoplasm. Oxidized thioredoxin (Trx) can be reversibly reduced by thioredoxin reductase (TrxR) enzyme in an NADPH-dependent manner, where Trx1 and Trx2 are localized in mitochondria. The combined action of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) helps GSH in the disposal of H₂O₂ in mitochondria as well as GSH reduced to GSSH in the presence of glutaredoxin (Grx). However, during S-nitrosylation of H₂S, cysteine protein structure is being changed and increases the glutamate uptake which mediates H₂S-induced antioxidative function. Overall, GSH, Trx, Prx, and Grx appear to have a protective action against oxidative stress. 3MST: 3-Mercaptopyruvate sulfurtransferase; H₂S: hydrogen sulfide.

ROS are responsible for alterations of cellular diversity. SOD maintains various aspects of normal physiology by reducing oxidative stress. The initial function of SOD is to reduce O₂^•–, although another oxidative agent, H₂O₂, is generated in the process. In particular, SOD does not interfere with the generation of H₂O₂; rather, it retards the adjustment of ROS. For instance, SOD connects with Rac1, which regulates an isoform of nitric oxide synthase (NOX) (Harraz et al., 2008). Following this, NOX produces O₂^•–, indicating the position of SOD1 (Figure 3) (Nunomura et al., 2006). By contrast, the antioxidant function of SOD2 facilitates the function of proteases and DNA repair enzymes (Nunomura et al., 2006).

Figure 3.

Enzymatic antioxidant function of H₂S against oxidative stress.

This schematic diagram explains various enzymatic antioxidant functions of H₂S against oxidative stress. Among the antioxidants, the enzymatic antioxidants mostly take part in retard oxidative stress. Super oxide dismutase (SOD) is one of them and both cytosolic, Cu/Zn, SOD (SOD1), and mitochondrial MnSOD (SOD2) inhibit superoxide (O₂^•–) to form peroxynitrite (NOOO^–). The presence of NOOO^– causes tyrosine nitration, whereas tyrosine is an oxidative marker of oxidative stress. Moreover, SOD interferes with H₂O₂ formation from O₂^•– which forms 8-hydrodeoxyguanosine (8-OHdG), an oxidative damage of DNA. Exposure to excessive H₂O₂, oxidative degradation of cysteine to pyruvate and sulfate are prohibited by SOD and catalase (CAT). At the same time, glutathione peroxidase (Gpx) exhibits antioxidant function examined knockout mice that show specifically 21.8% at the age of 7 weeks against 8-OHdG-induced degradation. GSH: glutathione; GSSH: oxidized glutathione; H₂S: hydrogen sulfide; OGD: oxygen glucose deprivation.

Cellular components are damaged by oxidative enzymes ROS or RNS. When free radicals like H₂O₂, O₂^•– are produced by cellular metabolic activities and environmental factors, Gpx provides antioxidant function against oxidative stress. Gpx is an intracellular enzyme of mitochondria and cytosol. The reducing equivalents produced by GSH help Gpx reduce high levels of H₂O₂ (Figure 3). Moreover, the reducing capacity of Gpx is mediated by GR, which catalyzes the reaction to form GSSH. The production of H₂O₂ causes microglial GSSH to increase by 30% (Navarro-Yepes et al., 2014). Gpx also neutralizes lipid peroxides from lipid alcohol. GSSH can induce the formation of disulfide bonds during oxidative stress. During the catalytic reaction, GSH is recycled (Dringen et al., 2000). The level of GSH in neurons, which is measured using a cysteine precursor, is low compared with that in astroglial cells (Navarro-Yepes et al., 2014).

CAT is a tetrameric enzyme found in numerous tissues that converts H₂O₂ to water molecules. According to Michaelis-Menten steady-state kinetics, CAT has a rate of 50 U/mL, where 1 U oxidizes 1 μmol of H₂O₂ (Scaglione et al., 2016). Additionally, due to oxidative stress, reduced levels of Aβ have been shown in hAPP mice that overexpress mitochondrial CAT. Catalase decreases 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ROS aggregation (Perier et al., 2010). CAT activity has been shown to increase with age as CAT inhibits the aggregation of 8-OHdG during aging (Perier et al., 2010). It triggers activation of glutathione S-transferases, which detoxifies endogenous electrophiles by binding GSH sites. To increase the catalytic function of above antioxidants, it will be necessary to increase binding site affinity, which would include the use of thiol substrates.

Contribution of H₂S in Neurodegenerative Diseases

As an endogenous gasotransmitter, H₂S is thought to play an important role in the CNS. The interrelationships between the cellular antioxidant function of H₂S and age-associated diseases are discussed below (Figure 4).

Figure 4.

The interrelationship between antioxidant effects of H₂S and oxidative stress-induced factors in age-related neurodegeneration.

This figure explains the cellular response of H₂S against Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Down’s syndrome (DS). The increased and decreased levels of H₂S in cells play different roles in each neurodegenerative disease. H₂S retards oxidative derivatives malonaldehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) in AD. In PD, cellular growth is regulated through protein kinases C (PKC), c-Jun NH2-terminal enzyme (JNK), and p38 mitogen activated protein kinase (p38 MAPK). These protein kinases decrease oxidative stress and facilitate antiapoptotic function. H₂S also inhibits MDA in HD cells and facilitates N-acetylcysteine (NAC) function with GSH. In the case of DS, GSH retards overexpression of SOD1 and increased level of GSH inhibits oxidative deterioration. H₂S: Hydrogen sulfide; SOD1: Cu/ZnSOD.

H₂S and AD

AD is an age-associated neurodegenerative disease characterized by senile plaques containing Aβ peptide. H₂S provides protection against oxidative stress by enhancing cell growth and storing mitochondrial function in a p38 and c-jun-N-terminal (JNK)-MAPK-dependent manner (Butterfield and Sultana, 2007). H₂S also provides antioxidant function by enhancing the activity of γ-glutamyl cysteine sulfur transferase and cysteine transport, altering the levels of GSH in glutamate-mediated oxidative stress (Kimura and Kimura, 2004). Moreover, H₂S inhibits the formation of Hcy-induced oxidative stress because the auto-oxidation of Hcy leads to O₂^•– and H₂O₂ formation (Wei et al., 2014). Therefore, Hcy is regarded as a novel therapeutic target for AD where H₂S releases sildenafil to prevent against Hcy-induced oxidative stress and neurotxicity (Wei et al., 2014). S-propargyl-cyysteine, an S-allyl cysteine, might inhibit Aβ_25–35-induced cognitive dysfunction in rats (Tan et al., 2010). Both S-allyl cysteine and S-propargyl-cyysteine are H₂S-modulating agents (Tan et al., 2010). Additionally, H₂S ameliorates oxidative stress-induced compounds, lipid oxidative products, and 4-HNE, to exert its antioxidant function (Mitani et al., 2002). H₂S donor, NaHS, provides neural protection and significantly increases SOD activity in brain tissue to exert its antioxidant function. NaHS significantly inhibits hypochlorous acid-induced cytotoxicity, intracellular ROS, protein oxidation, and lipid peroxidation (Praschberger et al., 2013). Hypochlorous acid is an oxidative stress factor that is found at an elevated level in temporal and frontal cortex of the AD brains (Wei et al., 2014).

Although the effects of H₂S have been elucidated using drug treatment, H₂S donors via ROS signaling, and the formation of different oxidative stress-induced molecules, it will also be important to determine the abnormal characteristics of CBS during H₂S release in AD.

H₂S and PD

The mitochondrial complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, has been observed as MPP⁺ in PD. Oxidative damage in PD has also been demonstrated by mutations in mtDNA. In the familial forms of PD, PINK1 and DJ-1, and their roles in reducing levels of oxidative ROS have been linked to the familial forms of PD. The DJ-1 protein was detected as an oxidatively-damaged molecule in the brains of PD (Lu et al., 2012), and diminished function of PINK1 has been shown to result in decreased mitochondrial complex 1, which results in increased SOD activity and damage to proteins, lipids, and DNA. On the other hand, antioxidant activity of GSH has been demonstrated in the SN of PD patients at a reduced level that is capable of reducing oxidative damage. GSH either inhibits monoamine oxidase to mediate neuroprotection or increases the function of the electron transport system. Coenzyme Q10, such as selenium, is one example of a compound that can slow the generation of free radicals. Following administration of L-3,4-dihydroxyphenylalanine (L-DOPA), glycine/cysteine molecules are reduced in the presence of oxidative stress with the deposition of GSH, where GSH is oxidized to form GSSH, as previously described by Muller and Muhlack (2007).

On the other hand, many studies have addressed that generating hiPSC-derived neurons from patients with defined genetic mutations associated with PD (Ohnuki et al., 2009; Li et al., 2018). α-Syn, encoded by the substantia compacta nigra, is a pathological hallmark of PD (LaMarca et al., 2018). Cortical neurons generated from hiPSC lines of patients with α-Syn mutations exhibited nitrosative and endoplasmic reticulum stress and accumulation, leading to increased expression of α-Syn (Dettmer et al., 2015). L-DOPA is also used to treat PD patients, although it cannot retard the progression of PD and dyskinesia is a common side effect (Zhang et al., 2017). Moreover, plasma levels of homocysteine in cells become elevated in PD when L-DOPA is administered (Zhang et al., 2017). H₂S release of the L-DOPA derivative ACS84 in a 6-OHDA-induced PD model demonstrated therapeutic action, particularly in SH-SY5Y neuroblastoma cells against 6-OHDA-induced oxidative stress, identifying MDA and decreased levels of GSH (Predmore et al., 2012). In addition, H₂S induces nucleus translocation of Nrf2 by s-sulfhydrating cysteine-151 of keap1 and thereby enhances the anti-oxidative capacity of mammalian cells (Hu et al., 2010). H₂S also inhibits the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase possibly through its suppressive effect on ERK phosphorylation (Cao et al., 2018).

Thus, the H₂S-releasing L-DOPA derivative ACS84 reduces cellular damage by reducing oxidative stress in PD. H₂S-mediated sulfhydration is an important mechanism for the attenuation of ROS generation, especially with respect to ACS84, and thus ACS84 may be useful in the treatment of PD.

H₂S and HD

HD is a prototypical age-associated disease caused by CAG trinucleotide repeats in the HTT protein, for which neural dysfunction and death occur due to excitotoxicity, oxidative damage, and apoptosis. Ca²⁺ signaling in the mitochondria implies mitochondrial dysfunction. H₂S exerts antioxidant function in HD patients through enzymatic antioxidants, including SOD, CAT, and Gpx. The GSH precursor N-acetyl transferase (NAC) provides protection against oxidative damage in HD (Schumann and Subramani, 2008). Moreover, administration of 3-nitropropainic acid before application of NAC reduces lesions in HD (Kimura and Kimura, 2004).

The level of CSE in HTT repeating cells (111 repeats) has been shown to be reduced by more than 90%. Similarly, the Q₁₇₅ and R6/2 mouse models also exhibit reduced levels of CSE (Ali et al., 2007). In HD patients, CSE provides cytoprotection, which originates from cysteine proteins, and CSE depletion suggests cysteine loss (Truong et al., 2006). On the other hand, cystamine, the decarboxylated form of cysteine, provides neuroprotection in HD (Zhai et al., 2005). In response to enzymatic dysfunction in HD, Gpx provides broad-spectrum antioxidant function (Fraunberger et al., 2016). In the clinical study of patients affected by HD, it has been observed that cysteamine treated HD patients showed intolerance and cysteamine treatment showed adverse effects such as nausea and weight loss (Dubinsky and Gray, 2006). Moreover, motor subscales of the unified HD rating scale showed motoric impairment after 2 weeks (Dubinsky and Gray, 2006).

In summary, the combined action of GSH and NAC suggest new therapeutic possibilities for HD patients, although further studies will be necessary to understand the antioxidant mechanism induced by GSH and NAC in HD.

H₂S and DS

The neuropathology of DS associated with dementia is related to age. The free radical metabolism of DS, which contributes to neuronal degradation, is also related to age. The mental retardation of DS occurs as a result of trisomy 21 (Das and Reeves, 2011). The overexpression of SOD1 gene as a response to the oxidative stress is observed in DS patients by the trisomic state, where SOD1 gene is located in chromosome 21. Apart from this, the main cause of DS is the elevated level of CBS enzyme. According to the study of Pogribna et al. (2001), DS patients with an increased level of CBS show decreased plasma levels of cystathionine, homocysteine, and SAM. Decreased homocysteine might play a role in the cognitive disability of DS. To maintain homocysteine levels, CBS catalyzes the folate and methionine cycle. CBS protein levels and enzymatic activity are increased in DS, and in particular, elevated CBS activity can lower the level of homocysteine (Hensley et al., 2010). As a consequence, carboxy transulfuration (1C-Ts) metabolism becomes imbalanced and H₂S reaches toxic levels. Metabolism of the 1C-Ts complex, which includes the enzyme CBS (Hensley et al., 2010), has been linked with DS (Hensley et al., 2010). This metabolic alteration associated with CBS causes cognitive disability in DS (Kamoun, 2001). Accumulation of 8-OHdG is an oxidative hallmark found in the cytoplasm of cells in DS patients (Nunomura et al., 2000). SOD1 mediates antioxidant defense by catalyzing the dismutation of O₂^•– to molecular O₂ and H₂O₂, which can be converted to water by CAT and Gpx (Perluigi and Butterfield, 2012).

In summary, DS is a result of the accumulation of H₂S in the brain, particularly the increase in CBS. In general, Gpx activity in DS is not broad. For a better understanding of the antioxidant function of H₂S as a gasotransmitter, clinical investigation will be necessary.

Interrelationship between H₂S and Other Gasotransmitters

In spite of the several biological functions of H₂S as a gasotransmitter, a recent study demonstrated an interaction between H₂S and NO, which exhibited combined kinetics (Wu et al., 2018). According to reaction basis analysis, the reaction of H₂S or –SH with disulfide represents a pathway of potential importance in the detection of H₂S. To form S-nitrosothiols, nitroxyl, and nucleophiles, as well as reducing agents, H₂S provides complementary action (Bruce King, 2013). The combined action of H₂S and NO exhibits positive inotropic effects during inflammation (Kolluru et al., 2013). NOOO^– rapidly interacts with H₂S, which produces sulfinyl nitrite and reduces oxidative molecules (Kolluru et al., 2013). Additionally, to observe H₂S bioavailability in cells, endothelial cells treated with NO donors exhibited increased cysteine uptake in a dose-dependent manner (Kolluru et al., 2013).

Complementary action of CO and H₂S has also been observed. To exert a physiological effect, CO and H₂S act as a signaling molecule, depending on the cellular state. Generally, while hypoxia inhibits HO-1, more H₂S is produced in the brain and CBS is considered a sensor for CO (Farrugia and Szurszewski, 2014). In the presence of HO-2 in neurons, CO inhibits the potential activity of CBS of astrocytes. In astrocytes, as well as other cell types, CO-mediated inhibition of CBS inhibits H₂S release during vasodilation. In the presence of hypoxia, CO also inhibits CSE and, as a consequence, Ca²⁺-dependent K⁺ channels are closed in neurons (Olson, 2013). The enzymatic activity of CBS is changed when CO binds to the heme moiety of CBS.

In summary, the interactions between H₂S, NO, and CO induce potential reactions capable of generating other biologically active species. Thus, further studies will be necessary to determine the complementary action of H₂S, NO, and CO.

Future Perspectives and Concluding Remarks

Based on previous investigations, lower levels of H₂S in the body are the root cause of age-associated diseases that hamper antioxidant function through cell signaling pathways in AD, PD, HD, and DS. Proper levels of H₂S in the body have been shown to be necessary for GSH generation as well as to provide protection against oxidative damage.

As the antioxidant function of H₂S involves GSH, the mechanisms underlying transsulfuration signaling and sulfur-containing molecules that include cysteine molecules may be helpful to clarify the antioxidant function. To address and understand further the biological as well as the clinical potential of H₂S, suitable selection of H₂S donors will also be crucial for the proper release of H₂S in vitro and in vivo. Properly maintained enzymatic pathways are important for H₂S release as well as its ability to induce the antioxidant functions of SOD, Gpx, and CAT. The role of H₂S is likely to be cell-specific under different pathological conditions wherein H₂S can provide proper neuromodulation against oxidative stress. Additional experimental and clinical studies will be necessary to understand further the pathophysiological pathways underlying aging to determine the possible therapeutic use of H₂S-mediated antioxidant function.

Additional files:

Additional Table 1: Database search strategy.

Additional file: Open peer review reports 1 ^{(104.8KB, pdf)} and 2 ^{(105.9KB, pdf)} .