Pathophysiological role of H2S,
H2Sn and NO
The overproduction of H2S suppresses cytochrome c
oxidase that is likely to be involved in the pathogenesis of Down’s
syndrome and ethylmalonic encephalopathy (Marechal et al., 2019;
Panagaki et al., 2019; Tiranti et al., 2009; Fernandez Cardoso et al.,
2017). In contrast, the lack of H2S production may cause
the pathology of Parkinson’s, Huntington’s, and Alzheimer’s diseases
(Chung et al., 2004; Vandiver et al., 2013; Xie et al., 2013; Paul et
al., 2014; Sbodio et al., 2016; Wright et al., 2016; He et al., 2016;
Cao et al., 2018; Sbodio et al., 2018). The detrimental effects caused
by the excess production of H2S and
H2Sn (Ide et al., 2019) as well as those
by lacking in the neuroprotective effect of these molecules (Xiong et
al., 2018; Topcuoglu et al., 2017; Unal et al., 2018; Koike et al.,
2016) have been reported for the pathogenesis of schizophrenia.
- Toxicity of H2S and
H2Sn
- Down’s syndrome
Down’s syndrome (DS) is characterized by impaired brain growth and
maturation, which causes mental retardation, has a trisomy of chromosome
21. CBS is encoded on chromosome 21 (21q22.3) and the expression of CBS
mRNA is 12 times greater in myeloblasts of DS children than those of
normal individuals (Taub et al., 1999). We found that CBS protein levels
in DS brains are approximately 3 times greater than those in the normal
brains that is twice greater than those expected from the trisomy
(Ichinohe et al., 2005). In addition, elderly adults of DS are
associated with an Alzheimer’s type of dementia where CBS is localized
to astrocytes that surround senile plaques in the brain (Ichinohe et
al., 2005).
The greater levels of thiosulfate, a metabolite of H2S,
were detected in urine of DS patients compared to that of normal
individuals (Kamoun et al., 2003). The increased production of
H2S by overexpressed CBS may be the cause of the
neurological impairments in DS patients (Fig. 4). In a mouse model of
DS, three copies of CBS gene are necessary to cause the DS-related
recognition memory deficit (Marechal et al., 2019). Panagaki et al
(2019) showed that the levels of CBS and H2S are
markedly elevated in DS fibroblast cells, and the mitochondrial electron
transport, oxygen consumption and ATP generation are profoundly
suppressed. They suggested the therapeutic potential of CBS inhibitors.
Ethylmalonyl encephalopathy
Ethylmalonyl encephalopathy (EE) is an autosomal recessive early-onset
and defective in cytochrome c oxidase in muscle and brain and excrete
ethylmalonic acid in urine. In this disease ETHE1, a gene encoding a
beta-lactamase-like iron-coordinating metalloprotein or sulfur
dioxygenase, is deficient. A great amount of thiosulfate, a metabolite
of H2S, is excreted in urine of ETHE1 knockout mice and
patients of this disease (Tiranti et al., 2009). H2S is
mainly metabolized by mitochondrial enzymes, SQR, sulfur dioxygenase,
and sulfur transferase. Deficiency of sulfur dioxygenase (ETHE1)
increases in the brain and skeletal muscle the basal levels of
H2S which suppress the cytochrome c oxidase that may
lead to progressive neurological failure (Tiranti et al., 2009) (Fig.
4). In addition, acyl-protein thioesterase, which hydrolyses fatty acids
bound to cysteine, and glutathione transferases are suppressed in ETHE1
knockout mice probably due to the increased levels of
H2S or persulfides (Hildebrandt et al., 2013).
The administration of metronidazole, an antibiotic, or N-acetylcysteine
prolonged the lifespan of ETHE1 knockout mice and marked clinical
improvement in patients with EE (Viscomi et al., 2010). Metronidazole
may be expected to decrease the levels of H2S
incorporated into blood from intestinal bacteria. N-acetylcystein is
metabolized in cells to cysteine, which is a precursor of gluthatione
being predicted to buffer H2S, while it is also a
substrate to produce H2S. In this instance the former
may be a dominant mechanism of N-acetylcysteine for the improvement of
the disease.
H2S decreased the activities of citrate synthase,
aconitase and creatine kinase in the brain of mouse model of EE
(Fernandez Cardoso et al., 2017). H2S also suppressed
mitochondrial respiration, decreased mitochondrial membrane potential,
and induced swelling caused by calcium in brain mitochondria. Changes in
mitochondrial membrane potential and the swelling caused by
H2S may be due to opening of mitochondrial permeability
transition pore (Fernandez Cardoso et al., 2017). Bioenergetics
disturbance, lipid peroxidation, and mitochondrial permeability
transition pore opening mediated by H2S may be involved
in the pathophysiology of brain damage observed in this disease
(Fernandez Cardoso et al., 2017).
- H2S and H2Snare beneficial
- Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenerative disorder mainly causing
motor dysfunction. Parkin and α-synuclein are associated with
pathophysiology of PD. Αlpha-synuclein is a major component of Lewy
bodies associated with rare cases of PD, while parkin, which is a E3
ubiquitin ligase that ubiquitinates diverse substrates and responsible
for the clearance of misfolded proteins including α-synuclein, and its
mutations cause autosomal recessive PD (Choi et al., 2001; Jesko et al.,
2019). Parkin is S-nitrosylated and suppressed its activity and thereby
decreases its protective role in the brains of PD patients (Chung et
al., 2004). In contrast, in the brains of normal individuals it is
active and S-sulfurated. Cys95, Cys 59 and Cys182 are S-sulfurated in
normal individuals, while the same cysteine residues are S-nitrosylated
in PD brains (Vandiver et al., 2013) (Fig. 5). H2S may
be involved in the conversion of S-nitrosylated cysteine to S-sulfurated
one in parkin to improve its function (Yao et al., 2004; Chung et al.,
2004; Vandiver et al., 2013).
Systemic administration of sodium salt of H2S, NaHS,
dramatically reversed the progression of movement dysfunction and loss
of dopaminergic neurons in the PD model rats (Hu et al., 2010). A
similar effect was observed with a H2S-releasing L-dopa
derivative compound (Xie et al., 2013). Overexpression of CBS increases
the endogenous levels of H2S, reversed the behavior
induced in PD model rats, decreased apoptotic neuronal loss of the
nigral dopaminergic neurons (Xie et al., 2013). The application of
H2S and the regulation of CBS activity have a
therapeutic potential (Yin et al., 2017).
Huntington’s disease
Huntington’s disease (HD) is a devastating neurodegenerative disorder
characterized by the progressive development of involuntary movements,
neuropsychiatric symptoms and cognitive impairment (Cepeda and Tong,
2018). HD belongs to triplet repeat diseases, in which elongated
polyglutamine stretches affect the protein product, and the mutant
huntingtin disrupts a number of vital cellular processes, including
neuronal transmission, metabolism and gene transcription (Chaganti et
al., 2017).
Although the levels of CSE are very low in the brain compared to other
tissues (Ishii et al., 2004), those are even much lower in mouse models
of HD and human HD brain compared to a control mice and normal
individuals, respectively (Paul et al., 2014). It is caused by the
suppression of the transcription factor specificity protein 1 (SP1),
which regulates the transcription of CSE, by mutant huntingtin (Ishii et
al., 2004; Paul et al., 2014) (Fig. 5). The expression of CSE is also
regulated by transcription factor 4 (ATF4), which is dysfunctional in
HD, under ER stress or amino acid deficiency (Sbodio et al., 2016).
Striatal cell lines derived from HD model mice have decreased levels of
cystine/glutamate antiporter xCT mRNA and protein expression, leading to
the lower basal levels of GSH and higher basal levels of reactive oxygen
species (ROS) (Wright et al., 2016) (Fig.5). Administration of
N-acetylcysteine ameliorates HD pathology in this model.
Alzheimer’s disease
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that
affects cognitive functions and memory formation. The cause of the
disease is mostly sporadic with much less familial. In familial cases of
AD the mutations in genes encoding amyloid precursor protein (APP),
presenilin (PS) 1 and 2, which constitute the catalytic subunits of
γ-secretase, have been identified (Selkoe and Hardy, 2016). In the
process of metabolism in normal individual, APP is digested by
α-secretase following by γ-secretase, leading to the product which is
easily eliminated, while in AD brain the metabolism by β-secretase
(BACE) and γ-secretase generates amyloid β-protein (Aβ1-42), which
aggregates and exerts neurotoxicity. Phosphorylated tau protein also
causes deposition as neurofibrillary tangles (Reddy and Oliver, 2019).
Neuropolypeptide h3, also known as hippocampal cholinergic
neurostimulating peptide, upregulates the levels of choline
acetyltransferase whose activity is decreased in patients with AD in
cholinergic neurons (Reed et al., 2009; Ojika et al., 1998). Nitration
of tyrosine in this peptide decreases its neurotropic activity on
cholinergic neurons and may lead to the decline in cognitive function
(Reed et al., 2009). The levels of BACE1, PS1 and pp38 mitogen-activated
protein kinase (MAPK) are increased while those disintegrin and
metalloproteinase domain-containing protein 17 (ADAM17) are decreased in
the APP/PS1 transgenic mice (He et al., 2016). The administration of
NaHS into the transgenic mice restores the changes in these factors
characterized in AD, suggesting that H2S inhibits the
expression of BACE1 and PS1 by activating phosphoinositide 3-kinase
(PI3K)/Akt pathway in AD (He et al., 2016).
H2S inhibited exogenous ATP-induced inflammatory
responses through reducing pro-inflammatory cytokines, ROS, and
activation of NF-kB pathway. H2S also suppressed the
production of Aβ1-42, which was induced by exogenous ATP probably due to
the augmented production of amyloid precursor protein and the activation
of β- and γ-secretase (Cao et al., 2018) (Fig. 5). As a mechanism for
H2S reducing inflammation and the production of Aβ1-42,
they suggested that H2S suppresses the activities of
signal transducer and activator of transcription 3 (STAT3) by inhibiting
ATP-induced phosphorylation and decreases the activity of cathepsin S
through S-sulfuration of this enzyme (Cao et al., 2018) (Fig. 5).
H2S and H2Snare beneficial or toxic
3-1) Schizophrenia
Schizophrenia is a chronic and severe mental disorder that affects a
person’s thinking, feeling and behaviors. Symptoms, which typically come
on gradually and begin in young adulthood, fall into three categories;
positive symptoms (hallucinations, delusions, etc.), negative symptoms
(flat affect, reduced feeling, etc.) and cognitive symptoms (poor
executive function, trouble focusing, etc.) (American Psychiatric
Association, 2013).
Although the excessive NO production has been shown to be involved in
the pathology of this disease (Pitsikas, 2016), the potential beneficial
effects have been reported both NO donors and inhibitors on
schizophrenia symptoms induced by amphetamine such as prepulse
inhibition disruption and hyperlocomotion (Issy et al., 2018),
suggesting the deviation of both decrease and increase of NO from the
normal levels may be involved in the pathology of this disease.
Both excess and deficiency of H2S and
H2Sn have also been proposed to be
involved in the pathogenesis of schizophrenia. Plasma
H2S levels were significantly lower in patients with
schizophrenia relative to healthy control subjects, and a positive
association was observed between plasma H2S levels and
working memory, visual memory or executive function in patients,
suggesting that decreased H2S is involved in the
psychopathology and cognitive deficits of this disease (Xiong et al.,
2018) (Fig. 5).
Untreated schizophrenia patients had significantly higher
(disulfide/total thiol) and (disulfide/free thiol) ratio in blood and a
significantly lower (free thiol/total thiol) ratio compared to those of
healthy individuals (Fig. 5). Thiol homeostasis is disturbed by a shift
to the disulfide bond formation (oxidized) in patients (Topcuoglu et
al., 2017). Similar results were also obtained in schizophrenia patients
using medication (Unal et al., 2018).
Methylglyoxal, a highly reactive dicarbonyl compound, is a major
precursor for advanced glycation end products (AGEs), of which the
production is associated with various neurological disorders including
schizophrenia (Toyoshima et al., 2019; Ohnishi et al., 2019).
H2Sn protect differentiated human
neuroblastoma SH-SY5Y cells from methylglyoxal-induced cytotoxicity,
suggesting that H2Sn scavenge
methylglyoxal and suppress the accumulation of AGEs and incidents
induced by carbonyl stress (Koike et al., 2013; Koike et al., 2016).
Excess production of H2S and
H2Sn has also been proposed to be
involved in the pathogenesis of schizophrenia. Yoshikawa and colleagues
found that C57BL/6N (B6) strain mice exhibited greater scores of
prepulse inhibition (PPI), which is the normal suppression of a startle
response, than C3H/HeN (C3H) mice did (Watanabe et al., 2007). The
impaired PPI is regarded as an endophenotype for schizophrenia (Braff et
al., 2001). By proteomics analysis the same group found that the
expression of MPST is increased in C3H mice compared to B6 (Ide et al.,
2019). DNA methylation levels at MPST gene was highly enhanced in C3H
mice, and the mean methylation levels of the sites were positively
correlated with the expression levels of MPST. MPST levels in
schizophrenia were positively correlated with symptom severity scores.
In MPST -transgenic mice the expression of genes for energy formation
was decreased and mitochondrial energy metabolism was impaired (Ide et
al., 2019) (Fig. 4).
Maternal immune activation model, which is induced by the injection of
polyriboinosinic-polyribocytidilic acid to mother, shows perturbed early
neural development via inflammation and oxidative insults (Meyer and
Feldon, 2012; Giovanoli et al., 2013; Bundo et al., 2014). In this model
the expression of MPST and other inflammatory and oxidative genes were
elevated in the brain when pups grow to the adult (Ide et al., 2019). In
human brains, catalase gene product was upregulated in schizophrenia
samples compared to the controls (Ide et al., 2019).
Inflammatory/oxidative insults in early brain development induce
upregulation of H2S/polysulfides production excessively
as an antioxidative response that suppresses cytocrhome c oxidase,
leading to schizophrenia.PerspectiveNeurotransmitters, cytokines, and hormones diffuse to reach their
targets to react with their receptors. An advantage of diffusion is that
many targets localized in the area within its reach can be activated.
After transmitting the signal, they are properly eliminated. For
example, neurotransmitters are released from presynapse and diffuse the
synaptic cleft to the receptors at postsynapse to exert their effects,
and for cessation of responses the transmitters are recovered by uptake
or degraded by enzymes to clear the synaptic cleft.
NO barely dissolve in water (5.6 mg/100 ml at 20oC),
while H2S does well (413 mg/100 ml at
20oC) (Kimura, 2015b). H2S dissociates
to H+ and HS- (pK1 =
7.04), and further to S2- (pK2 =
11.96). Because H2S is also lipophilic, it readily
passes through plasma membrane. These characteristics of
H2S have an advantage to transmit signals across the
membrane by diffusion. HS- channels or transporters,
which have been identified in both bacteria and mammals (Czyzwski and
Wang, 2012; Jennings, 2013), enable H2S to pass through
plasma membrane even more efficiently and selectively.
H2Sn, which can pass through the plasma
membrane, diffuse to the targets on nearby cells (Nagai et al., 2006;
Oosumi et al., 2010; Kimura et al., 2013; Greiner et al., 2013; Kimura
et al., 2017). For example, H2Snactivate TRPA1 channels by passing through the plasma membrane to
S-sulfurate the amino terminus located in the cytoplasm (Nagai et al.,
2006; Oosumi et al., 2010; Kimura et al., 2013). Although 23 out of 31
cysteine residues are localized to the amino-terminus (Wang et al.,
2012), only Cys422 and Cys634 are responsible for regulating the
activity of TRPA1 channels (Hatakeyama et al, 2015; Kimura, 2015a). The
remaining 21 cysteine residues were not involved in the activation of
channels whether or not they are S-sulfurated. Signaling by diffusion
may be less specific to target proteins than that by enzymatic
modification. In this case, however, S-sulfuration of the two specific
cysteine residues by sulfur transferases, if any, may not have any
advantage on specificity to activate the channels compared to the
diffusion of H2Sn.
S-sulfuration is compared to phosphorylation, in which kinases
incorporate phosphate to residues of serine, threonine and tyrosine
(Kimura, 2020). H2S and
H2Sn S-sulfurate cysteine residues even
in the other cells but not specific ones. In contrast, MPST transfers
sulfur from 3MP to specific cysteine residues, but the reaction is
restricted only inside the cells (Shibuya et al., 2009; Shibuya et al.,
2013; Kimura et al., 2017). H2S and
H2Sn endogenously exist (Kimura et al,,
2015; Koike et al., 2017), and both their diffusion and enzyme mediated
mechanisms play a role in S-sulfuration under physiological conditions.
Bacteria use H2S produced by MPST to protect themselves
from antibiotics (Shatalin et al., 2011). Because bacteria have channels
specific to HS- (Czyzewski and Wang, 2012), signaling
by H2S with other cells must have emerged in the early
history of life on earth. Mammalian have developed
HS-/Cl- transporter on erythrocytes
to rapidly and selectively exchange HS- with the
extracellular milieu (Jennings, 2013).
Patients exposed to high concentrations of H2S are
suffered from cognitive disability (Reiffenstain et al., 1992), and the
levels of neurotransmitters in the brain were affected in animals
exposed to H2S (Warenycia et al., 1989). The expression
of SQR, which is the first step for the metabolism of
H2S, is very low in the brain (Linden et al., 2012).
These observations suggest the vulnerability of the brain to excessive
H2S.
In DS, EE, and schizophrenia, the high levels of H2S or
its producing enzymes exert a toxic effect on cytochrome c oxidase,
leading to neuronal dysfunction (Taub et al., 1999; Ichinohe et al.,
2004; Panagaki et al., 2019; Tiranti et al., 2009; Viscomi et al., 2010;
Linden et al., 2012; Ide et al., 2019). In addition, high concentrations
of H2S metabolized by SQR must generate the toxic levels
of polysulfides on neurons. The inhibitors of H2S
producing enzymes, which may also decrease the levels of polyslufldes,
have suggested to have therapeutic potential in these diseases. The
accurate comparisons of the levels of H2S and
polysulfides between patients and normal individuals are required to
examine the efficiency of these inhibitors for therapeutic uses.
S-sulfuration makes parkin active in the brains of normal individuals,
while S-nitrosylation inactivates it in those of PD patients (Paul et
al., 2014). It is intriguing to know whether or not exogenously applied
H2S or the enhancement of H2S producing
enzymes is able to convert S-nitrosylated cysteine to S-sulfurated one.
The difference in the levels of H2S between patients and
normal individuals is not well understood in PD. The concentrations of
polysulfides, which must be accompanied by the changes of
H2S levels, should also be clarified. Controlling the
levels of these signaling molecules and the activities of enzymes
related to S-nitrosylation and S-sulfuration may have a therapeutic
benefit for diseases in the central nervous system.