Redox Biology 34 (2020) 101567

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Redox Biology
journal homepage: www.elsevier.com/locate/redox

The role of nitric oxide in brain disorders: Autism spectrum disorder and T
other psychiatric, neurological, and neurodegenerative disorders
Manish Kumar Tripathi, Maryam Kartawy, Haitham Amal∗
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

A R T I C LE I N FO A B S T R A C T

Keywords: Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in
Nitric oxide physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differ-
S-nitrosylation entiation and proliferation of neurons. It also regulates synaptic activity, plasticity and vesicle trafficking. NO
Autism spectrum disorder affects cellular signalling through protein S-nitrosylation, the NO-mediated posttranslational modification of
Alzheimer's disease
cysteine thiols (SNO). SNO can affect protein activity, protein-protein interaction and protein localization.
Psychiatry
Neurodegeneration
Numerous studies have shown that excessive NO and SNO can lead to nitrosative stress in the nervous system,
Neurodevelopmental disorders contributing to neuropathology. In this review, we summarize the role of NO and SNO in the progression of
Brain disorders neurodevelopmental, psychiatric and neurodegenerative disorders, with special attention to autism spectrum
SHANK3 disorder (ASD). We provide mechanistic insights into the contribution of NO in diverse brain disorders. Finally,
we suggest that pharmacological agents that can inhibit or augment the production of NO as well as new ap-
proaches to modulate the formation of SNO-proteins can serve as a promising approach for the treatment of
diverse brain disorders.

1. Introduction peroxynitrite, which ultimately damages DNA, lipid and protein during
oxidative stress [10]. NO may affect cellular signalling through proteins
Nitric oxide (NO) is one of the most important signalling molecules S-nitrosylation (SNO), tyrosine nitration, and S-nitrosoglutathione
of the central nervous system (CNS) and peripheral nervous system (GSNO) formation [11–15] (see Fig. 1). SNO is the NO-mediated post-
(PNS) [1–3]. NO is produced in the brain from L-arginine by three nitric translational modification (PTM) of cysteine thiols, in which a ni-
oxide synthase) isoforms (NOS1, NOS2, NOS3) [1]. Neuronal NOS trosogroup is incorporated into a reactive cysteine thiol and forms a
(nNOS or NOS1) is constitutively expressed in the cytosol of neurons nitrosothiol group [16,17]. SNO plays a role in protein localization,
and requires Ca2+ for its activity. Inducible NOS (iNOS or NOS2) is axonal transport, maintenance of synaptic plasticity and regulation of
found in the cytosol of glial cells and its activity is independent of Ca2+. various neuronal pathways [9,18] (see Fig. 1). However, dysregulation
Endothelial NOS (eNOS or NOS3) is constitutively expressed in en- of NO and SNO signalling is involved in progression of many neuro-
dothelial cells in the membrane-bound state and requires Ca2+ for its developmental, neurobehavioral and neurodegenerative disorders.
activity [4–6]. nNOS is attached to N-methyl-D-aspartate receptor In this review, we summarize the role of NO and SNO in the pro-
(NMDAR), post synaptic density protein-95 (PSD-95) and PSD-93 [7]. gression of neurodevelopmental disorders, paying special attention to
When the NMDAR gets activated by extracellular stimuli, it allows entry autism spectrum disorder (ASD). We discuss the involvement of SNO in
of Ca2+ inside the cell. Ca2+ can form a complex with calmodulin, and the pathogenesis of ASD (See Fig. 2), which we have recently dis-
together they initiate the NO formation by activating NOS enzyme [8]. covered in our studies [19]. We have summarize the involvement of NO
NO is a small gaseous molecule, which diffuses to activate guanosine and SNO signalling in Alzheimer's disease (AD) (Fig. 3). We also sum-
monophosphate (GMP) cyclase (see Fig. 1). At low concentration, NO marize the involvement of NO and SNO signalling in a number of other
acts as a signalling molecule, taking part in the regulation of multiple brain disorders including psychiatric, neurodevelopment, and neuro-
functions in different organs and systems of the body. In the nervous degenerative ones. Alterations in NO and other NO-related molecular
system, it regulates synaptic activity, plasticity, and vesicle trafficking. changes in the different brain disorders are described in detailes
However, at higher concentrations, NO may be toxic and could lead to (Fig. 4). Further, we list the key SNO-proteins involved in different
cell death [9]. It reacts with superoxide radical (O2−) and forms brain disorders (Table 1). Table 2 summarizes different

∗
Corresponding author.
E-mail address: Haitham.amal@mail.huji.ac.il (H. Amal).

https://doi.org/10.1016/j.redox.2020.101567
Received 13 February 2020; Received in revised form 4 May 2020; Accepted 5 May 2020
Available online 15 May 2020
2213-2317/ © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

Fig. 1. Schematic representation of NO signalling

pathways in physiological conditions. Ca+2 influx
activates nNOS by binding with calmodulin, leading
to NO production. NO activates soluble guanylate
cyclase to produce cGMP which interacts with many
intracellular proteins such as PKG. PKG leads to
CREB phosphorylation which leads into transcrip-
tional activation of different genes. NO, directly and
indirectly, leads to S-nitrosylation (SNO) of many
proteins and receptors. SNO modification of proteins
can alter the receptor activity, protein-protein in-
teraction and protein localization leading to altera-
tion in signalling. Increased level of NO increases
nitrosative stress, proxynitrite formation, tyrosine
nitration of proteins, which ultimately may lead into
cell death.

pharmacological agents used for therapies by manipulating NO. Finally, SUV39H1 degradation enhances the binding and activation of CREB
we provide mechanistic insight into the contribution of NO in diverse [23]. In conjunction with BDNF-induced SNO, CREB binds to the cAMP
brain disorders and suggest potential and promising therapeutic targets response element of the promoters of its target genes upon phosphor-
for treatment. ylation at Ser-133 in the KID domain [25] by different receptor-acti-
vated protein kinases, such as protein kinase A (PKA), calmodulin-de-
2. Role of nitric oxide in neuronal development pendent protein kinase (CaMK), mitogen-activated protein kinases
(MAPK), and other kinases. These kinases are activated by Ca2+ influx
NO plays major roles in neurogenesis and neurodevelopment [20]. triggered upon depolarization [26,27]. The phosphorylation of Ser-133
Importantly, NO regulates the activity of the brain-derived growth leads to a 10- to 20-fold increase in CREB's transcriptional activity [28].
factor (BDNF) [21]. BDNF promotes SNO of many nuclear proteins, Interestingly that both NO signalling, which produces cGMP, and cAMP
including those related to the cAMP response element-binding protein signalling could regulate the phosphorylation of CREB (see Fig. 1).
(CREB), a cellular transcription factor that is involved in regulation of cAMP activates CREB through the canonical cAMP/PKA pathway and
neuronal and dendritic development [22]. Sen and Snyder [23] have the exchange protein directly activated by cAMP (Epac) pathway. Epac
shown that BDNF, along with other nerve-growth factors, activate activates extracellular signal-regulated kinase 1/2 (ERK1/2) signalling,
nNOS leading to S-nitrosylation of glyceraldehyde 3-phosphate dehy- which subsequently leads to Ser-133 phosphorylation of CREB [29].
drogenase (GAPDH)/seven in absentia (Siah) homolog complex (SNO- Meanwhile, cGMP activates the downstream protein cGMP-dependent
GAPDH-Siah). SNO of GAPDH at Cys-150 promotes its association with protein kinase G (PKG), which also phosphorylates the transcription
Siah, which leads to formation of SNO-GAPDH-Siah complex. Further, factor CREB at Ser-133 [29]. This dual phosphorylation by cAMP/PKA/
SNO-GAPDH-Siah complex translocate into the nucleus [24], initiating Epac and cGMP/PKG pathways may amplify the CREB activity [29].
the ubiquitination and degradation of the histone-methyltransferase Once CREB is activated and CREB-binding protein is recruited, tran-
enzyme, suppressor of variegation 3–9 homolog 1 (SUV39H1) protein. scription is initiated [30].
SUV39H1 is the principal enzyme responsible for trimethylation of Further, under normal NO concentration, SNO-GAPDH-Siah trans-
histone H3 at Lys-9, a molecular marker associated with transcriptional location is negatively regulated by GAPDH's competitor of Siah protein
silencing. Therefore, inhibition of the trimethylation of histone H3 via enhancer life (GOSPEL) protein. SNO of GOSPEL at Cys-47 enhances its

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

Fig. 2. NO signalling in autism spectrum disorder (ASD). Schematic representation of NO involvement in ASD. Mutation in SHANK3 gene may cause imbalance in
Ca+2 homeostasis. Ca+2 is responsible for intracellular NO production which leads to S-nitrosylation of many proteins. S-nitrosylation of calcineurin inhibited its
phosphatase activity which leads to increased levels of phosphorylated (P) synapsin-1 and CREB. P-synapsin-1 increases vesicle mobilization and P-CREB increases
the recruitment of transcriptional co-activators and cortical activity. S-nitrosylation of syntaxin1a, inhibited its binding with Munc-18 which ultimately leads to
increased vesicle docking and fusion.

ability to bind to GAPDH, which terminates the translocation of SNO- inhibits its transcriptional activity [40]. SNO-MEF2 also reduces the
GAPDH-Siah complex. SNO-GAPDH-GOSPEL remains in the cytosol expression of nuclear receptor tailess (TLX) [41], which is a regulator of
[31]. In contrast, nuclear translocation of SNO-GAPDH promotes adult neurogenesis and is responsible for learning and memory [42].
transnitrosylation of many proteins, such as histone deacytylase 2 Lipton and co-workers have found high level of SNO-MEF2 in Alzhei-
(HDAC2), DNA-activated protein kinase, sirtulin −1, and others mer's disease (AD), leading to neurodegeneration. These changes were
[32,33]. BDNF-induced transnitrosylation reaction between SNO- present in the post-mortem brains and mutant transgenic mice [41].
GAPDH and HDAC2 results in SNO of HDAC2 at Cys-262 and Cys-274 Thus, SNO-MEF2 inhibits neurogenesis and neuronal differentiation in
[34]. Normally, HDAC2 remains attached to CREB target gene pro- brain [41]. Studies on nNOS knockout mice showed abnormal dendritic
moters. However, SNO of HDAC2 promotes its dissociation and rapid branching [43] and reduction in neurogenesis [37]. All these reports
acetylation of histone H3 and H4, resulting in association of CREB with imply that NO plays an important role in neurodevelopment. Thus,
its target genes. Consequently, BDNF-mediated SNO of HDAC2 plays a dysregulation of the NO signalling can bring about a variety of neuro-
role in dendritic development [32,34]. developmental diseases. Below, we discuss the role of NO in different
Rearrangement of actin and myosin in cytoskeletons is necessary for brain disorders.
axonal growth, axonal guidance, axonal modification and brain devel-
opment [20] and these processes are also mediated by NO [35]. Fur- 3. Autism spectrum disorder (ASD)
thermore, SNO of microtubule-associated protein B1 (MAPB1) leads to
a modification of axon retraction [36]. MAPB1 contains a heavy chain ASD is a neurodevelopmental disorder associated with impaired
(HC) and a light chain (LC1) domains. LC1 domain can be S-ni- communication, impaired social skills and repetitive behaviour [44].
trosylated at Cys-2657 of MAPB1, which increases the binding capacity ASD is caused by genetic mutations, as well as environmental and non-
of HC/LC1 MAPB1 complex with microtubules. This complex inhibits genetic factors [45]. According to the world health organization
the dynein leading to inhibition of axonal extension and increases of (WHO), 1–1.5% of children suffer from ASD globally [46,47]. Cur-
axonal retraction [36]. rently, there is no treatment for ASD and symptomatic features are
Previous work has shown the involvement of NO in neurogenesis reduced by different psychiatric medications.
[37–39]. nNOS knockout rats or inhibition of nNOS by pharmacological SHANK3 mutation is one of the most promising ASD-associated
agents negatively regulate neurogenesis [37–39]. Thus, SNO of myo- mutations [48]. Several reports on Shank3 KO mouse models showed
cyte enhancer factor 2 (MEF2), a transcription factor involved in neu- defects in biochemical, electrophysiological and cellular pathways
rogenesis at Cys-39 reduces its binding affinity to DNA and ultimately [49–51]. As per our knowledge, Amal et al. was the first to report the

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

Fig. 3. NO signalling in Alzheimer's disease (AD). Schematic representation of the involvement of NO in AD progression. Altered Ca+2 influx leads into aberrant NO
production in cells, which S-nitrosylates many proteins and increases nitrosative stress, peroxynitrite formation, protein tyrosine nitration, which alters the signalling
pathways and lead into cell death in AD. SNO of parkin and XIAP alter their E3 ubiquitin ligase activity. SNO of PDI disrupts its chaperone activity which enhances
the accumulation of misfolded proteins in cells. SNO of Cdk and DRP-1 alters the mitochondrial dynamics.

involvement of NO in the development of ASD [19]. Amal et al. has (protein phosphatase catalystic subunit alpha-Ppp3ca, syntaxin 1a,
hypothesized that Shank3 mutation leads to an increase of Ca2+ influx vesicle associated membrane protein 3 and others) and in glutamatargic
that in turn activates nNOS activity leading to the dramatic NO for- pathway (glutamate dehydrogenase 1, mGluR, G protein subunit alpha
mation and NO-related molecular changes, including S-ni- O1 Gnao-1 and others) [19]. Analyzing the shared SNOed proteins in
trosoglutathione (GSNO), 3-nitrotyrosine (Ntyr), and SNO [19]. SNO the cortex of KO mice of both 6-week-old and 4-month-old mice showed
targets a wide range of prominent intracellular proteins leading to al- an evidence of enriched processes known to be affected in ASD, such as
teration in signalling pathways, which may converge onto synaptic, synaptic vesicle cycle. The interactome analysis of the shared proteins
neuronal and behavioral deficits. The work has reported that in Shank3 in the cortex of KO mice showed protein clusters that function in the
mutated mice [InsG3680 (+/+)], the SNO-proteome is reprogrammed synaptic vesicle cycle (syntaxin 1a, Ppp3ca, Nsf and Dnm1) and glu-
and dysregulation of proteins by S-nitrosylation and de-nitrosylation tamate regulation (glutamic-oxaloacetic transaminase-Got1, Got2,
occurs [19]. System biology analysis of both wild type (WT) and Shank3 Gnao-1). This work showed an increase of 3-nitrotyrosine level in dif-
KO mice revealed 9-fold change in SNO level of proteins involved in the ferent cortical regions. Level of GSNO was found to be increased in the
synaptic vesicle cycle (Syntaxin1a (Stx1a), synaptotagmin 1, and N- cortex of both KO groups as compared with WT groups. The study also
ethylmaleimide sensitive fusion protein (Nsf)) in cortex of KO mice but showed that calcineurin was SNOed in the cortex which inhibited its
not in WT mouse brain. Gene ontology (GO) and KEGG analysis of 6- phosphatase activity (see Table 1 and Fig. 2). Inhibition of calcineurin
week-old KO mice showed enrichment of many proteins that involved activity increased the levels of p-Synapsin-1 and p-CREB protein [19],
in neurodevelopment and ASD. Further, systems biology analysis (see Fig. 2). Synapsin-1 is involved in regulation of vesicle exocytosis
showed the enriched SNO proteins involved in synaptic vesicle cycle and its phosphorylation increases exocytosis of vesicles [52]. Increase
and oxidative phosphorylation in Shank3 KO mice. These results con- in phosphorylated level of Synapsin-1 in the cortex of the mutant mice
vincingly show an association between Shank3 mutation and NO [19]. may indicate that SNO of calcineurin is responsible for increased vesicle
Further, this work showed that protein-protein interaction analysis in mobilization. The study found a significant increase in p-CREB levels,
the cortex of KO mice showed a network of S-nitrosylated proteins which is another substrate of calcineurin [19]. Increased level of p-
functionally involved in synaptic vesicle cycle, neurotransmission CREB has also been reported in another model of ASD [53]. Syntaxin1a,

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

Fig. 4. The involvement of NO in brain disorders. Alterations in NO and other NO-related molecular changes in the different brain disorders are presented.
Abbreviations: NO: nitric oxide; Ntyr: nitrotyrosine; GSNO: S-Nitrosoglutathione; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase.

which enhances the formation of the SNARE complex, was SNOed in and working memory) (see Table 2) [68,69]. All these studies suggested
Shank3 KO mice [19]. SNO of this protein enhances the formation of the that NO deficiency plays a role in the pathology of schizophrenia.
SNARE complex leading to increase of synaptic vesicle docking and
fusion [54], (see Fig. 2). SNO of metabotropic glutamate receptor 7
5. Bipolar disorder (BPD)
(mGluR7) was found in the cortex of the mutant mice. The study sug-
gested that SNO of mGlur7 may increase the influx of Ca2+ in pre-
BPD is a chronic mental illness also referred to as manic depressive
synaptic neurons, which in turn increases vesicle fusion [19]. Taken
illness [70]. Accurate and early diagnosis of BPD is difficult and more
together, the study implies that NO is an important factor in ASD. The
than 1% of individuals suffer from this kind of neuropathology globally
insights obtained from the SHANK3 mutation study may likely be ap-
[71]. On the basis of severity and duration of the manic and depressive
plicable to a broader group of patients with genetically diverse but
episodes, the Diagnostic and Statistical Manual of Mental Disorders,
mechanistically related etiology, thus it may imply NO as an important
Fifth Edition (DSM-5) [72] divide BPD into four categories, bipolar I
pathological factor in ASD.
disorder, bipolar II disorder, cyclothymia and residual category [70]. It
has been revealed in some studies that defects in dopaminergic and
serotonergic pathways are responsible for the development of BPD
4. Schizophrenia
[70,73]. The role of NO signalling in BPD has also been reported [74].
NOS activity was reduced in blood platelets of patients suffering from
Schizophrenia is a severe and chronic mental disorder, that affects
BPD compared to healthy individuals [75]. Another study has shown
person's thinking, feeling, and behaviour. It accounts for approximately
that lithium treatment increases the level of NO in plasma of patients
1% of the total world population [55]. The cause of schizophrenia is
suffering from this disease, indicating a role of lithium in regulation of
unknown and it is considered as a multifactorial disorder [56]. Symp-
NO signalling in subjects with this pathology during depressive epi-
toms of schizophrenia can be divided into three different categories,
sodes (see Table 2) [76]. In this study, plasma NO level in bipolar de-
such as positive symptoms, negative symptoms and cognitive dis-
pression was not different from healthy controls. Other works revealed
turbances [56,57]. Hallucinations, catatonic behaviour, delusion and
that NO and nitrite level in plasma of bipolar patients was higher than
disturbed thought procession are considered as positive symptoms.
in healthy controls (see Fig. 4) [77]. A meta-analysis carried out by
Avolition, anhedonia and social withdrawal represent negative symp-
Andreazza et al. has confirmed an increased activity of the NO signal-
toms [55]. Studies suggested that NO may play a role in the develop-
ling in patients with BPD [78]. The controversy of these data can be
ment of schizophrenia [58,59]. Researchers hypothesized that impair-
explained by the differences in the stage of the disease and medications
ments of dopaminergic and cholinergic pathways may be involved in
used [76]. Nevertheless, the accumulated data can show the involve-
the development of schizophrenia through the involvement of NMDA
ment of NO in BPD, although its mechanistic role needs further in-
receptors-dependent NO signalling [60–62]. Polymorphism of nNOS
vestigation.
gene is found to be a critical risk factor for the development of schi-
zophrenia [63]. Also, the levels of NO metabolites, such as nitrite and
nitrate, were found to be reduced in plasma, serum and cerebrospinal 6. Migraine
fluid (CSF) of schizophrenic patients (see Fig. 4) [64–66]. Previous
work showed that the genetic ablation of nNOS results in cognitive Migraine is a reversible and chronic neurological disorder with se-
deficit in mice, emphasizing the role of NO in learning and memory vere or moderate headache. The major symptoms associated with mi-
[67]. Schizophrenic patients that were treated with NO donor ni- graine are cutaneous allodynia, phonophobia, photophobia, dizziness,
troprusside, showed improvement of symptoms (attention, cognitive vertigo and different gastrointestinal problems [79]. According to

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Table 1
List of S-nitrosylated proteins involved in diverse brain disorders.
Protein Disease Sites of SNO modification Experimental models Suggested molecular/biological consequences of S-nitrosylation Reference

Calcineurin ASD – Mice Inhibition of the phosphatase activity [19]

Syntaxin 1a ASD – Mice Enhanced binding with SNARE complex [19]
mGluR7 ASD – Mice Increase of Ca2+ influx in presynaptic neurons [19]
RNF213 AD – Mice Inhibition of the ligase activity [122]
Drp1 AD, HD Cys-644 Human, mice, cell lines Increase the rate of mitochondrial fission [130,178]
Cdk-5 AD Cys-83 and Cys-157 Human, mice, cell lines Hyperactivation of the kinase activity [125,126]
PSD 95 AD Cys-3 and Cys-5 Animal, cell lines Blocks translocation of the protein [205]
IDE AD Cys-110 and Cys 819 Cell lines Inhibition of the metalloprotease activity [9,18,206]
ApoE AD Cys-112 Human, cell lines Reduction of affinity to LDL receptors [136,207]
MEF2 AD Cys-39 Human, mice, cell lines Reduction of the binding affinity to DNA [41]
Aldolase C, fructose bisphosphate AD – Human Reduction of the metalloprotease activity [137]

6
MAP1B AD Cys-2457 Mice, cell lines Enhancement of the binding affinity with microtubules [36,208]
Carbonic anhydrase-II (CAH-II) AD – Human Reduction of the enzymatic activity leading to protein accumulation [209]
Caspases AD Cys-163 Human cell lines Decline in protease activity [9,210]
GSK3β AD Cys-76, cys-199, cys-317 Mice, cell lines Inhibition of the kinase activity and increased translocation into nucleus [119]
XIAP PD, AD, HD – Human, mice, cell lines Inhibition of the anti-apoptotic function [150]
GAPDH AD, ALS, cerebral Cys-150, cys-152 Human, mice, cell line Enhancement of the binding with Siah complex and activation of p300/CBP resulting in [33,183,184]
ischemia, PD the increased neuronal death
Parkin PD – Human, mice, cell lines Autoubiquitination and degradation. [147,152]
DJ-1 PD Cys-46, cys-53, cys106 Human, cell lines Reduction of the antioxidant activity [148,211]
PTEN PD, AD Cys-83 Human, cell lines Reduction of the phosphatase activity [148]
PDI PD, ALS – Human, mice, cell line Inhibition of the dithiol isomerase activity [133,149]
Prx2 PD Cys-51, cys-172 Human, cell lines Inhibition of the antioxidant activity [151]
Huntingtin HD – Mice, cell lines Protein aggregate formation leading to cell death [174]
NMDAR AD, Prion disease Cys −744, cys-798 Animal Inhibition of the receptor activity and NO production [9,18,212]
MMP9 Cerebral ischemia – Animal, cell lines Reduction of the metalloprotease activity [213]
PLP MS – Animal Conformational and functional alteration [195,204]
Redox Biology 34 (2020) 101567
M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

Table 2
Summarization of different pharmacological agents used for therapies by manipulating NO.
Disease name Pharmacological agents Protective versus detrimental effects References

Schizophrenia Sodium nitroprusside Improvement in attention, cognitive and working memory [68,69]
Bipolar disorder Lithium Increased NO level in plasma and improved symptoms. [76]
Migraine 1 Sodium nitroprusside 1-Initiated headache and migraine [87–89,94–96]
2 Isosorbide dinitrite 2 Initiated migraine
3 Sildenafil 3 Increased migraine pain
4 Mepyramine 4 Reduced headache
Epilepsy 1-Methylene blue 1-Increased symptoms of epilepsy [99,100,102,103]
2 L-arginine 2 Reduced symptoms of epilepsy
3 L-NAME 3 Induced seizures
Addiction 1-L-NAME 1 Reduced morphine abstinence syndrome [108–110,112]
2 L-NNA 2-Reduced opioid withdrawal syndrome
3-Tempol 3-Abolished cocaine psychomotor sensitization
AD L-NNA Reduced apoptosis [126]
PD 1-7 -nitroindazole 1-Protection from cell death [164–167,170]
2 Pargyline 2 Protection from cell death
3 L-NAME 3 Protection from cell death
4 GW274150 4 Reduced microglial activation, cytokine and NO production
ALS 1 Deprenyl 1 Reduced apoptosis [183,185,191]
2 Diethyl NONOate 2 Reduced cell death
3 L-NNA 3 Reduced aggregates formation

WHO, migraine is the second most common disabling neurological [98]. Here we discuss the involvement of NO in epilepsy. NO regulates
disorder and the third most common medical condition of the world, in excitatory and inhibitory neurotransmission in both physiological and
which 33% of women and 13% of men are suffering from it [79,80]. pathological conditions [99]. There is some controversy over the role of
The role of NO in migraine was reported many years ago. Blood sample NO signalling in the development of epilepsy. Previous reports in-
analysis of migraine patients revealed an increased level of cGMP, ni- dicated that NO plays a role of anticonvulsant while other showed that
trite, neurokine A and calcitonin gene-related peptide (CGRP), which it leads to pro-convulsant effect [99]. Thus, rats with epilepsy induced
indicates the association of NO with migraine [81,82]. A variety of by NMDA injection were treated with methylene blue, known as a
factors affect the formation and release of NO, such as bradykinin, nNOS inhibitor. The methylene blue treatment increased the symptoms
NMDA, 5-hydroxytryptamine (5-HT2B/C) receptors, substance P, hista- of epilepsy [100]. It is worth mentioning that methylene blue appears
mine, acetylcholine, and others [83–85], which indicates its involve- to be a guanylate cyclase inhibitor that does not interfere with NOS
ment in central pain sensation. Altogether, these data indicate the in- [101]. This casts doubt on the conclusion of the above-mentioned [100]
volvement of NO in the mechanisms of migraine and headache [82,86]. study. Nevertheless, when a precursor of NO L-arginine was given, it
Glyceryl trinitrite (GTN), or sodium nitroprusside, was found to initiate reduced the symptoms of epilepsy [99,102]. Also, in DL, homocysteine-
headache and migraine symptoms in workers at explosive industry. thoiolactone (H)-induced seizure model, L-arginine provided protection
This was the first direct evidence of the role of NO in migraine [87]. and the NOS inhibitor N(G)-nitro-L-Arginine methyl ester (L-NAME)
Further studies of NO donor molecules, such as GTN and isosorbide treatment potentiated the incidence of seizure (see Table 2) [103]. The
dinitrate, on migraineurs (people who are suffering from migraine) and researchers concluded that NO is responsible for protection against
non-migraineurs showed that migraineurs are more sensitive to the NO epilepsy. However, in another study, increased level of NMDA subunit
donor compounds than non-migraineurs [88,89]. Nitrate and nitrite NR2B receptor in epileptic dysplastic human neocortex indicated the
concentration in blood was higher in migraineurs compared to control involvement of NO [104] and overexpression of nNOS [105] in the
patients (see Fig. 4). These results indicate that NO is involved in in- pathogenesis of epilepsy was found. In Pentylenetetrazol (PTZ)-induced
itiation and maintenance of pain in migraine [90]. In animal models, epilepsy in rats, overexpression of NO and lipid peroxidation was re-
headache feature was not investigated, but biochemical analysis has ported in the brain and antioxidant treatment normalised the level of
been done. Treatment with GTN in rats resulted in the increase of nNOS both (see Fig. 4) [106].
in trigeminal nerve ending, NO in cortical regions, and c-fos expression
in trigeminal nucleus caudalis [82,91]. Along with this, reduced su-
peroxide dismutase (SOD) expression and increased cortical blood flow 8. Addiction
were also found in animal models after GTN injections [92,93].
Treatment with cGMP-hydrolyzing phosphodiesterase 5 inhibitor, Sil- Addiction is a brain disorder distinguished by compulsive engage-
denafil, led to increased migraine pain in migraineurs compared to ment in rewarding stimuli. To test the involvement of NO in addiction,
controls [94]. Histamine is reported to induce headache in migraineurs morphine addict rats were treated with NOS inhibitors, L-NAME and
and use of a histamine antagonist, Mepyramine, reverted this effect (see nitro-L-arginine (L-NNA) and tested the drug withdrawal symptoms.
Table 2) [95,96]. However, when the NOS-inhibitor L-NG-methylargi- The rats showed reduced morphine withdrawal symptoms and when
nine hydrochloride (was administered to histamine-induced migraine treated with NO donor compound, isosorbide nitrate, relapse of with-
patients, no significant changes were found [97]. Nevertheless, in drawal symptoms were detected [108,109]. Immunohistochemical
general, the published data indicate that NO signalling may play a role studies in morphine-dependent mice showed increased number of
in the development of migraine. nNOS positive cells in olfactory bulb, cerebellum, medulla oblongata,
and locus coeruleus and reduction in the hypothalamus. When treated
with an opioid receptor antagonist naloxone, increased nNOS im-
7. Epilepsy munoreactivity was found in hypothalamus [110]. These results can
explain the role of NO in opioid dependence and withdrawal symptoms
Epilepsy is the most common neurological disorder that affects ap- [110]. Cocaine is also responsible for induction of nNOS activity in
proximately 50 million people worldwide [98]. It is characterized hippocampus of rat brain [111] and tempol treatment, an antioxidant
mainly by recurrent seizures accompanied by loss of consciousness agent, abolished cocaine psychomotor sensitization and condition

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

reward via reduction in oxidative stress [112]. Studies on alcohol ad- compared to the normal brain [126]. S-nitrosylation of Cdk5 at Cys-83
diction showed that ethanol reduces the NO synthesis in peripheral and Cys-157 residues activate the function of Cdk5 (see Table 1)
system and also the level of NO in exhaled breath (see Fig. 4) [113]. [124,125]. Activation of Cdk5 leads to phosphorylation of its substrate
When L-NAME (an inhibitor of NO) was given to rats, it led to increase ataxia telangiectasia mutated kinase (ATM), which is a proapoptotic
in ethanol-induced narcosis; and when isosobarbide dinitrate (an NO protein kinase. In cultured cortical neurons, SNO-Cdk5 is found to en-
donor) was applied, the effect of necrosis was reduced in rats [114]. hance the amyloid β (Aβ)-induced synaptic degeneration [126]. Cdk5
Further, treatment with 7-nitroindazole(7-NI) (an inhibitor of nNOS) mutant protein or treatment with NOS inhibitor, N-nitro-L-arginine
enhances hypnotic effect of ethanol in animals (see Table 2) [115]. (NNA), in the cellular system provided protection against apoptosis (see
Following the mentioned evidence, we suggest that NO signalling plays Table 2) [126]. In summary, aberrant SNO of Cdk5 is responsible for
an important role in addiction. Aβ-induced synaptic degeneration (see Fig. 3) [126]. Importantly,
NMDAR plays a role in Aβ-induced synaptic loss [127,128]. Cdk5 ac-
9. Alzheimer's disease (AD) tivates NMDAR via phosphorylation and p-NMDAR activates nNOS in
ischemic insult [129]. The resulting SNO-Cdk5 transnitrosylates Drp-1
Alzheimer's disease (AD) is the most common chronic neurodegen- protein, a GTPase protein that regulates mitochondrial dynamics such
erative disorder [116]. Aging is the main causative factor for the de- as mitochondrial fission and fusion in cells, with detrimental effects.
velopment of AD and memory loss [116]. Cognitive deficits and lan- For example, treatment of the primary cortical neurons with Aβ led to
guage impairment are major symptoms of AD [117,118]. Senile plaques SNO of Drp-1 at Cys-644 residue, which resulted in enhanced mi-
and neurofibrillary tangles are the main pathological hallmarks of AD tochondrial fission, impairment of energy homeostasis and dendritic
[117]. Tannenbaum and co-workers have tested the involvement of spine loss (see Table 1) [130]. A mutant of Drp-1 (C644A) protected the
SNO in AD using SNO trapping by TriAryl Phosphine (SNOTRAP) cells from Aβ-induced synaptic loss [130]. Post mortem studies have
method in conjunction with mass spectrometry [119]. They used the confirmed the presence of SNO-Drp-1 in the brain of AD patients and
CK-p25-inducible mouse model of AD, and a total of 251 SNO-proteins peripheral blood lymphocytes but not in controls [131,132]. The re-
were detected in the AD model. Among them, 135 SNO proteins were searchers concluded that S-nitrosylation of Drp-1 plays a major role in
found exclusively for early neurodegeneration in cortex [119]. These AD progression (see Fig. 3) [131,132].
proteins found are known to be associated with metabolism, synaptic Protein disulphide isomerase (PDI) is a chaperon protein, located in
function and AD progression [119]. According to the GO analysis of CK- endoplasmic reticulum (ER) and plays a major role in protein proces-
p25 mouse model of AD, increased number of SNO proteins were found sing and folding. SNO-PDI was found in post-mortem AD brain [133].
in cortex and hippocampus compared to control mice. Increased level of PDI was S-nitrosylated in its active site and inhibited its activity, which
amyloid β protein, DNA damage, neuroinflammation and behavioral led to accumulation of unfolded proteins (see Fig. 3) [133]. Further-
abnormalities were observed in CK-p25 mice. An increase in GSNO was more, a zinc metalloprotease insulin degrading enzyme (IDE) was found
found in hippocampus and cortex but not in cerebellum of 2-week-old to be S-nitrosylated at multiple sites (Cys819, Cys789, Cys966, Cys178)
CK-p25 mice. SNO level of PSD95 was also detected in these mice. SNO in the presence of GSNO (see Table 1). S-nitrosylation of IDE was found
proteins associated with AD, such as glutamate ionotrophic receptor to be involved in the pathogenesis of AD [134]. Mutation in Apo lipo-
NMDA 2B (Grin2b), microtubule associated protein (MAPT), glycogen protein E (ApoE) was reported in late onset of AD [135]. ApoE appears
synthase kinase 3β(Gsk3b), lipoprotein receptor-related (LRP), NADH, to be S-nitrosylated in patients with AD, and recent studies have re-
ubiquinone oxidoreductase core subunit S1 (Ndufs1), cytochrome c ported hippocampal SNOs of ApoE2 and ApoE3. These studies suggest
oxidase subunit 6B1(Cox6b1) and GAPDH were detected in cortex of that SNO of ApoE proteins may play a role in AD development by in-
Ck-p25 mice brain. Elevated phosphorylation of GSK3β and tau (Mapt) hibiting lipid homeostasis (see Table 1) [136]. SNO-GAPDH has also
was found in the transgenic mice. It has been shown that these proteins found to be S-nitrosylated in various brain regions including cortex,
are involved in neuronal cell death in AD [120]. PKCε and PKCγ, iso- substantia nigra, and hippocampus in postmortem AD brain compared
forms of PKC were found to be SNOed in CK-p25 mice brain. Lipo- to control brains [137], which suggested the involvement of SNO-
protein receptor-related protein (LRP) gene is associated with pro- GAPDH in AD [137].
gression of AD [119,121]. Researchers suggested that SNO-LRP and Thus, SNO plays a crucial role in the pathogenesis of AD, affecting
SNO-PKC in CK-p25 mice disturbed amyloid β processing and clear- the activity of numerous proteins. We believe that unravelling the SNO-
ance, which further lead to amyloid plaque deposition [119]. Amal related signalling pathways will pave the way to new effective therapies
et al. used P301S mouse model of tauopathy to test the involvement of against the development of AD.
SNO in the pathology [122]. This work revealed reprogramming of the
S-nitroso-proteome in the mutant compared to the control group in 10. Parkinson's disease (PD)
both cortex and hippocampus of 2-month-old mice. Increased level of 3-
nirotyrosine in the CA1 and entorhinal cortex regions of P301S mice Parkinson's disease (PD) is the second most common disease after
was found. This indicates nitrosative and oxidative stress in the brain of AD in elderly people [138]. It is characterized by four major cardinal
the mutant. This study revealed the role of the noncanonical Wnt/Ca2+ features: bradykinesia, rigidity, postural instability and resting tremor
(NC-WCa) signalling in the cortex of P301S mice and found an elevated [139]. In PD, NO plays both a neuroprotective and neuro-destructive
level of phosphorylated CaMKII. Ring Finger Protein 213 (RNF213), an role and was reported in rodent models and human cases of PD
E3 ubiquitin ligase, was S-nitrosylated, and led to an increase in the [9,140,141]. S-nitrosylation of many proteins was found to be involved
level of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, in PD progression [9]. Biochemical analysis of postmortem PD brains
which resulted in the potentiation of the NC-WCa signalling [122]. revealed increase in oxidative/nitrosative stress, which plays a major
Cyclin dependent kinase (Cdk5) is a serine/threonine kinase enzyme role in PD pathogenesis [142]. NO forms peroxynitrite in the presence
which has diverse functions in the development of brain, synaptic of hydrogen peroxide [143]. Production of peroxynitrite leads to the
plasticity, regulation of neuronal migration and differentiation [123]. modification of α-synuclein protein by di-tyrosine synthesis, which
Dysregulation/dysfunction or modification of Cdk5 leads to the devel- further stabilizes the filamentous structure of α-synuclein resulting in
opment of many neurological disorders [123]. In neuronal cells, Cdk5 aggregate formation [144]. Analysis of postmortem PD brains in sub-
scaffolds with the nNOS/PSD95/NMDAR complex which are embedded stantia nigra and cortical regions showed increased level of nitrated α-
in the membrane. Cdk5 is S-nitrosylated by interacting with nNOS synuclein [145]. Nitrated α-synuclein was also found in substantia
complex under pathological conditions [124,125]. Post-mortem studies nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice
revealed the presence of high level of SNO-Cdk5 protein in the AD brain model of PD [146]. S-nitrosylation of different proteins, such parkin

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

[147], DJ-1 [148], PDI [133,149], X-linked inhibitor of apoptosis PD.

(XIAP) [150] and Prx2 [151] were found to be associated with PD (see
Table 1). Previous works have shown that nitrosative stress led to S- 11. Huntington disease (HD)
nitrosylation of parkin, causing inhibition of its ubiquitination activity,
which lead to the formation of Lewy bodies and PD progression. These Huntington disease (HD) is a dominantly inherited autosomal neu-
changes were found both in rodents and in human postmortem PD brain rodegenerative disorder [173]. The main features of HD are motor
[147,152]. Further, human studies confirmed the SNO modification of dysfunction, cognitive impairment and psychiatric disturbances [174].
parkin in PD pathogenesis [147,152,153] as well as in different mouse The main cause of this disease is expansion of CAG repeats in Hun-
models of PD [140,152]. tingtin (HTT) protein on chromosome number 4 [173]. The expansion
PDI is a chaperone protein residing inside the endoplasmic re- of CAG repeats in Mutant HTT (mHTT) protein results in the formation
ticulum and contributing to protein folding and disulfide formation by of long polyglutamine (polyQ) repeats making mHTT a toxic protein.
its isomerase activity [154]. Researchers found that S-nitrosylation of This causes dysfunction of normal homeostasis and cell death of the
PDI inhibits its activity [133]. They have showed that toxicant rotenone neurons [175]. The disease starts from the striatum, and when it pro-
increases the S-nitrosylation of PDI in SH-SY-5Y cell lines [133]. Fur- gresses, it reaches the cortex [173]. Although not enough information is
ther, SNO-PDI was also found in the brain of postmortem PD patients, available on the involvement of NO in HD, it is known that the key
which may emphasize its involvement in the pathology [133,155]. proteins involved in the progression of HD also become S-nitrosylated.
XIAP is an E3 ubiquitin ligase protein which participates in ubi- In R6/1 mutant HD mouse, the level of expression and biochemical
quitination and degradation of caspase 3,7,9 and promotes cell survival activity of nNOS was found to be reduced in the striatum and cere-
[156]. High level of NO leads to SNO modification of XIAP and in- bellum (see Fig. 4). Along with this, behavioral abnormalities were also
hibition of its ubiquitination activity. In rotenone-treated HEK-293 and reported in R6/1 HD mice [176]. In another study on SK-N-SH human
N2a cell line models of PD, S-nitrosylation of -XIAP is well reported (see neuroblastoma cell lines, knockdown of nNOS appeared to be protec-
Table 1) [150]. Human studies on PD patient's postmortem brain also tive for the cells. This can be explained by the fact that inhibition of
confirm the SNO modification of XIAP [150,157]. nNOS may induce autophagy [177]. Mitochondrial dysfunction is the
Prx2 has antioxidant properties since it catalyzes the removal of major cause of the development of neurodegenerative disorders. In this
peroxides from cells, and its level is upregulated when oxidative stress context, SNO of dynamin-related protein (Drp-1), the activator of mi-
is increased in the cells [158]. S-nitrosylation of Prx2 at Cys-51 and Cys- tochondrial fission, was found to be increased in the human post-
172 inhibited its antioxidant activity [151], which leads to increase of mortem HD brain and striatum of the transgenic HD mouse model
oxidative stress. Importantly, increased level of SNO-Prx2 is reported in [178]. Further investigation reported that SNO-Drp-1 disrupts the mi-
PD human postmortem samples and PD animal models (see Table 1) tochondrial dynamics eventually leading to cell death [179]. Another
[151]. study has revealed that PTM of HTT protein in N-548 fragment is im-
PD toxicant rodent models, such as MPTP, 6-hydroxydopamine (6- plicated in the expansion of polyQ repeats. Overexpression of NOS is
OHDA), lipopolysaccharides (LPS), manganese ethylene bis-dithio- responsible for SNO of normal HTT protein (see Table 1) [174]. In-
carbamate (maneb) and 1,1′-dimethyl-4,4-bipyridinium dichloride vestigation of the human HD patients indicate that abnormal NO sig-
(paraquat), found to have high expression levels of iNOS, nNOS and NO nalling in the peripheral blood tissues is also responsible for the disease
in the brain (see Fig. 4) [159–162]. iNOS-KO mouse model showed progression [178].
resistance to MPTP-induced cell death [163]. Furthermore, NOS in-
hibitors, 7-nitroindazole and monoamine B oxidase (MAO-B) inhibitor 12. Amyotrophic Lateral Sclerosis (ALS)
pargyline, protected cell death of dopaminergic neurons in mouse
model of PD induced by MPTP(see Table 2) [164]. Together, these Amyotrophic Lateral Sclerosis (ALS) is an idiopathic neurodegen-
studies conclude that NO is involved in MPTP-mediated neurodegen- erative disorder [180]. It is also known as Motor Neuron Disease. This
eration. 6-OHDA, is another toxicant used to induce PD in rat, which its disease is mainly characterized with permanent impairment of lower
intoxication leads to the increased level of iNOS and NO in the rat and upper motor neurons [181]. ALS is sporadic in nature in 85–90% of
brain. Pretreatment of animals with NOS inhibitor L-NAME protects cases but genetic factors (10–15%) also contribute in the development
from dopaminergic cell death in substantia nigra pars compacta (SNPc) of this disease. ALS is more common in men than in women [182]. Until
and from dopamine depletion in striatum [165,166]. Intranigral injec- now, approximately 30 genes responsible for the development of ALS
tion of 6-OHDA caused activation of microglial cells, cytokine pro- pathogenesis have been detected [181]. Toxic gain of function due to
duction, generation of free radicals and increase of NO production, mutations in SOD1 is one of the major culprits in ALS [180]. Mutant
which ultimately led to the death of dopaminergic neurons in PD [160]. SOD1 G93A is responsible for SNO of GAPDH, which enhances the nu-
GW274150, an iNOS inhibitor, reduced microglial activation, cytokine, clear translocation of GAPDH-Siah complex in NSC34 motor neurons,
ROS and NO production, and provided neuroprotection against the 6- which further enhances apoptotic cell death. When deprenyl, a selective
OHDA-induced rodent model of PD (see Table 2) [167]. Rotenone, used inhibitor of Type B monoamine oxidase, was added, it inhibited the
as a toxicant to induce PD in rodents, inhibited mitochondrial complex SNO of GAPDH and provided protection against apoptosis (see Table 2).
1 and induced oxidative stress [168]. Furthermore, it reduced the level This study concludes that mutations of SOD induce SNO of GAPDH,
of glutathione, which further leads to the increase in nitrite levels and which plays a role in the neuronal apoptosis in ALS model [183]. In
apoptosis [169]. Rotenone enhanced NOS enzymatic activity, increased contrast, it has been found that mutations of SOD1 increase its deny-
3-nitrotyrosine (3NT) level, reduced dopamine content and promoted trosylation activity, and denytrosylation of many mitochondrial pro-
the degeneration of dopaminergic cells [170]. Treatment with the NOS teins can hamper the normal homeostasis in mitochondria, ultimately
inhibitor 7-NI reduced NOS activity and 3-NT level and provided pro- leading to cell death in ALS models, whilst addition of SNO-donor
tection against rotenone-induced toxicity (see Table 2) [170]. Rotenone compounds to the mutant SOD1-containing cells prevents this course of
can induce nitrosative stress by disrupting the redox activity of PDI events [184]. This study implies that denytrosylation is important for
[171]. In rat striatal synaptosomes treated with methamphetamine, the cell survival. This conclusion was confirmed by another study,
which is also used to produce a toxic model of PD, activated alpha(7) where lymphocyte cells of ALS patients were treated with the NO-re-
nicotinic receptors and increased the level of intrasynaptosomal cal- leasing agent diethyl NONOate. In this work, the cell death ratio was
cium, NOS and PKC [172]. All this led to cell death of dopaminergic found to be lower in the diethyl NONOate-treated lymphocytes of ALS
neurons in the PD rat model [172]. The above data unequivocally point patients compared to controls [185].
to the involvement of NO and nitrosative stress in the pathogenesis of The role of PDI in the development of ALS is well established. The

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M.K. Tripathi, et al. Redox Biology 34 (2020) 101567

level of PDI is increased in spinal cord and CSF of ALS patients [186] Acknowledgments
and spinal cord of SOD1 G93A transgenic rat [187] and mice [188]
models of ALS. SNO of PDI in the spinal cord of ALS patients and SOD1 We thank Dr. Igor Khaliulin for his contribution in the discussion of
G93A
transgenic mice was found to be responsible for the disease pro- this work.
gression. Pharmacological agents that mimic the active site of PDI
provide protection to SOD1 G93A transgenic mice [155]. Tyrosine ni- References
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