Epilepsy is a complex neurological disorder
characterized by abnormal synchronized neural activity in the
brain, resulting in memory impairment, loss of consciousness, and
sensory disturbances. It has a prevalence of 0.3-0.5% worldwide,
and its incidence is estimated to be between 5 and 10 per 1,000
individuals in different countries (1,2). Due to
the lack of a complete understanding of the pathophysiology of the
disease, research into novel drugs for the treatment of epilepsy
remains ongoing (3). Furthermore,
although numerous antiepileptic drugs are currently used to control
the disease, drug resistance developing in approximately one-third
of patients and severe neurological side-effects that reduce the
quality of life of patients limit the clinical success of current
treatments. These shortcomings necessitate the development of
novel, more effective and reliable therapeutic strategies. The
disruption of the balance between excitatory and inhibitory
neurotransmitters triggers cellular oxidative stress; while
increased reactive oxygen species (ROS) increase nitric oxide (NO)
production and consequent peroxynitrite formation, creating a
vicious cycle that accelerates neurodegeneration (4,5).
Furthermore, NO, a retrograde messenger, is a potential
neurotransmitter linked to the regulation of brain excitability and
the induction of seizure activity (6).
NO is synthesized from L-arginine and plays critical
roles in various neuroinflammatory disorders due to its prooxidant
properties (7). The activation of
soluble guanylyl cyclase induces the formation of cyclic guanosine
monophosphate (cGMP) (6). The
activation of the glutamate and N-methyl-D-aspartate (NMDA)
receptor leads to an increase in Ca2+ in brain cells,
resulting in the activation of neuronal NO synthase (nNOS)
(8). Activated nNOS enables the
synthesis of NO from L-arginine. nNOS inhibition reduces the
frequency of epileptic seizures in epileptic animals by preventing
neuronal damage (9). Although NO has
antioxidant properties, in some cases, it can play crucial roles in
neurodegenerative disorders due to its prooxidant effects (10,11). The
increased production of cGMP in neurons stimulates NMDA receptor
(NMDAR) (12). Consequently,
Ca2+-calmodulin-dependent systems are activated, thus
continuously inducing the overproduction of NO with nNOS (6). During epileptic seizures, excessive NO
production inactivates mitochondrial respiratory enzymes and
results in impaired oxidative phosphorylation (13). Mitochondrial respiratory chain
enzymes are not resistant to excessive amounts of NO and
peroxynitrite products. Therefore, excess NO leads to impaired
mitochondrial respiration function. Impaired mitochondrial function
in neuronal cells leads to apoptosis and ultimately cellular death
(14,15).
Previous studies have focused on the differing and
controversial roles of NO in the central and peripheral nervous
systems (16,17). Some studies have shown that NO exerts
anticonvulsant (18,19) and proconvulsant effects (20). It has been reported that the
controversial results in epilepsy models may stem from the
inappropriate use of NOS inhibitors in terms of dose and the timing
of treatment, method of seizure induction, solvents used as
carriers and the route of administration (16).
NO, produced by glial cells in the central nervous
system, has been reported to exert cytotoxic effects (21). Therefore, agents that block NO
production may reduce neural excitability and improve brain
function through their neuroprotective effects. The present review
aimed to discuss the potential therapeutic effects of neuronal
NO-cGMP pathway inhibitors in epileptic seizures.
Under normal physiological conditions, the
electrical activity of the brain is not synchronized. By contrast,
in epilepsy, the electrical activity of the brain consists of
synchronized neuronal discharges. These abnormal synchronized
discharges are associated with a specific group of neurons in the
cerebral cortex known as the epileptic focus (22). Subsequently, this focus tends to
spread to other areas of the brain, resulting in symptoms, such as
abnormal sensations and thoughts (23). In general, epileptic seizures result
from the abnormal transmission of neuronal impulses and occur due
to the overstimulation of neurons. Under physiological conditions,
excitatory neurons do not develop a new action potential due to
hyperpolarization that develops over time. By contrast, during
seizures, there is a decrease in the neuronal excitability
threshold, which increases neuronal excitability (24-26).
Antiepileptic drugs exert their effects primarily
through three key mechanisms: The inactivation of ion channels
(such as sodium), increased inhibitory gamma-aminobutyric
acid-dergic (GABAergic) transmission, and the inhibition of
excitatory glutamatergic transmission (27,28).
Voltage-dependent sodium/calcium channels located in the neuron
membrane open with excitatory signals, leading to rapid
depolarization. This, in turn, causes the release of certain
neurotransmitters at the axon terminal. Some antiepileptic drugs
function by blocking these channels and have high selectivity for
abnormal depolarizations (29).
Of note, some antiepileptic drugs reduce
excitability by creating hyperpolarization in neurons through the
activation of potassium channels (30,31).
Antiepileptic drugs that function via GABA receptors either
increase the release of the GABA inhibitory neurotransmitter or
activate chloride channels coupled to GABAA receptors (32,33). One
of the causes of epilepsy is the overactivation of NMDA receptors
by glutamate. Therefore, some antiepileptic drugs exert their
effects through the inhibition of glutamatergic stimulation
(34,35). Drugs that function via glutamate
receptors include those targeting
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and
the presynaptic release mechanism of synaptic vesicle protein 2A
and the α2δ subunit of voltage-gated calcium channels (36).
Epileptogenesis is the process by which functional
changes occur in a previously normally functioning brain network,
leading to increased seizure susceptibility and, consequently, to
an increased likelihood of seizures (37-39).
Furthermore, there is evidence to indicate that the frequency of
spontaneous seizures continues to increase after the initial
spontaneous seizure (40-42).
This indicates that epileptogenesis is not an acute process, but a
continuous and long-term one. Various molecular and cellular
changes that trigger the first seizure then continue persistently,
leading to the progression of epilepsy (37,43).
The vast majority of information underlying the
molecular mechanisms of epileptogenesis has been derived from
studies focusing on the hippocampus. This information demonstrates
that excitatory positive feedback is a necessary feature of
epileptic networks (44,45). Synaptic connections can switch back
and forth between normal and epileptic modes of activity and
exhibit bivariate stability (46).
Of note, two possible mechanisms are proposed for the development
of positive feedback in the formation of epileptogenesis: The first
mechanism is the elimination of inhibitory circuits through the
degeneration of mossy cells that excite inhibitory basket cell
interneurons in the dentate gyrus (37). Normal hippocampal neural networks
have a moderate level of positive feedback due to recurrent
glutamatergic connections with major neurons. It has been
demonstrated that the proportion of neuron pairs with excitatory
interneurons in hippocampal preparations is ~1-3% (47). A second proposed mechanism is the
re-sprouting of numerous new synaptic connections among neurons
that survive any brain injury (48).
Axon sprouting is a consequence of a natural reparative response
observed in neurons in various brain injuries (49). The predominance of glutamatergic
sprouting in interneurons may lead to epileptogenesis (50). Conversely, the development of
molecules that promote the sprouting of GABAergic terminals may
suppress epileptogenesis.
Studies aimed at elucidating the molecular
mechanisms of epileptogenesis have allowed for the identification
of affected molecules, functional gene and protein networks. These
include TGF-β and IGF-1 signaling (51), complement activation (52), and gene expression modulation related
to glial oxidative stress (53) and
mTOR (54).
During epileptogenesis, seizures lead to persistent
mitochondrial dysfunction and an increase in free radicals and
pro-inflammatory cytokines in the brain. Physiologically, normal
levels of free radical increase are essential for the function of
brain cells (55). However, highly
increased levels of ROS and peroxynitrite derived from NO lead to
the formation of reactive nitrogen species, a toxic compound for
molecules such as lipids, proteins and DNA (56,57).
Reactive species consist of hydroxyl radicals (OH-),
superoxide (O2−) and hydrogen peroxide
(H2O2) molecules. These compounds are
synthesized by NOS, NADPH oxidase (NOX) and halo-peroxidases
(58). Under physiological
conditions, the level of oxidative stress is precisely regulated
via the transcription factor, nuclear factor erythroid 2-associated
factor 2, and antioxidant response elements (59).
Endogenous antioxidants include enzymes, such as
catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase
(SOD) and glutathione reductase. In addition, the body contains
compounds with antioxidant properties that are not enzymes, such as
transferrin, albumin, ferritin, vitamins C and E, and melatonin
(17). Although the central nervous
system constitutes only 2% of body weight, it consumes a high
amount of O2, ~20%. Therefore, it exhibits a very high
sensitivity to oxidative stress (60). Electron transport chain regions in
mitochondria, particularly during ATP synthesis, cause high levels
of ROS formation. Furthermore, xanthine oxidase, NOX and cytochrome
P450 are other sources of O2− (61). Superoxide produced in the body is
converted to hydrogen peroxide (H2O2) by the
SOD enzyme under physiological conditions. This is then treated
with CAT and GPx to form water (H2O) molecules. During
epileptogenesis, mitochondrial stress increases, creating an
imbalance between oxidants and antioxidant enzyme defenses. In this
situation, excess superoxide reacts with H2O2
to form highly toxic hydroxyl radicals, causing significant damage
to brain cells and neurodegeneration (62,63).
NO is synthesized by NOS from arginine, one of the
essential amino acids, and NOS has three main isoforms: nNOS,
inducible NOS (iNOS) and endothelial NOS (eNOS) (10). Under physiological conditions, NO is
produced in small amounts in the brain by eNOS and nNOS, and the NO
synthesized in this manner exhibits tissue-protective properties.
By contrast, iNOS produces high levels of NO in pathological
conditions, particularly in brain injuries and in response to
various cytokines, and the NO synthesized by iNOS causes neuronal
toxicity (64-66).
However, NO synthesized by eNOS prevents atherosclerosis, reduces
arterial blood pressure by relaxing smooth muscle and stimulates
angiogenesis (67). The activation
of NMDAR in neuronal synaptic junctions increases NO synthesis by
nNOS. NO activates soluble guanylate cyclase, strengthening cGMP
signaling and modulating learning and memory mechanisms (68). There is evidence to suggest that nNOS
plays critical roles in kainic acid-induced seizures (69). Increased levels of oxidative stress
in the brain lead to excessive superoxide and NO accumulation.
These products combine to produce toxic peroxynitrite and
dinitrogen trioxide, ultimately resulting in the development of
pathologies, such as epileptic seizures and Alzheimer's disease
(70).
NO is a gas molecule that can diffuse freely in
tissues and cannot be stored in cells, and it exerts its effects
through the activation of soluble guanylate cyclase or the
nitrosylation of intracellular proteins. Specifically,
S-nitrosylation plays a role in regulating NMDAR activity and
blocks excessive Ca2+ influx to protect neurons
(71,72). It has been demonstrated that the
intraperitoneal administration of allopurinol at a dose of 50 mg/kg
in mice exerts significant anticonvulsant activity in
pentylenetetrazole (PTZ)-induced seizures; pre-treatment with
L-arginine enhances the anticonvulsant effects of allopurinol in
PTZ-induced seizures (73). It has
been suggested that synapic acid exerts anticonvulsant effects by
reducing prefrontal cortex nitrite levels and regulating
glutamatergic signaling (74).
Whether NO is a neuroprotective or toxic molecule
depends on the source of NO production following an injury and the
relevant NO synthase isoform (75).
There is evidence to indicate differences in the pathophysiological
roles of NO in the peripheral and central nervous systems (16,76). The
reason why NO exerts anticonvulsant effects in some studies and
proconvulsant effects in others is attributed to the types of
chemical convulsants used in the studies (12,16).
Under normal conditions, NO is synthesized by NADPH-dependent NOS
of L-arginine (77). By contrast, in
pathological conditions, the activation of NMDARs leads to the
increased intracellular expression of Ca2+, resulting in
high levels of NO production by stimulating
Ca²/calmodulin-dependent NOS (78).
Furthermore, NMDARs and the NO-cGMP pathway play a role in the
mechanisms of benzodiazepine withdrawal sensitivity (79).
Previous research has demonstrated increases in all
three NOS isoforms at different stages of epileptogenesis. In an
experimental epilepsy model, eNOS levels were found to increase
within 3 to 24 h following the intracranial injection of kainate
(80). However, iNOS and nNOS have
been reported to be upregulated in a mouse model of
electrically-induced epilepsy (81).
In another study, in a rat model of epilepsy, the levels of nNOS
and iNOS increased for 3 days following a seizure, and the increase
persisted for a long period of time (82).
While numerous studies have demonstrated that NO and
oxidative stress play a crucial role in the development of
epilepsy, the anticonvulsant role of NOS inhibitors remains
controversial. Some studies emphasize their anticonvulsant effects,
while others highlight their proconvulsant effects (83). However, the efficacy of NOS
inhibitors varies depending on the strength of their inhibition and
isoform selectivity (76). Under
physiological conditions, NO promotes the expression of
activity-dependent neuroprotective proteins, whereas
N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, or a
soluble guanylate cyclase inhibitor, accelerates seizures in an
epilepsy model. This suggests a crucial role for the NO-cGMP
signaling pathway in epileptic seizures (16). Recent evidence has revealed a
significant increase in 3-nitrotyrosine levels in iNOS-non-reactive
microglia cells long following seizure induction (~3 months)
(84). However, recent studies have
shown that blocking NO production reduces epileptic seizures.
However, the use of appropriate NOS inhibitors and the timing of
treatment are crucial for a successful anticonvulsant effect
(66,85).
L-NAME is a non-selective inhibitor of NOS enzymes,
widely used in biochemical and pharmacological research. Side
effects associated with NOS inhibition can be reduced by using a
selective NOS inhibitor. Significant increases in nNOS expression
can be observed in the early stages of epileptogenesis (69). nNOS is isolated in the postsynaptic
membranes of neurons in interaction with the NMDA receptor-PSD-95
complex (68). NMDAR activation
leads to increased calcium levels, resulting in nNOS activation,
stimulating NO synthesis in neurons (Fig. 1). The increased expression of NO
contributes to oxidative stress, ultimately leading to
neurodegeneration and acute seizures. Nw-propyl-L-arginine (L-NPA),
a specific inhibitor of nNOS, has a much higher affinity for iNOS
and eNOS (69,86,87).
Evidence has indicated that L-NPA exerts a potent
anticonvulsant effect in kainic acid-induced seizures. The
administration of L-NPA has been shown to significantly reduce
seizures and to result in a substantial decrease in epileptogenesis
biomarkers measured at intervals (69). In another study, PTZ preconditioning
was shown to exert an anticonvulsant effect against
lithium-pilocarpine-induced status epilepticus in rats; however,
this anticonvulsant effect was reversed by NOS inhibitors [L-NAME
and 7-nitroindazole (7-NI)] (88).
Furthermore, another study demonstrated that reductions in
seizure-like events were observed following the administration of
the nNOS selective inhibitor, 7-NI (89). In addition, the intraperitoneal
administration of L-NAME (10 mg/kg) and 7-NI (30 mg/kg, i.p.) to
mice was previously shown to enhance the anticonvulsant effect of
ivermectin (90). In a PTZ kindling
model of epilepsy, nNOS was shown to trigger hippocampal
endoplasmic reticulum stress and oxidative damage via peroxynitrite
(91). In the PTZ model,
pentoxifyllin increased the seizure threshold, and this effect was
potentiated by L-arginine. However, the administration of L-NAME
and 7-nitroindazole resulted in a decrease in this effect (92). Genetic deletion of the nNOS gene
significantly increases hippocampal neuropeptide Y expression,
reducing hippocampal neuronal damage and cognitive decline caused
by temporal lobe epilepsy (9). The
co-administration of modafinil, a substance with
alertness-enhancing and neuroprotective effects, with an NOS
inhibitor has been shown to exert anticonvulsant effects in
epileptic animals (93).
Transcranial direct current stimulation in rats has been shown to
suppress seizures by reducing TNF-α and IL-1β levels, and nNOS
expression (94). Coenzyme Q10 has
been reported to induce absence seizures in WAG/Rij rats by
increasing NO levels (95). Studies
on the effects of NOS inhibitors on epileptic seizures are
presented in Table I (96-104).
Another NOS inhibitor with potential to reduce NO
synthesis in the brain is iNOS inhibitor. Studies have shown that
iNOS inhibitors have minimal effects on pain. However, positive
results have been obtained when used in neurodegenerative diseases,
cancer and experimental models of epilepsy (85). The most selective and potent iNOS
inhibitor is N-(3-(Aminomethyl)benzyl)acetamidine (1,400 W)
(105). 1400W is a nitric oxide
inhibitor that is 5,000-fold more selective for iNOS compared to
eNOS (106). In a previous in
vitro study, a significant reduction in kainic acid-induced
epileptiform spikes was shown following treatment with 1,400 W
(64). In another study using
animals, early epileptogenic neuronal hyperexcitability, glial cell
proliferation, and neurodegeneration were significantly reduced
after 1,400 W of kainat administration (64). The levels of pro-inflammatory
mediators increase abruptly following brain injury, and these high
levels persist for several months (66,84). The
increase in 3-NT protein and iNOS activity, an indicator of
nitro-oxidative stress in M1 type microglia cells in the brain, was
significantly reduced with 1,400 W 1 week following the
administration of kainat (64).
Decreased iNOS activity in microglial cells is a possible
consequence of the reduction in epileptic seizures and
neurodegeneration. The results of these studies suggest that the
neuroprotective effects of 1,400 W may occur by blocking the
microglial supply of pro-inflammatory mediator molecules.
Despite the compelling anticonvulsant results
obtained, significant obstacles remain as regards the clinical use
of NOS inhibitors. The success observed in acute seizure models may
not be equally consistent in chronic epilepsy. Furthermore, the
blood-brain barrier crossing rates, systemic side-effects and
therapeutic dose ranges of NOS inhibitors have not yet been fully
optimized.
The present review discussed the complex effects of
the NO signaling pathway on epileptogenesis, and seizure mechanisms
and comprehensively reveals the anticonvulsant potential of NOS
inhibitors. There is ample evidence to indicate that NO may play a
bidirectional role (both neuroprotective and neurotoxic) in the
central nervous system, demonstrating that specific NOS inhibition
is a potent therapeutic strategy for raising the seizure threshold.
The selective blockade of non-structural nNOS and iNOS isoforms
suppresses glutamatergic hyperexcitability. nNOS inhibitors reduce
neuronal damage by limiting intracellular Ca2+ influx
and associated free radical production caused by NMDA receptor
activation. By contrast, eNOS inhibition carries the risk of
worsening seizures by disrupting cerebral blood flow. Therefore,
‘isoform specificity’ is crucial for the successful treatment of
epilepsy. Future research is required to focus on developing
next-generation smart molecules targeting nNOS and iNOS to improve
the safety and efficacy of therapies targeting the NO pathway. From
a real-world clinical perspective, the development of
isoform-specific NOS inhibitors holds significant potential for
pharmacoresistant epilepsy patients. Unlike broad-spectrum drugs,
which often cause serious neurocognitive side-effects, these
targeted therapies may provide a dual benefit: They can precisely
suppress abnormal seizure activity while preserving the
physiological NO pathways necessary for normal cognitive
function.
Not applicable.
Funding: No funding was received.
Not applicable.
The author EO confirms being the sole contributor of
the present review. EO conceived and designed the study, and wrote
and edited the manuscript. EO has read and approved the final
manuscript for publication. Data authentication is not
applicable.
Not applicable.
Not applicable.
The author declares that he has no competing
interests.
|
1
|
Lesani A, Behbahani FM, Manavi MA, Jafari
RM, Shafaroodi H, Khosravi S and Dehpour AR: Acute anticonvulsant
effects of dapsone on PTZ-and MES-induced seizures in mice: NLRP3
inflammasome inhibition and Nrf2/HO-1 pathway preservation.
Pharmacol Rep. 77:450–462. 2025.PubMed/NCBI View Article : Google Scholar
|
|
2
|
Anovadiya AP, Sanmukhani JJ and Tripathi
CB: Epilepsy: Novel therapeutic targets. J Pharmacol Pharmacother.
3:112–117. 2012.PubMed/NCBI View Article : Google Scholar
|
|
3
|
Sumadewi KT, Harkitasari S and Tjandra DC:
Biomolecular mechanisms of epileptic seizures and epilepsy: A
review. Acta Epileptologica. 5(28)2023.PubMed/NCBI View Article : Google Scholar
|
|
4
|
Ozdemir E: Serotonin receptors as a
potential therapeutic target in epilepsy. Neurochem J. 19:27–40.
2025.
|
|
5
|
Sarlo GL and Holton KF: Brain
concentrations of glutamate and GABA in human epilepsy: A review.
Seizure. 91:213–227. 2021.PubMed/NCBI View Article : Google Scholar
|
|
6
|
Kumar A, Lalitha S and Mishra J: Possible
nitric oxide mechanism in the protective effect of hesperidin
against pentylenetetrazole (PTZ)-induced kindling and associated
cognitive dysfunction in mice. Epilepsy Behav. 29:103–111.
2013.PubMed/NCBI View Article : Google Scholar
|
|
7
|
Togo T, Katsuse O and Iseki E: Nitric
oxide pathways in Alzheimer's disease and other neurodegenerative
dementias. Neurol Res. 26:563–566. 2004.PubMed/NCBI View Article : Google Scholar
|
|
8
|
Bahdar ZI, Abu-El-Rub E, Almazari R,
Alzu'bi A and Al-Zoubi RM: The molecular mechanism of nitric oxide
in memory consolidation and its role in the pathogenesis of
memory-related disorders. Neurogenetics. 26(22)2025.PubMed/NCBI View Article : Google Scholar
|
|
9
|
Yao Y, Hu Y, Yang J, Zhang C, He Y, Qi H
and Zhu X: Inhibition of neuronal nitric oxide synthase protects
against hippocampal neuronal injuries by increasing neuropeptide Y
expression in temporal lobe epilepsy mice. Free Radic Biol Med.
188:45–61. 2022.PubMed/NCBI View Article : Google Scholar
|
|
10
|
Iova OM, Marin GE, Lazar I, Stanescu I,
Dogaru G, Nicula CA and Bulboacă AE: Nitric oxide/nitric oxide
synthase system in the pathogenesis of neurodegenerative
disorders-An overview. Antioxidants. 12(753)2023.PubMed/NCBI View Article : Google Scholar
|
|
11
|
Amini-Khoei H, Boroujeni SN, Lorigooini Z,
Salehi A, Sadeghian R and Rahimi-Madiseh M: Implication of
nitrergic system in the anticonvulsant effects of ferulic acid in
pentylenetetrazole-induced seizures in male mice. J Basic Clin
Physiol Pharmacol. 34:197–203. 2023.PubMed/NCBI View Article : Google Scholar
|
|
12
|
Eghbali F, Dehkordi H, Amini-Khoei H,
Lorigooini Z and Rahimi-Madiseh M: The potential role of nitric
oxide in the anticonvulsant effects of betulin in
pentylenetetrazole (PTZ)-induced seizures in mice. IBRO Neurosci
Rep. 16:527–534. 2024.PubMed/NCBI View Article : Google Scholar
|
|
13
|
Poderoso JJ, Carreras MC, Lisdero C, Riobo
N, Schopfer F and Boveris A: Nitric oxide inhibits electron
transfer and increases superoxide radical production in rat heart
mitochondria and submitochondrial particles. Arch Biochem Biophys.
328:85–92. 1996.PubMed/NCBI View Article : Google Scholar
|
|
14
|
Xu XX, Shi RX, Fu Y, Wang JL, Tong X,
Zhang SQ and Guo F: Neuronal nitric oxide synthase/reactive oxygen
species pathway is involved in apoptosis and pyroptosis in
epilepsy. Neural Regen Res. 18:1277–1285. 2023.PubMed/NCBI View Article : Google Scholar
|
|
15
|
Carresras MC, Franco MC and Peralta JG:
Nitric oxide, complex I, and the modulation of mitochondrial
reactive species in biology and disease. Mol Aspects Med.
25:125–139. 2004.PubMed/NCBI View Article : Google Scholar
|
|
16
|
Cosgrave AS, McKay JS, Bubb V, Morris R,
Quinn JP and Thippeswamy T: Regulation of activity-dependent
neuroprotective protein (ADNP) by the NO-cGMP pathway in the
hippocampus during kainic acid-induced seizure. Neurobiol Dis.
30:281–292. 2008.PubMed/NCBI View Article : Google Scholar
|
|
17
|
Puttachary S, Sharma S, Stark S and
Thippeswamy T: Seizure-induced oxidative stress in temporal lobe
epilepsy. Biomed Res Int. 2015(745613)2015.PubMed/NCBI View Article : Google Scholar
|
|
18
|
Royes LF, Fighera MR, Furian AF, Oliveira
MS, Fiorenza NG, Petry JC and Mello CF: The role of nitric oxide on
the convulsive behavior and oxidative stress induced by
methylmalonate: An electroencephalographic and neurochemical study.
Epilepsy Res. 73:228–237. 2007.PubMed/NCBI View Article : Google Scholar
|
|
19
|
Sardo P and Ferraro G: Modulatory effects
of nitric oxide-active drugs on the anticonvulsant activity of
lamotrigine in an experimental model of partial complex epilepsy in
the rat. BMC Neurosci. 8(47)2007.PubMed/NCBI View Article : Google Scholar
|
|
20
|
De Sarro GB and De Sarro A: Anticonvulsant
properties of noncompetitive antagonists of the
N-methyl-D-aspartate receptor in genetically epilepsy-prone rats:
Comparison with CPPene. Neuropharmacology. 32:51–58.
1993.PubMed/NCBI View Article : Google Scholar
|
|
21
|
Zhao W, Xie W, Le W, Beers DR, He Y,
Henkel JS, Simpson EP, Yen AA, Xiao Q and Appel SH: Activated
microglia initiate motor neuron injury by a nitric oxide and
glutamate-mediated mechanism. J Neuropathol Exp Neurol. 63:964–977.
2004.PubMed/NCBI View Article : Google Scholar
|
|
22
|
Islam MR, Zhao X, Miao Y, Sugano H and
Tanaka T: Epileptic seizure focus detection from interictal
electroencephalogram: A survey. Cogn Neurodyn. 17:1–23.
2023.PubMed/NCBI View Article : Google Scholar
|
|
23
|
Conde-Blanco E, Reyes-Leiva D, Pintor L,
Donaire A, Manzanares I, Rumia J, Roldan P, Boget T, Bargalló N,
Gil-Lopez FJ, et al: Psychotic symptoms in drug resistant epilepsy
patients after cortical stimulation. Epilepsy Res.
173(106630)2021.PubMed/NCBI View Article : Google Scholar
|
|
24
|
Villasana-Salazar B and Vezzani A:
Neuroinflammation microenvironment sharpens seizure circuit.
Neurobiol Dis. 178(106027)2023.PubMed/NCBI View Article : Google Scholar
|
|
25
|
Deng ZD, Robins PL, Regenold W, Rohde P,
Dannhauer M and Lisanby SH: How electroconvulsive therapy works in
the treatment of depression: Is it the seizure, the electricity, or
both? Neuropsychopharmacology. 49:150–162. 2024.PubMed/NCBI View Article : Google Scholar
|
|
26
|
Khan S, Nobili L, Khatami R, Loddenkemper
T, Cajochen C, Dijk DJ and Eriksson SH: Circadian rhythm and
epilepsy. Lancet Neurol. 17:1098–1108. 2018.PubMed/NCBI View Article : Google Scholar
|
|
27
|
Kwan P, Sills GJ and Brodie MJ: The
mechanisms of action of commonly used antiepileptic drugs.
Pharmacol Ther. 90:21–34. 2001.PubMed/NCBI View Article : Google Scholar
|
|
28
|
Li C, Wang X, Deng M, Luo Q, Yang C, Gu Z,
Lin S, Luo Y, Chen L, Li Y and He B: Antiepileptic drug
combinations for epilepsy: Mechanisms, clinical strategies, and
future prospects. Int J Mol Sci. 26(4035)2025.PubMed/NCBI View Article : Google Scholar
|
|
29
|
Catterall W: Sodium channels, inherited
epilepsy, and antiepileptic drugs. Annu Rev Pharmacol Toxicol.
54:317–338. 2014.PubMed/NCBI View Article : Google Scholar
|
|
30
|
Köhling R and Wolfart J: Potassium
channels in epilepsy. Cold Spring Harb Perspect Med.
6(a022871)2016.PubMed/NCBI View Article : Google Scholar
|
|
31
|
Wolfart J and Laker D: Homeostasis or
channelopathy? Acquired cell type-specific ion channel changes in
temporal lobe epilepsy and their antiepileptic potential. Front
Physiol. 6(168)2015.PubMed/NCBI View Article : Google Scholar
|
|
32
|
Chen ZP, Zhao X, Wang S, Cai R, Liu Q, Ye
H, Wang MJ, Peng SY, Xue WX, Zhang YX, et al: GABA-dependent
microglial elimination of inhibitory synapses underlies neuronal
hyperexcitability in epilepsy. Nat Neurosci. 28:1404–1417.
2025.PubMed/NCBI View Article : Google Scholar
|
|
33
|
Chandran D, Hegde S, Upadhya R, SE PK,
Shenoy S, Devi V and Upadhya D: Cell-specific extracellular
vesicle-encapsulated exogenous GABA controls seizures in epilepsy.
Stem Cell Res Ther. 15:1–15. 2024.PubMed/NCBI View Article : Google Scholar
|
|
34
|
Zhou Q and Sheng M: NMDA receptors in
nervous system diseases. Neuropharmacology. 74:69–75.
2013.PubMed/NCBI View Article : Google Scholar
|
|
35
|
Chen TS, Huang TH, Lai MC and Huang CW:
The role of glutamate receptors in epilepsy. Biomedicines.
11(783)2023.PubMed/NCBI View Article : Google Scholar
|
|
36
|
Klein P, Kaminski RM, Koepp M and Löscher
W: New epilepsy therapies in development. Nat Rev Drug Discov.
23:682–708. 2024.PubMed/NCBI View Article : Google Scholar
|
|
37
|
Dudek FE and Staley KJ: The time course of
acquired epilepsy: Implications for therapeutic intervention to
suppress epileptogenesis. Neurosci Lett. 497:240–246.
2011.PubMed/NCBI View Article : Google Scholar
|
|
38
|
Pitkänen A, Lukasiuk K, Dudek FE and
Staley KJ: Epileptogenesis. Cold Spring Harb Perspect Med.
5(a022822)2015.PubMed/NCBI View Article : Google Scholar
|
|
39
|
Bonosi L, Benigno UE, Musso S, Giardina K,
Gerardi RM, Brunasso L, Costanzo R, Paolini F, Buscemi F, Avallone
C, et al: The role of aquaporins in epileptogenesis-a systematic
review. Int J Mol Sci. 24(11923)2023.PubMed/NCBI View Article : Google Scholar
|
|
40
|
Williams PA, White AM, Clark S, Ferraro
DJ, Swiercz W, Staley KJ and Dudek FE: Development of spontaneous
recurrent seizures after Kainate-induced status epilepticus. J
Neurosci. 29:2103–2112. 2009.PubMed/NCBI View Article : Google Scholar
|
|
41
|
Kadam SD, White AM, Staley KJ and Dudek
FE: Continuous electroencephalographic monitoring with
radio-telemetry in a rat model of perinatal hypoxia-ischemia
reveals progressive post-stroke epilepsy. J Neurosci. 30:404–415.
2010.PubMed/NCBI View Article : Google Scholar
|
|
42
|
Kachhadia MP, Codreanu S, Sibhai I,
Topiwala U, Iqbal PMR, Vaghela R, Chauhan S and Shaikh JD:
Epileptogenesis after stroke: Current insights into molecular and
structural mechanisms. Cureus. 18(e101385)2026.PubMed/NCBI View Article : Google Scholar
|
|
43
|
Rakhade SN and Jensen FE: Epileptogenesis
in the immature brain: Emerging mechanisms. Nat Rev Neurol.
5:380–391. 2009.PubMed/NCBI View Article : Google Scholar
|
|
44
|
Sloviter RS: Hippocampal epileptogenesis
in animal models of mesial temporal lobe epilepsy with hippocampal
sclerosis: The importance of the ‘latent period’ and other
concepts. Epilepsia. 49:85–92. 2008.PubMed/NCBI View Article : Google Scholar
|
|
45
|
Hussein MA, Kiwan NA, Aly YR, Badawy AA
and Hussein AM: Role of hippocampus in epileptogenesis: New
insights in the cross-talks between the underlying mechanisms. Acta
Neurol Belg: August 9, 2025 (Epub ahead of print).
|
|
46
|
Jirsa VK, Stacey WC, Quilichini PP, Ivanov
AI and Bernard C: On the nature of seizure dynamics. Brain.
137:2210–2230. 2014.PubMed/NCBI View Article : Google Scholar
|
|
47
|
Miles R and Wong RK: Inhibitory control of
local excitatory circuits in the guinea-pig hippocampus. J Physiol.
388:611–629. 1987.PubMed/NCBI View Article : Google Scholar
|
|
48
|
Sutula TP and Dudek FE: Unmasking
recurrent excitation generated by mossy fiber sprouting in the
epileptic dentate gyrus: An emergent property of a complex system.
Prog Brain Res. 163:541–563. 2007.PubMed/NCBI View Article : Google Scholar
|
|
49
|
Lew FH and Buckmaster PS: Is there a
critical period for mossy fiber sprouting in a mouse model of
temporal lobe epilepsy? Epilepsia. 52:2326–2332. 2011.PubMed/NCBI View Article : Google Scholar
|
|
50
|
Zhang W, Yamawaki R, Wen X, Uhl J, Diaz J,
Prince DA and Buckmaster PS: Surviving hilar somatostatin
interneurons enlarge, sprout axons, and form new synapses with
granule cells in a mouse model of temporal lobe epilepsy. J
Neurosci. 29:14247–14256. 2009.PubMed/NCBI View Article : Google Scholar
|
|
51
|
Cacheaux LP, Ivens S, David Y, Lakhter AJ,
Bar-Klein G, Shapira M, Heinemann U, Friedman A and Kaufer D:
Transcriptome profiling reveals TGF-b signaling involvement in
epileptogenesis. J Neurosci. 29:8927–8935. 2009.PubMed/NCBI View Article : Google Scholar
|
|
52
|
Aronica E, Boer K, van Vliet EA, Redeker
S, Baayen JC, Spliet WG, van Rijen PC, Troost D, da Silva FH,
Wadman WJ and Gorter JA: Complement activation in experimental and
human temporal lobe epilepsy. Neurobiol Dis. 26:497–511.
2007.PubMed/NCBI View Article : Google Scholar
|
|
53
|
Winden KD, Karsten SL, Bragin A, Kudo LC,
Gehman L, Ruidera J, Geschwind DH and Engel J Jr: A systems level,
functional genomics analysis of chronic epilepsy. PLoS One.
6(e20763)2011.PubMed/NCBI View Article : Google Scholar
|
|
54
|
Okamoto OK, Janjoppi L, Bonone FM, Pansani
AP, da Silva AV, Scorza FA and Cavalheiro EA: Whole transcriptome
analysis of the hippocampus: Toward a molecular portrait of
epileptogenesis. BMC Genomics. 11(230)2010.PubMed/NCBI View Article : Google Scholar
|
|
55
|
Salim S: Oxidative stress and the central
nervous system. J Pharmacol Exp Ther. 360:201–205. 2017.PubMed/NCBI View Article : Google Scholar
|
|
56
|
Sinha SN, Kumpati RK, Ramavath PN,
Sangaraju R, Gouda B and Chougule P: Investigation of acute
organophosphate poisoning in humans based on sociodemographic and
role of neurotransmitters with survival study in South India. Sci
Rep. 12(16513)2022.PubMed/NCBI View Article : Google Scholar
|
|
57
|
Walker MC: Reactive oxygen species in
status epilepticus. Epilepsia Open. 8 (Suppl 1):S66–S72.
2023.PubMed/NCBI View Article : Google Scholar
|
|
58
|
Pearson-Smith JN and Patel M: Antioxidant
drug therapy as a neuroprotective countermeasure of nerve agent
toxicity. Neurobiol Dis. 133(104457)2020.PubMed/NCBI View Article : Google Scholar
|
|
59
|
Schreibelt G, van Horssen J, van Rossum S,
Dijkstra CD, Drukarch B and de Vries HE: Therapeutic potential and
biological role of endogenous antioxidant enzymes in multiple
sclerosis pathology. Brain Res Rev. 56:322–330. 2007.PubMed/NCBI View Article : Google Scholar
|
|
60
|
Carvalho C and Moreira PI: Oxidative
stress: A major player in cerebrovascular alterations associated to
neurodegenerative events. Front Physiol. 9(806)2018.PubMed/NCBI View Article : Google Scholar
|
|
61
|
Kim JH, Jang BG, Choi BY, Kim HS, Sohn M,
Chung TN, Choi HC, Song HK and Suh SW: Post-treatment of an NADPH
oxidase inhibitor prevents seizure-induced neuronal death. Brain
Res. 1499:163–172. 2013.PubMed/NCBI View Article : Google Scholar
|
|
62
|
Angelova PR and Abramov AY: Role of
mitochondrial ROS in the brain: From physiology to
neurodegeneration. FEBS Lett. 592:692–702. 2018.PubMed/NCBI View Article : Google Scholar
|
|
63
|
Samanta S, Chakraborty S and Bagchi D:
Pathogenesis of neurodegenerative diseases and the protective role
of natural bioactive components. J Am Nutr Assoc. 43:20–32.
2024.PubMed/NCBI View Article : Google Scholar
|
|
64
|
Puttachary S, Sharma S, Verma S, Yang Y,
Putra M, Thippeswamy A, Luo D and Thippeswamy T: 1400W, a highly
selective inducible nitric oxide synthase inhibitor is a potential
disease modifier in the rat kainate model of temporal lobe
epilepsy. Neurobiol Dis. 93:184–200. 2016.PubMed/NCBI View Article : Google Scholar
|
|
65
|
Staunton CA, Barrett-Jolley R, Djouhri L
and Thippeswamy T: Inducible nitric oxide synthase inhibition by
1400W limits pain hypersensitivity in a neuropathic pain rat model.
Exp Physiol. 103:535–544. 2018.PubMed/NCBI View Article : Google Scholar
|
|
66
|
Massey N, Vasanthi SS, Samidurai M, Gage
M, Rao N, Meyer C and Thippeswamy T: 1400 W, a selective inducible
nitric oxide synthase inhibitor, mitigates early neuroinflammation
and nitrooxidative stress in diisopropylfluorophosphate-induced
short-term neurotoxicity rat model. Front Mol Neurosci.
16(1125934)2023.PubMed/NCBI View Article : Google Scholar
|
|
67
|
Garcia V and Sessa WC: Endothelial NOS:
Perspective and recent developments. Br J Pharmacol. 176:189–196.
2019.PubMed/NCBI View Article : Google Scholar
|
|
68
|
Maccallini C and Amoroso R: Targeting
neuronal nitric oxide synthase as a valuable strategy for the
therapy of neurological disorders. Neural Regen Res. 11:1731–1734.
2016.PubMed/NCBI View Article : Google Scholar
|
|
69
|
Beamer E, Otahal J, Sills GJ and
Thippeswamy T: N (w)-propyl-L-arginine (L-NPA) reduces status
epilepticus and early epileptogenic events in a mouse model of
epilepsy: Behavioural, EEG and immunohistochemical analyses. Eur J
Neurosci. 36:3194–3203. 2012.PubMed/NCBI View Article : Google Scholar
|
|
70
|
Liy PM, Puzi NNA, Jose S and Vidyadaran S:
Nitric oxide modulation in neuroinflammation and the role of
mesenchymal stem cells. Exp Biol Med (Maywood). 246:2399–2406.
2021.PubMed/NCBI View Article : Google Scholar
|
|
71
|
Koriyama Y and Furukawa A: S-nitrosylation
regulates cell survival and death in the central nervous system.
Neurochem Res. 43:50–58. 2018.PubMed/NCBI View Article : Google Scholar
|
|
72
|
Banach M, Piskorska B, Czuczwar SJ and
Borowicz KK: Nitric oxide, epileptic seizures, and action of
antiepileptic drugs. CNS Neurol Disord Drug Targets. 10:808–819.
2011.PubMed/NCBI View Article : Google Scholar
|
|
73
|
Rahimi N, Modabberi S, Faghir-Ghanesefat
H, Shayan M, Maroufi SF, Dafe EA and Dehpour AR: The possible role
of nitric oxide signaling and NMDA receptors in allopurinol effect
on maximal electroshock-and pentylenetetrazol-induced seizures in
mice. Neurosci Lett. 778(136620)2022.PubMed/NCBI View Article : Google Scholar
|
|
74
|
Ghasemi M, Amini-Khoei H, Bijad E,
Rafieian-Kopaei M, Sureda A and Lorigooini Z: Sinapinic acid as a
potential therapeutic agent for epilepsy through targeting NMDA
receptors and nitrite level. Sci Rep. 14(24941)2024.PubMed/NCBI View Article : Google Scholar
|
|
75
|
Sharma S, Puttachary S and Thippeswamy T:
Glial source of nitric oxide in epileptogenesis: A target for
disease modification in epilepsy. J Neurosci Res. 97:1363–1377.
2019.PubMed/NCBI View Article : Google Scholar
|
|
76
|
Thippeswamy T, McKay JS, Quinn JP and
Morris R: Nitric oxide, a biological double-faced Janus-is this
good or bad? Histol Histopathol. 21:445–458. 2006.PubMed/NCBI View Article : Google Scholar
|
|
77
|
Turrens JF: Mitochondrial formation of
reactive oxygen species. J Physiol. 552:335–344. 2003.PubMed/NCBI View Article : Google Scholar
|
|
78
|
Jacobsson SOP, Cassel GE and Persson SA:
Increased levels of nitrogen oxides and lipid peroxidation in the
rat brain after Soman-induced seizures. Arch Toxicol. 73:269–273.
1999.PubMed/NCBI View Article : Google Scholar
|
|
79
|
Talarek S, Listos J, Orzelska-Gorka J,
Serefko A and Kotlińska J: NMDA receptors and NO: cGMP signaling
pathway mediate the diazepam-induced sensitization to withdrawal
signs in mice. Neurotox Res. 33:422–432. 2018.PubMed/NCBI View Article : Google Scholar
|
|
80
|
Chuang YC, Chen SD, Lin TK, Liou CW, Chang
WN, Chan SHH and Chang AYW: Upregulation of nitric oxide synthase
II contributes to apoptotic cell death in the hippocampal CA3
subfield via a cytochrome c/caspse-3 signaling cascade following
induction of experimental temporal lobe status epilepticus in the
rat. Neuropharmacology. 52:1263–1273. 2007.PubMed/NCBI View Article : Google Scholar
|
|
81
|
Catania MV, Giuffrida R, Seminara G,
Barbagallo G, Aronica E, Gorter JA, Dell'Albani P, Ravagna A,
Calabrese V and Giuffrida-Stella AM: Upregulation of neuronal oxide
synthase in in vitro stellate astrocytes and in vivo reactive
astrocytes after electrically induced status epilepticus. Neurochem
Res. 28:607–615. 2003.PubMed/NCBI View Article : Google Scholar
|
|
82
|
Vezzani A, French J, Bartfai T and Baram
TZ: The role of inflammation in epilepsy. Nat Rev Neurol. 7:31–40.
2011.PubMed/NCBI View Article : Google Scholar
|
|
83
|
Del-Bel EA, Oliveira PR, Oliveira JA,
Mishra PK, Jobe PC and Garcia-Cairasco N: Anticonvulsant and
proconvulsant roles of nitric oxide in experimental epilepsy
models. Braz J Med Biol Res. 30:971–979. 1997.PubMed/NCBI View Article : Google Scholar
|
|
84
|
Putra M, Sharma S, Gage M, Gasser G,
Hinojo-Perez A, Olson A, Gregory-Flores A, Puttachary S, Wang C,
Anantharam V and Thippeswamy T: Inducible nitric oxide synthase
inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in
the rat model. Neurobiol Dis. 133(104443)2020.PubMed/NCBI View Article : Google Scholar
|
|
85
|
Vasanthi SS, Rao NS, Samidurai M, Massey
N, Meyer C, Gage M, Kharate M, Almanza A, Wachter L, Mafuta C, et
al: Disease-modifying effects of a glial-targeted inducible nitric
oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat
soman (GD) model of epilepsy. J Neuroinflammation.
20(163)2023.PubMed/NCBI View Article : Google Scholar
|
|
86
|
Soares-Santos RR, Machado DP, Romero TL
and Duarte ID: Nitric oxide and potassium channels but not opioid
and cannabinoid receptors mediate tramadol-induced peripheral
antinociception in rat model of paw pressure withdrawal. Can J
Physiol Pharmacol. 102:218–227. 2023.PubMed/NCBI View Article : Google Scholar
|
|
87
|
Nilsson D, Chess-Williams R and Sellers D:
Phosphodiesterase-5 inhibitors tadalafil and sildenafil potentiate
Nitrergic-nerve mediated relaxations in the bladder vasculature.
Eur J Pharmacol. 960(176152)2023.PubMed/NCBI View Article : Google Scholar
|
|
88
|
Eslami F, Shayan M, Amanlou A, Rahimi N,
Dejban P and Dehpour AR: Pentylenetetrazole preconditioning
attenuates severity of status epilepticus induced by
lithium-pilocarpine in male rats: Evaluation of opioid/NMDA
receptors and nitric oxide pathway. Pharmacol Rep. 74:602–613.
2022.PubMed/NCBI View Article : Google Scholar
|
|
89
|
Kovács R, Rabanus A, Otáhal J, Patzak A,
Kardos J, Albus K, Heinemann U and Kann O: Endogenous nitric oxide
is a key promoting factor for initiation of seizure-like events in
hippocampal and entorhinal cortex slices. J Neurosci. 29:8565–8577.
2009.PubMed/NCBI View Article : Google Scholar
|
|
90
|
Jourian S, Rahimi M, Manavi MA,
Pahlevan-Fallahy MT, Mohammad Jafari R, Amini A and Dehpour AR:
Possible interaction of opioidergic and nitrergic pathways in the
anticonvulsant effect of ivermectin on pentylenetetrazole-induced
clonic seizures in mice. Neurochem Res. 48:885–894. 2023.PubMed/NCBI View Article : Google Scholar
|
|
91
|
Zhu X, Dong J, Han B, Huang R, Zhang A,
Xia Z and Yao H: Neuronal nitric oxide synthase contributes to PTZ
kindling epilepsy-induced hippocampal endoplasmic reticulum stress
and oxidative damage. Front Cell Neurosci. 11(377)2017.PubMed/NCBI View Article : Google Scholar
|
|
92
|
Keshavarzi M, Ghasemi M, Manavi MA,
Dehpour AR and Shafaroodi H: Anticonvulsant effects of
pentoxifylline on seizures induced by pentylenetetrazole and
maximal electroshock in male mice: The role of the nitrergic
pathway. IBRO Neurosci Rep. 17:485–492. 2024.PubMed/NCBI View Article : Google Scholar
|
|
93
|
Moradi F, Eslami F, Rahimi N, Koohfar A,
Shayan M, Maadani M and Dehpour AR: Modafinil exerts anticonvulsive
effects against lithium-pilocarpine-induced status epilepticus in
rats: A role for tumor necrosis factor-α and nitric oxide
signaling. Epilepsy Behav. 130(108649)2022.PubMed/NCBI View Article : Google Scholar
|
|
94
|
Arslan AO, Akcay S, Akcay G, Zaqzouq D and
Him A: Neuroprotective effects of anodal tDCS on oxidative stress
and neuroinflammation in temporal lobe epilepsy. Biomedicines.
14(23)2025.PubMed/NCBI View Article : Google Scholar
|
|
95
|
Gunes H, Ozdemir E and Arslan G: Coenzyme
Q10 increases absence seizures in WAG/Rij rats: The role of the
nitric oxide pathway. Epilepsy Res. 154:69–73. 2019.PubMed/NCBI View Article : Google Scholar
|
|
96
|
Gunes H, Ozdemir E and Taskiran AS: 5-HT7
receptor antagonist SB269970 attenuates seizures by modulating
NO/cGMP signaling pathway and neuroinflammation in a
pentylenetetrazol-induced epilepsy model in rats. Nitric Oxide.
159:78–88. 2025.PubMed/NCBI View Article : Google Scholar
|
|
97
|
Zhu XH, Zhou YP, Zhang Q, Zhu MY, Song XW,
Li J and Zhou QG: A novel anti-epileptogenesis strategy of temporal
lobe epilepsy based on nitric oxide donor. EMBO Mol Med.
17(85)2024.PubMed/NCBI View Article : Google Scholar
|
|
98
|
Garg N, Joshi R, Bhatia A, Bansal S,
Chakrabarti A, Prakash A, Saikia B, Modi M and Medhi B: Study of
fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in
modulating the P-glycoprotein expression via an
endothelin-sphingolipid pathway in an animal model of
pharmacoresistant epilepsy. Indian J Pharmacol. 55:307–314.
2023.PubMed/NCBI View Article : Google Scholar
|
|
99
|
Rehni AK, Singh TG, Kalra R and Singh N:
Pharmacological inhibition of inducible nitric oxide synthase
attenuates the development of seizures in mice. Nitric Oxide.
21:120–125. 2009.PubMed/NCBI View Article : Google Scholar
|
|
100
|
Singh T and Goel RK: Adjuvant neuronal
nitric oxide synthase inhibition for combined treatment of epilepsy
and comorbid depression. Pharmacol Rep. 69:143–149. 2017.PubMed/NCBI View Article : Google Scholar
|
|
101
|
Meskinimood S, Rahimi N, Faghir-Ghanesefat
H, Gholami M, Sharifzadeh M and Dehpour AR: Modulatory effect of
opioid ligands on status epilepticus and the role of nitric oxide
pathway. Epilepsy Behav. 101(106563)2019.PubMed/NCBI View Article : Google Scholar
|
|
102
|
Carletti F, Gambino G, Rizzo V, Ferraro G
and Sardo P: Cannabinoid and nitric oxide signaling interplay in
the modulation of hippocampal hyperexcitability: Study on
electrophysiological and behavioral models of temporal lobe
epilepsy in the rat. Neuroscience. 303:149–159. 2015.PubMed/NCBI View Article : Google Scholar
|
|
103
|
Watanabe M, Miyai A, Danjo S, Nakamura Y
and Itoh K: The threshold of pentylenetetrazole-induced convulsive
seizures, but not that of nonconvulsive seizures, is controlled by
the nitric oxide levels in murine brains. Exp Neurol. 247:645–652.
2013.PubMed/NCBI View Article : Google Scholar
|
|
104
|
Aminirad A, Mousavi SE, Fakhraei N,
Mousavi SM and Rezayat SM: The role of nitric oxide in
anticonvulsant effect of nanocurcumine on
pentylenetetrazole-induced seizure in mice. Neurosci Lett.
651:226–231. 2017.PubMed/NCBI View Article : Google Scholar
|
|
105
|
Pasten C, Lozano M, Méndez GP and
Irarrázabal CE: 1400W prevents renal injury in the renal cortex but
not in the medulla in a murine model of ischemia and reperfusion
injury. Cell Physiol Biochem. 56:573–586. 2022.PubMed/NCBI View Article : Google Scholar
|
|
106
|
Minhas R, Bansal Y and Bansal G: Inducible
nitric oxide synthase inhibitors: A comprehensive update. Med Res
Rev. 40:823–855. 2020.PubMed/NCBI View Article : Google Scholar
|
