Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling-Induced Cognitive Impairment and Depressive-Like Behavior

Zhu, Xinjian; Dong, Jun; Han, Bing; Huang, Rongrong; Zhang, Aifeng; Xia, Zhengrong; Chang, He; Chao, Jie; Yao, Honghong

doi:10.3389/fnbeh.2017.00203

Cited by 31 publications

(8 citation statements)

References 66 publications

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“…No significant changes in the anxiety-related response in the elevated plus maze test were reported. However, we found that PTZ-induced kindling led to the depressive-like behavior in mice, which is in agreement with many previous reports [54][55][56]. Repeated injection of AS-1 did not alleviate the kindling-induced behavioral despair in mice.…”

Section: Discussionsupporting

confidence: 92%

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

et al. 2020

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In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZinduced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).

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Section: Discussionsupporting

confidence: 92%

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

et al. 2020

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“…Oxidative damage to vulnerable mitochondrial and hippocampal molecules and even neuronal death have been found in multiple animal models of acquired epilepsy, such as glutamate agonist (e.g., KA), acetylcholine agonist (e.g., pilocarpine), electric kindling, and PTZ models [[49], [50], [51]]. Additional reports on KA treatment, lithium-pilocarpine, and PTZ-kindling models of epilepsy have all demonstrated that seizures result in increased ROS production [52,53]. The production of ROS, which is associated with mitochondrial defects, also impacts epileptogenesis [9,54].…”

Section: Discussionmentioning

confidence: 99%

Succinate accumulation induces mitochondrial reactive oxygen species generation and promotes status epilepticus in the kainic acid rat model

Zhang

Zhu

et al. 2020

Redox Biology

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Though succinate accumulation is associated with reactive oxygen species (ROS) production and neuronal injury, which play critical roles in epilepsy, it is unclear whether succinate accumulation contributes to the onset of epilepsy or seizures. We sought to investigate changes in succinate, oxidative stress, and mito-SOX levels, as well as mitophagy and neuronal change, in different status epilepticus (SE) rat models. Our results demonstrate that KA-induced SE was accompanied by increased levels of succinate, oxidative stress, and mito-SOX, as well as mitophagy and neuronal degeneration. The similarly increased levels of succinate, oxidative stress, and mito-SOX were also found in pilocarpine-induced SE. Moreover, the reduction of succinate accumulation by the inhibition of succinate dehydrogenase (SDH), malate/aspartate shuttle (MAS), or purine nucleotide cycle (PNC) served to reduce succinate, oxidative stress, and mito-SOX levels, thereby preventing oxidative stress-related neuronal damage and lessening seizure severity. Interestingly, simulating succinate accumulation with succinic acid dimethyl ester may induce succinate accumulation and increased oxidative stress and mito-SOX levels, as well as behavior and seizures in electroencephalograms similar to those observed in rats exposed to KA. Our results indicate that succinate accumulation may contribute to the increased oxidative stress/mitochondrial ROS levels, neuronal degeneration, and SE induced by KA administration. Furthermore, we found that succinate accumulation was mainly due to the inverse catalysis of SDH from fumarate, which was supplemented by the MAS and PNC pathways. These results reveal new insights into the mechanisms underlying SE and that reducing succinate accumulation may be a clinically useful therapeutic target in SE.

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“…Several studies have indicated the involvement of nNOS, but not iNOS, in the neuroprotective property of phytochemical ingredients, such as curcumin or oleuropein, in various models of seizures in rats and mice . On the other hand, it has been suggested that nNOS can trigger psychiatric comorbidities like cognitive impairment and depression‐like behavior in PTZ‐kindled mice …”

Section: Discussionmentioning

confidence: 99%

Methadone's effects on pentylenetetrazole‐induced seizure threshold in mice: NMDA/opioid receptors and nitric oxide signaling

Roodsari

Bahramnejad

Rahimi

et al. 2019

Annals of the New York Academy of Sciences

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Methadone is a synthetic opioid used to treat opiate withdrawal and addiction. Studies have demonstrated the impact of methadone on seizure susceptibility. This study investigated the modulatory impacts of acute and subchronic (three times daily for 5 days) intraperitoneal methadone treatment on pentylenetetrazole‐induced clonic seizure threshold (CST) in mice, as well as the involvement of the nitric oxide, N‐methyl‐d‐aspartate (NMDA), and µ‐opioid pathways. Acute administration of different doses of methadone (0.1, 0.3, 1, and 3 mg/kg) 45 min before CST significantly decreased the seizure threshold. Additionally, pretreatment with noneffective doses of an opioid receptor antagonist (naltrexone) and NMDA receptor antagonists (ketamine and MK‐801) inhibited methadone's proconvulsive activity in the acute phase, while l‐NAME (a nonspecific nitric oxide synthase (NOS) inhibitor) did not affect that activity. In the subchronic phase, methadone (3 mg/kg) demonstrated an anticonvulsive effect. Although subchronic pretreatment with noneffective doses of l‐NAME and 7‐nitroindazole (a specific neuronal NOS inhibitor) reversed methadone's anticonvulsive activity, aminoguanidine (a specific inducible NOS inhibitor), naltrexone, MK‐801, and ketamine did not change methadone's anticonvulsive characteristic. Our results suggest that NMDA and µ‐opioid receptors may be involved in methadone's proconvulsive activity in the acute phase, while methadone's anticonvulsive activity may be modulated by neuronal NOS in the subchronic phase.

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Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling-Induced Cognitive Impairment and Depressive-Like Behavior

Cited by 31 publications

References 66 publications

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

Succinate accumulation induces mitochondrial reactive oxygen species generation and promotes status epilepticus in the kainic acid rat model

Methadone's effects on pentylenetetrazole‐induced seizure threshold in mice: NMDA/opioid receptors and nitric oxide signaling

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