PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: relevance and reliability

Singh, Tanveer; Mishra, Awanish; Goel, Rajesh Kumar

doi:10.1007/s11011-021-00823-3

Cited by 52 publications

(38 citation statements)

References 103 publications

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“…Furthermore, chemical convulsion-induced histopathological changes similar to those in human TLE provide additional justification for the use of TLE rodent models. 41 Our study showed that treatment with the KD for 28 days, starting after pilocarpine-induced SE, not only exerted antiepileptogenic effects but also exhibited excellent cognitive improvement and neuroprotective effects in the rats with TLE. Furthermore, the biochemical and flow cytometry results demonstrated that the KD inhibited seizure-induced upregulation of ASIC1a and the ensuing intracellular Ca 2+ overload and restored the disrupted structure and function of the mitochondria.…”

Section: Discussionmentioning

confidence: 55%

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Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy

Qiao¹,

Qu²,

Shuang³

et al. 2022

NDT

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Background The ketogenic diet (KD) is a proven therapy for refractory epilepsy. Although the anti-seizure properties of this diet are understood to a certain extent, the exploration of its neuroprotective effects and underlying mechanisms is still in its infancy. Tissue acidosis is a common feature of epileptogenic foci. Interestingly, the activation of acid-sensing ion channel 1a (ASIC1a), which mediates Ca 2+ -dependent neuronal injury during acidosis, has been found to be inhibited by ketone bodies in vitro. This prompted us to investigate whether the neuroprotective effects induced by the KD occur via ASIC1a and interconnected downstream mechanisms in a rat model of temporal lobe epilepsy. Methods Male Sprague-Dawley rats were fed either the KD or a normal diet for four weeks after undergoing pilocarpine-induced status epilepticus (SE). The effects of KD on epileptogenesis, cognitive impairment and hippocampal neuron injury in the epileptic rats were subsequently evaluated by video electroencephalogram, Morris water maze test and Nissl staining, respectively. The expression of ASIC1a and cleaved caspase-3 in the hippocampus were determined using Western blot analysis during the chronic period following SE. Moreover, the intracellular Ca 2+ concentration, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mROS) and cell apoptosis of hippocampal cells were detected by flow cytometry. Results We found that the KD treatment strongly attenuated the spontaneous recurrent seizures, ameliorated learning and memory impairments and prevented hippocampal neuronal injury and apoptosis. The KD was also shown to inhibit the upregulation of ASIC1a and the ensuing intracellular Ca 2+ overload in the hippocampus of the epileptic rats. Furthermore, the seizure-induced structure disruption of neuronal mitochondria, loss of MMP and accumulation of mROS were reversed by the KD treatment, suggesting that it has protective effects on mitochondria. Finally, the activation of caspase-3 was also inhibited by the KD. Conclusion These findings indicate that the KD suppresses mitochondria-mediated apoptosis possibly by regulating ASIC1a to exert neuroprotective effects. This may provide a mechanistic explanation of the therapeutic effects of KD.

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Section: Discussionmentioning

confidence: 55%

“…Furthermore, chemical convulsion-induced histopathological changes similar to those in human TLE provide additional justification for the use of TLE rodent models. 41 …”

Section: Discussionmentioning

confidence: 99%

Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy

Qiao¹,

Qu²,

Shuang³

et al. 2022

NDT

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“…We investigated the effect of the cardiac glycoside digoxin in a subcardiotonic dose, classic AED sodium valproate, the selective COX-2 inhibitor celecoxib per se and the combination of digoxin with sodium valproate on the cyclooxygenase pathway of the arachidonic acid cascade, the content of 8-isoprostane and NSE in the brain of mice under PTZ-induced kindling. This animal model of kindling and increasing the state of epileptic readiness of the brain with long-term use of subthreshold doses of a convulsant approximates the natural conditions of long-term formation of the epileptic brain (Singh et al 2021). Therefore, this model is relevant when studying the effect of drugs on various links of epileptogenesis, including the neuroin ammatory pathway.…”

Section: Discussionmentioning

confidence: 71%

Digoxin and sodium valproate, but not celecoxib, render a pronounced effect on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice

Tsyvunin

Shtrygol

Mishchenko

et al. 2022

Preprint

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Epilepsy is a chronic neurological disease characterized by a persistent tendency to seizures. The development of new approaches to the treatment of epilepsy is an urgent issue in modern pharmacology. Such studies are especially necessary in view of the growing number of cases of drug-resistant epilepsy, which reaches 30 %. To improve the results of treatment, adjuvant non-antiepileptic drugs are offered. Promising adjuvant agents include, in particular, the lipophilic cardiac glycoside digoxin in subcardiotonic doses as well as non-steroidal anti-inflammatory drugs. Taking into account the important role of neuroinflammation in the pathogenesis of epilepsy, it is necessary to clarify the influence of standard antiepileptic drugs and adjuvant agents on individual links of the inflammatory process and neurons’ damage under the conditions of chronic epileptogenesis. The aim of the work is to determine the effect of digoxin, sodium valproate and celecoxib per se as well as the combination of digoxin with sodium valproate on the content of cyclooxygenase 1 and 2 types (COX-1, COX-2), prostaglandins (PG) E2, F2α, I2, thromboxane (TX) B2, 8-isoprostane and neuron-specific enolase (NSE) in the brain of mice in the pentylenetetrazole (PTZ)-induced kindling model. It was found that during 16 days of kindling (PTZ 30 mg/kg daily) sodium valproate in a sub-effective dose of 150 mg/kg and digoxin 0.8 mg/kg (1/10 LD50) per se moderately effectively affected the course of the seizure syndrome in mice. Sodium valproate significantly (p<0.05) increased the seizure latency and decreased the number of days with convulsions, when digoxin significantly (p<0.05) decreased the number of animals with seizures. Digoxin clearly potentiated the effect of sodium valproate – against the background of their combination, seizures were absent. Celecoxib 4 mg/kg only tended to reduce the number of animals with convulsions. In the brains of untreated animals with the PTZ-kindling model, a clear shift of the cyclooxygenase pathway of the arachidonic acid cascade was revealed, indicating neuroinflammation: the level of COX-1 and especially COX-2, PGF2α, and TXB2 increased, while the content of PGE2 and PGI2 decreased compared to the vehicle control group (p<0.001). These violations occurred against the background of strong oxidative stress, as evidenced by an almost 18-fold increase in the content of cerebral 8-isoprostane (p<0.001), and were accompanied by massive destruction of neurons, the marker of which is a 2.7-fold increase in the content of NSE (p<0.001). The anti-inflammatory and antioxidant properties of digoxin, sodium valproate and especially their combinations have been shown. They are manifested in a significant decrease in the level of COX-1 and COX-2 (p<0.001), an increase in the content of PGE2 and PGI2 (p<0.001), a decrease in the level of PGF2α and TXB2, 8-isoprostane and NSE (p<0.001) compared to the positive control (PC). Despite its selectivity for COX-2, celecoxib had almost no effect on the level of this cerebral COX isoform, mainly inhibiting COX-1. Compared with PC, celecoxib did not have a significant effect on COX-2, PGI2, and NSE, significantly inferior to valproate (except for the effect on PGF2α), digoxin and its combination (except for the effect on COX-1), which corresponds to the absence of a pronounced impact on the course of kindling and indicates the limitation of its anti-inflammatory and antioxidant properties in the CNS without a neurocytoprotective effect. Predominant suppression of COX-2 indicates a moderate selectivity of the combination of valproate and digoxin to this enzyme, which is a predictor of a reduction in the risk of side effects against the background of long-term use. Complete normalization of the level of 8-isoprostane under the combination of valproate + digoxin indicates the most favorable effect on the course of cerebral oxidative stress, as well as the maximum decrease in the content of NSE (p<0.001) indicates the neurocytoprotective properties of this combination in the model of chronic epileptogenesis. The set of obtained results experimentally substantiates the expediency of using a combination of digoxin with classical anticonvulsants, in particular with sodium valproate, to increase the effectiveness of pharmacotherapy of epilepsy.

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“…Traditional seizure models induced by pentylenetetrazole and maximal electroshock are classical animal models for the evaluation of novel antiepileptic drugs, which provide an effective means for rapid identification of potential antiepileptic drugs (Barker-Haliski and Steve White, 2020). However, these acute seizure models cannot effectively evaluate antiepileptic drugs that are used for the treatment of drug-resistant epilepsy (Singh et al, 2021). The KAinduced animal model with spontaneous seizures solves this problem well.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Kv7 Channel Activator Retigabine against Seizures and Neurodegeneration in Kainic Acid-Induced Seizure Model

Zhuang¹

2022

ijSciences

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Aims:The current study evaluates whether Kv7 channel activator retigabine (RTG) could attenuate seizures and hippocampal neurodegeneration in the kainic acid (KA) induced seizure model. Methods: The anticonvulsant activity of RTG is evaluated by electroencephalography (EEG) recordings in KA-kindled rats. Tunel assay and immunofluorescence of NeuN are used to evaluate the neuroprotective effect of RTG in the hippocampus of KA-kindled rats. Results: RTG effectively reduces epileptiform discharges induced by KA injection. Tunel assay and immunofluorescence of NeuN show that RTG exerts neuroprotection in the hippocampus of KA-kindled rats. Conclusion: Taken together, this study demonstrates that RTG effectively alleviates seizures and hippocampal neurodegeneration in the KA-induced seizure model.

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PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: relevance and reliability

Cited by 52 publications

References 103 publications

Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy

Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy

Digoxin and sodium valproate, but not celecoxib, render a pronounced effect on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice

Therapeutic Effects of Kv7 Channel Activator Retigabine against Seizures and Neurodegeneration in Kainic Acid-Induced Seizure Model

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