Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: Involving AKT/m-TOR pathway

Abstract

ABSTRACT The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate (TOP) against pentylenetetrazol (PTZ)-induced convulsions. Male Wister rats received either saline or pentylenetetrazole (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (o.5 Gy), Topiramate (50 mg/kg, p.o., 7 days) and TOP with LDR respectively before PTZ injection. Racine’ score, latency and duration of the convulsions were assessed. Glutamate and GABA were measured. As well as AKT/m-TOR signalling pathway including AKT (protein kinase –B), m-TOR (mammalian target of rapamycin), protein S6 and caspase3 were also assessed. Measurements of markers of oxidative stress including MDA (malondialdehyde), GSH (glutathione) and NO (nitric oxide) were carried out. Histological examinations of hippocampi were done. Results: PTZ produced behavioural changes (high Racine score, short latency and long duration. It elevated MDA and NO contents, while reduced GSH content. TOP treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioural changes, brain mediators, m-TOR pathway, oxidative stress and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ- treated rats exhibited necrosis, pyknosis and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. Conclusions The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signalling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate. Highlights Male Wistar rats were treated with topiramate 50 mg/kg p.o. for 7 days. on the 6th day of topiramate treatment, rats were exposed to a single low dose whole body gamma radiation (0.5 Gy). on the 7th day of topiramate treatment, rats were injected with pentylenetetrazole 75 mg/kg i.p. 2h after the 7th dose of TOP to illustrate the protective effects of TOP against acute convulsions induced by PTZ. Low dose whole body gamma irradiation purveyed novel anticonvulsant activity which could offer a possible contributor in the basic management of convulsions to avoid side effects of traditional anticonvulsant drugs such as liver and kidney impairments.