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

Abstract

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine’ score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral 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. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Keywords:

• Low dose whole body gamma irradiation
• topiramate
• m-TOR
• pentylenetetrazole
• rapamycin
• oxidative stress

Acknowledgements

The authors are thankful to Atomic Energy Authority and Faculty of Pharmacy Cairo University for providing support to complete research.

Compliance with ethical standards: This research approved by the research ethics committee for experimental and clinical studies at Faculty of Pharmacy Cairo University.

Author contributions

SK, SM, and MS conceived and designed research. DL conducted experiments. DL contributed new reagents and analytical tools. SM and DL analyzed data. SM and DL wrote the manuscript. SK and SM read and approved the manuscript. All authors approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).