Axitinib displays antiseizure activity on pentylenetetrazol – induced kindling mode

Abstract

This work aimed to investigate the effects of a specific inhibitor of vascular endothelial growth factor receptor generic axitinib upon pentylenetetrazol (PTZ) - induced kindled and acute convulsions and to compare axitinib effects with diazepam. Wistar rats kindled with PTZ (30.0 mg/kg, intraperitoneally) during three weeks up to a stage of generalized convulsions stage 5 were observed. The assessment of seizures was performed immediately after completing the kindling procedure, after PTZ-free two weeks, and on acute PTZ-induced convulsions. Axitinib was administered perorally with PTZ injection 60 min later. Diazepam was administered intraperitoneally followed with PTZ in 30 min. Axitinib prevented generalized convulsions in 5 out of 8 kindled rats in a dose of 2.5 mg/kg, and the pronouncement of effect was comparable with such one caused by diazepam in a dose of 0.1 mg/kg. Axitinib in the dose of 10.0 mg/kg completely protected generalized convulsions. A significant reduction of seizure severity was observed when axitinib (2.5 and 10.0 mg/kg) was administered to kindled rats after two weeks free from PTZ, while diazepam caused the suppression of convulsions only in the highest dose of 1.0 mg/kg. Acute PTZ seizures were suppressed by diazepam in both doses, while axitinib was not effective. Axitinib reduced the density of neomicrovessels in the frontal cortex by 47.0% in early kindling and 43.9% in the postponed period. The effectiveness of axitinib on the kindling model of epilepsy might be explained by preventing neoangiogenesis as a valid mechanism of chronic brain epileptization development.