Oxidative stress suppression contributes to antiseizure action of axitinib and rapamycin in pentylenetetrazol-induced kindling

Abstract

Rapamycin and axitinib block different kinases in signaling pathways such as PI3K-Akt-mTOR and BDNF-TrkB, respectively. Both have antiseizure and antioxidative actions, which justify studying the combined effects of these drugs upon seizures and oxidative stress in the chronic model of epilepsy. The investigation aimed to look for the combined effect of rapamycin and axitinib upon pentylenetetrazol (PTZ)-kindled seizures and oxidative stress. Experiments were performed on 300 two- to four-month-old Wistar male rats, which had been kindled daily with PTZ (35.0 mg/kg, i.p.). Malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione (GSH) level were determined in brain tissues of kindled rats before and after the treatment. The analysis of antiseizure and antioxidative actions was performed using ED50 of rapamycin and axitinib, with their combined administration using graded dosages of ED50 of each drug. The median effective dose (ED50 ) for rapamycin and axitinib was 0.93 and 4.97 mg/kg, respectively. ED50 of rapamycin when combined with axitinib (2.0 mg/kg) was 0.60 mg/kg, which was reduced by 35.6% when compared with the ed 50 administered alone (P < 0.05). The MDA level increased from 152.9±24.8 to 388.3±49.2 nmol/mg of protein (P < 0.05), while SOD activity reduced from 11.14±2.33 to 3.54±1.08 IU/mg of protein (P < 0.05) in brain tissues of the kindled rats. Combined treatment with rapamycin (0.56 mg/kg, i.p.) and axitinib (2.0 mg/ kg, i.p.) resulted in a significant rise in SOD activity (11.09±1.86 IU/mg) and GSH level (7.32±1.34 µg/mg) when compared with the kindled rats (P < 0.05). Combined axitinib and rapamycin therapy have an antiepileptic and antioxidative effect on PTZ-kindled seizures.