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 ED 50 of rapamycin and axitinib, with their combined administration using graded dosages of ED 50 of each drug. The median effective dose (ED 50 ) for rapamycin and axitinib was 0.93 and 4.97 mg/kg, respectively. ED 50 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.
The research is dedicated to in-depth study of neurotrophic and antiepileptic properties of original potential anticonvulsant agents from 4-thiazolidinones – LES-2658 (5-(3-nitro-benzylidene)-2-(thiazol-2-ylimino)-thiazolidin-4-one) and LES-1205 ([2,4-dioxo-5-(thiazol-2-ylcarbamoylmethyl)-thiazolidin-3-yl]-acetic acid ethyl ester), synthesized at the Department of Pharmaceutical, Organic and Bioorganic Chemistry of Danylo Halytsky Lviv National Medical University, Ukraine. Studying of sleep - wakefulness cycle characteristics in animals with chronic epileptic syndrome in conditions of 4-thiazolidinones derivatives LES-2658 and LES-1205 use was performed. The kindling syndrome was induced in Wistar rats via daily pentylenetetrazol (PTZ) (30 mg/kg, i.p.) administrations during three weeks and sleep - wakefulness cycle was studied under conditions of LES-2658 and LES-1205 administrations at doses 25.0and 100.0 mg/kg i.p.. Total wakefulness, non - rapid eye movement sleep, rapid eye movement sleep, falling asleep latency, REM - onset latency and also number of REM sleep episodes have been determined by behavioral characteristics of experimental animals. It was established that 4-thiazolidinone derivatives Les-1205 and Les-2658 reduce REM sleep fragmentation and increase its duration in PTZ-kindled rats. Les-1205 compound at dose 100.0 mg/kg show a clear correcting influence on kindling - induced sleep disturbances.
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