The Protection by Vitamin E Against Tramadol-Induced Proconvulsant Effects and Brain Damage in Pentylenetetrazole-Induced Status Epilepticus in Rats

Abstract

We investigated the effect of the opioid analgesic tramadol on the development of epileptic seizures and neuronal injury and the possible modulatory effect of vitamin E (Vit E) in rats with pentylenetetrazole (PTZ)-induced status epilepticus. Rats received repeated intraperitoneal (i.p.) injections of PTZ till the development of status epilepticus and were pretreated once with tramadol (30, 60 or 90 mg/kg), vitamin E (Vit E, 70 mg/kg) or both tramadol (90 mg/kg) and Vit E (70 mg/kg) prior to starting PTZ injections. Seizure scores, the latency time and the PTZ dose for each group required to reach status epilepticus were determined and histopathological examination of the brain tissue was done. Results indicated that tramadol produced both anticonvulsant and proconvulsant effects. The anticonvulsant effects of tramadol were observed for facial twitching (stage 1), convulsive body waves (stage 2), and myoclonic jerks and rearing (stage 3) and turn over onto one side position (stage 4) that were significantly inhibited by tramadol. In contrast, tonic-clonic convulsions (stage 5) were significantly increased by 60 or 90 mg/kg of tramadol as compared to PTZ control group. The mean latency and PTZ threshold dose for status epilepticus were markedly decreased after tramadol. The administration of Vit E exerted beneficial effects in decreasing epilepsy scores and increasing both the latency time and threshold dose of PTZ for reaching status epilepticus. Meanwhile, rats treated with both tramadol and Vit E exhibited significant increase in tonic-clonic convulsions and markedly shortened latency time to reach status epilepticus compared to those treated with only Vit E. In cerebral cortex and hippocampus, PTZ resulted in apoptotic cells, darkly stained degenerated and vacuolated neurons and gliosis. These pathological changes increased after tramadol but were markedly reduced by Vit E treatment. Collectively, these results suggest that: (i) tramadol exerts both anticonvulsant and proconvulsant effects; (ii) tramadol shortened the latency time and decreased the threshold dose of PTZ for evoking status epilepticus; (iii) PTZ-induced seizures and brain damage can be inhibited by Vit E; (iv) tramadol at high doses interferes with the effect of Vit E in inhibiting tonic-clonic convulsions and in reducing brain damage.