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Oxidative stress is implicated in epileptogenesis as well as in the metabolic changes associated with increased risk of atherosclerotic vascular disease in epilepsy. The present work investigated the impact of the antioxidant trimetazidine (TMZ) on the antiepileptic activity of valproic acid (VPA) and on the metabolic and histological changes in hippocampal, aortic, and hepatic tissues associated with epilepsy and (or) VPA. Rats were divided into non-pentylenetetrazole (non-PTZ) group subdivided into control and VPA-treated groups, and PTZ-treated group subdivided into PTZ, PTZ/VPA, PTZ/TMZ, and PTZ/VPA + TMZ groups. VPA treatment in PTZ rats resulted in an antioxidant effect with improvement in oxidative stress, metabolic and histopathological changes induced by PTZ in hippocampus, aortic, and hepatic tissues. TMZ exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. Combination of TMZ with VPA induced a greater reduction in oxidative stress, improvement in the metabolic and histopathological changes compared to VPA treatment. In contrast, VPA administration in non-PTZ-treated rats induced a pro-oxidative effect, associated with metabolic and histopathological changes in aortic and hepatic tissues. These findings suggest that co-administration of TMZ with VPA in epilepsy might antagonize not only the oxidative stress associated with epilepsy but might also counteract a potential pro-oxidative effect of VPA.

Various antiepileptic drugs (AEDs) especially enzyme-inducing AEDs might be associated with increased vascular risk, through impairment of the endogenous antioxidative ability which may trigger oxygen-dependent tissue injury. Lamotrigine (LTG) a non-enzyme-inducing AED has scarce information regarding its effects on oxidative stress. The present study aimed to study the possible modulation of vascular risk factors of epileptogenesis by LTG, in a rat model of kindling seizure induced by pentylenetetrazole (PTZ). Four groups of male Wister rats were used; vehicle control group, PTZ group (alternate day PTZ, 30 mg/kg, i.p), LTG/PTZ group (LTG 20 mg/kg/day p.o and alternate day PTZ) and LTG group. The study period was 5 weeks. Lipoproteins and total homocysteine (tHcy), malondialdehyde (MDA) and reduced glutathione (GSH) were measured. Aortic endothelial function study and histopathological examination of the rats' brains, aortas and coronaries were conducted. Serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), tHcy, MDA, GSH levels were significantly higher in epileptic rats than normal controls rats. A decrease in HDL-cholesterol with high atherosclerotic index was also demonstrated. The administration of LTG improved the PTZ-kindled seizures. It produced a significant decrease in TC, TG and LDL-cholesterol, MDA, aortic GSH and increase in HDL-cholesterol with no significant effect on serum GSH and tHcy levels. LTG improved endothelium-dependent relaxation, decreased hippocampal neurodegenerative changes and atherosclerotic changes of aortas and coronaries. LTG decreased seizures severity, hippocampal damage and improved vascular risk markers in this rat model of kindling seizures.

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