The effects of valproate on the arachidonic acid metabolism of rat brain microvessels and of platelets

Long-term administration of the antiepileptic drug valproate can induce hem atologic, hepatic and endocrine abnormalities and morphologic alterations i n the brain capillaries and glial cells. Valproate elicits bone marrow supp ression, reducing the number of red blood cells and platelets, and causes p latelet functional abnormalities. Various data suggest that more than one m echanism of valproate-associated toxicity may exist, but the pathomechanism of cell function alterations elicited by valproate has not yet been elucid ated. The reported ex vivo experiments were designed to investigate the eff ects of valproate on the arachidonic acid cascade of rat brain capillaries and platelets. Valproate was administered (300 mg/kg body weight/day) in th e drinking water to male Wistar rats for 2 weeks. isolated platelets and br ain microvessels were labelled with [C-14]arachidonic acid and the released [C-14]eicosanoids were separated by overpressure thin-layer chromatography and determined quantitatively by liquid scintillation counting. Valproate treatment reduced the synthesis of cyclooxygenase and lipoxygenase products in rat platelets, in brain microvessels valproate stimulated the synthesis of Lipoxygenase metabolites and attenuated the cyclooxygenase pathway. Mod ifications of the arachidonate cascade in platelets and brain microvessels may contribute to the cell function alterations caused by valproate. (C) 20 00 Elsevier Science B.V. All rights reserved.