Effects of levetiracetam on blood-brain barrier disturbances following hyperthermia-induced seizures in rats with cortical dysplasia

The mechanisms underlying the changes in blood-brain barrier (BBB) integrity and the generation of seizures in childhood associated with preexisting brain lesions like cortical dysplasia (CD) are poorly understood. We investigated the effects of levetiracetam (LEV) on BBB integrity and the survival during hyperthermic seizures in rats with CD. Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. On postnatal day 28, hyperthermia-induced seizures were evoked in offspring with CD. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopy were performed. Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P < 0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P < 0.01). While glial fibrillary acidic protein (GFAP) immunoreactivity slightly increased in brain sections of animals with CD during hyperthermia-induced seizures, LEV led to GFAP immunoreactivity comparable to that of controls. Decreased occludin immunoreactivity and expression in CD plus hyperthermia-induced seizures was increased by LEV. Opening of tight junctions and abundance of pinocytotic vesicles representing ultrastructural evidences of BBB impairment and severe perivascular edema were observed in animals with CD exposed to hyperthermia-induced seizures and LEV treatment led to the attenuation of these findings. These results indicate that LEV may present a novel approach for the protection of the BBB besides its antiepileptic impact on hyperthermic seizures in the setting of CD.