Chloride Co-Transporter Nkcc1 As A New Pharmacological Target For Adult Chronic Epilepsy

Abstract

Epilepsy is a chronic disease characterized by periodic and unpredictable occurrence of seizures, due to high neuronal activity, product of a dysregulation of excitatory and inhibitory activity. Studies in neurons from epileptic tissue, have shown a higher concentration of chloride, producing a depolarization (excitatory effects). On the other hand studies in hippocampal slices, from animal models of acute epilepsy, have shown an overexpression of co-transporter NKCC1, which may be causing the increase in the chloride concentration. For neonatal it has been proposed that the specific blocker of NKCC1 Bumetanide can be used as antiepileptic. However it has not been evaluated if this is an useful treatment for adult chronic epilepsy. In the present study, in order to study the antiepileptic effect of Bumetanide, chronic epilepsy was induced in adult rats by pilocarpine administration. After 2 weeks, the epileptic animals were treated with the antiepileptic Diazepam (GABA agonist), Bumetanide (Blocker NKCC1), and the combination of both. o Diazepam treated animals showed seizures during the two first hours post-injection, suggesting that activating GABAergic transmission has excitatory effects. NKCC1 expression assayed showed an increase in epileptic animals, suggesting that the excitatory GABA effects arise from a reversion of chloride driving force. By the present work it is shown that animal models of chronic epilepsy do not respond to treatment with Diazepam, due to increased expression of the co-transporter NKCC1, and Bumetanide could be an effective antiepileptic drug for refractory epilepsy.