Endogenous control of hippocampal epileptogenesis by a molecular cascade involving brain-derived neurotrophic factor and neuropeptide Y

Epileptic seizures increase the expression of brain-derived neurotrophic fa ctor (BDNF) in the hippocampus. Because this neurotrophin exerts modulatory effects on hippocampal neuronal excitability, it may play an important rol e in epileptogenesis initiated in this structure. Moreover, BDNF is known t o regulate the expression of neuropeptide Y, which displays modulatory prop erties on seizure activity. This suggests that the effects of BDNF on epile ptogenesis may be mediated by neuropeptide Y. The roles of BDNF and neurope ptide Y during epileptogenesis were thus investigated in the kindling model , induced in the rat by repeated electrical stimulations of the hippocampus . Recombinant BDNF chronically infused in the hippocampus during the first week of hippocampal stimulations significantly delayed the progression of k indling, an effect that outlasted the end of the infusion by at least seven days. Conversely, infusion of anti-BDNF antisense oligodeoxynucleotides, t o reduce the expression of endogenous BDNF in the hippocampus, aggravated t he electroencephalographic expression of seizures. Chronic infusion of BDNF also increased the expression of neuropeptide Y in the hippocampus with a time course similar to the protective effect of the neurotrophin on kindlin g. Finally, chronic infusion of neuropeptide Y in the hippocampus delayed t he progression of hippocampal kindling, whereas anti-neuropeptide Y antibod ies had an aggravating effect. Altogether, our results suggest that the sei zure-induced increase in BDNF expression in the hippocampus may constitute an endogenous protective mechanism able to counteract hippocampal epileptog enesis, This protective effect appears to be mediated at least in part thro ugh regulation of neuropeptide Y expression.