Brain-derived neurotrophic factor delays hippocampal kindling in the rat

Epileptic seizures increase the expression of brain-derived neurotrophic fa ctor in the hippocampus. Since this neurotrophin exerts modulatory effects on neuronal excitability in this structure, it may play an important role i n hippocampal epileptogenesis. This question was addressed by studying the effects of chronic infusions of recombinant brain-derived neurotrophic fact or and brain-derived neurotrophic factor antisense in the hippocampus durin g the first seven days of hippocampal kindling. Infusion with brain-derived neurotrophic factor (6-24 mug/day) significantly delayed the progression o f standard hippocampal kindling and strongly suppressed seizures induced by rapid hippocampal kindling. These suppressive effects were dose dependent, long lasting, not secondary to neuronal toxicity and specific to this neur otrophin, as nerve growth factor accelerated hippocampal kindling progressi on. They also appeared to be specific to the hippocampus, as infusion of br ain-derived neurotrophic factor (48 mug/day) in the amygdala only resulted in a slight and transient delay of amygdala kindling. Conversely to the pro tective effects of exogenous brain-derived neurotrophic factor, chronic hip pocampal infusion of antisense oligodeoxynucleotides (12 nmol/day), resulti ng in reduced expression of endogenous brain-derived neurotrophic factor in the hippocampus. aggravated seizures during hippocampal kindling. Taken together, our results lead us to suggest that the seizure-induced inc rease in brain-derived neurotrophic factor expression in the hippocampus ma y constitute an endogenous regulatory mechanism able to restrain hippocampa l epileptogenesis. (C) 2000 IBRO. Published by Elsevier Science Ltd. All ri ghts reserved.