L-type Ca(2+) channel blocker inhibits mossy fiber sprouting and cognitive deficits following pilocarpine seizures in immature mice.
Behavioral and cognitive deficits are one of the most frequent sequelae of childhood epilepsy. Accumulating evidence indicates that epilepsy induces aberrant development of the mossy fibers in the hippocampus, the region that is commonly accepted to play a key role in learning and memory. We have therefore proposed that such abnormal maturation of the central nervous system may cause the adverse prognoses following epilepsy. Based on this hypothesis, using primary cultures of the dentate granule cells, we showed that the L-type Ca(2+) channel blocker nicardipine was neuroprotective against excessive mossy fiber synaptogenesis induced by prolonged depolarization that was assumed to mimic epileptiform conditions. Therefore, we evaluated the in vivo effect of nicardipine on aversive sequelae following epileptiform seizures. We found aberrant sprouting of the mossy fibers and poor performance of spatial and contextual tasks in the mice that had received treatment with pilocarpine at their early postnatal age. Repetitive administration of nicardipine prevented the mossy fiber sprouting and ameliorated the cognitive deterioration, although it did not show anticonvulsant actions against pilocarpine seizures. In the present study, we proposed two in vitro and in vivo models for evaluating epilepsy sequelae and noticed that L-type Ca(2+) channel blocker nicardipine was effective in both models. L-type Ca(2+) channel blocker may be a good candidate for a preventive for childhood epilepsy sequelae. Likewise, these useful systems will disclose additional candidates in future.
Ikegaya
Y
Y
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan. ikegaya@tk.airnet.ne.jp
Nishiyama
N
N
Matsuki
N
N
D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000503:physiopathology / Q000517:prevention & control*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists; D009529:Nicardipine / Q000494:pharmacology* / Q000627:therapeutic use; D010862:Pilocarpine; D012640:Seizures / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018721:Muscarinic Agonists; D010862:Pilocarpine; D009529:Nicardipine