Selective blockade of N-type calcium channels by levetiracetam

被引:270
作者
Lukyanetz, EA [1 ]
Shkryl, VM [1 ]
Kostyuk, PG [1 ]
机构
[1] AA Bogomolets Physiol Inst, UA-01024 Kiev, Ukraine
关键词
levetiracetam; antiepileptic drugs; calcium channels; hippocampal neurons; epilepsy;
D O I
10.1046/j.1528-1157.2002.24501.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Purpose: We investigated the effect of the new antiepileptic drug (AED) levetiracetam (LEV) on different types of high-voltage-activated (HVA) Ca2+ channels in freshly isolated CA I hippocampal neurons of rats. Methods: Patch-clamp recordings of HVA Ca2+ channel activity were obtained from isolated hippocampal CAI neurons. LEV was applied by gravity flow from a pipette placed near the cell, and solution changes were made by electromicrovalves. Ca2+ channel blockers were used for separation of the channel subtypes. Results: The currents were measured in controls and after application of 1-200 muM LEV. LEV irreversibly inhibited the HVA calcium current by similar to18% on the average. With a prepullse stimulation protocol, which can eliminate direct inhibition of Ca2+ channels by G proteins, we found that G proteins were not involved in the pathways underlying the LEV inhibitory effect. This suggested that the inhibitory effect arises from a direct action of LEV on the channel molecule. The blocking mechanism of LEV was not related to changes in steady-state activation or inactivation of Ca2+ channels. LEV also did not influence the rundown of the HVA Ca2+ current during experimental protocols lasting similar to10 min. Finally, LEV at the highest concentration used (200 muM) did not influence the activity of L-, P- or Q-type Ca2+ channels in CAI neurons, while selectively influencing the activity of N-type calcium channels. The maximal effect on these channels separated from other channel types was -similar to37%. Conclusions: Our results provide evidence that LEV selectively inhibits N-type Ca2+ channels of CAI pyramidal hippocampal neurons. These data suggest the existence of a subtype of N-type channels sensitive to LEV, which might be involved in the molecular basis of its antiepileptic action.
引用
收藏
页码:9 / 18
页数:10
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