Carbamazepine prevents breakdown of neurotransmitter release induced by hyperactivation of ryanodine receptor
Carbamazepine prevents breakdown of neurotransmitter release induced by hyperactivation of ryanodine receptor
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DOI：
10.1016/j.neuropharm.2007.02.009
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发表时间：
2007-06-01
影响因子：
4.7
通讯作者：
Kaneko, Sunao
中科院分区：
文献类型：
--
作者：
Yoshida, Shukuko;Okada, Motohiro;Kaneko, Sunao
为阐明卡马西平（CBZ）的药理作用机制，我们采用微透析技术，观察了CBZ对大鼠海马Ryanodine受体（Ryr）敏感的Ca ~（2+）诱导的Ca ~（2+）释放系统（CICR）相关的GABA和谷氨酸释放的影响。治疗相关浓度的CBZ增加基础GABA释放，而不影响基础谷氨酸释放;然而，K+诱发的释放CBZ浓度依赖性地减少。低浓度ryanodine增加基础和K+诱发释放的GABA和谷氨酸的浓度依赖性的方式，而高浓度ryanodine减少它们。这些拐点的浓度-反应曲线的ryanodine神经递质释放（临界浓度）被移到左边的K+诱发的刺激。Ryanodine释放GABA的临界浓度低于释放谷氨酸的临界浓度。在静息期，Ryanodine的临界浓度不受L型、N型和P型电压敏感性钙通道（VSCC）抑制剂的影响，但可被CBZ阻止;然而，在神经元超兴奋期，CBZ、L型和P型VSCC抑制剂可增加临界浓度，但N型VSCC抑制剂则不增加临界浓度。因此，治疗相关浓度的CBZ通过抑制L型和P型VSCC以及抑制Ryr敏感性CICR来防止Ryr过度活化诱导的神经递质释放机制的破坏。CBZ的这些作用似乎至少部分参与其抗癫痫机制。皇冠版权所有（c）2007年出版的爱思唯尔有限公司保留所有权利。
To clarify the mechanisms of the pharmacological action of carbamazepine (CBZ), we determined the effect of CBZ on GABA and glutamate release associated with the ryanodine receptor (Ryr)-sensitive Ca2+-induced Ca2+-releasing system (CICR) in the rat hippocampus using microdialysis. The therapeutically relevant concentration of CBZ increased basal GABA release without affecting basal glutamate release; however, K+-evoked releases were concentration-dependently reduced by CBZ. Lower-concentration ryanodine increased basal and K+-evoked releases of GABA and glutamate in a concentration dependent manner, whereas higher-concentration ryanodine reduced them. These inflection points in the concentration-response curves of ryanodine for neurotransmitter release (critical concentrations) were shifted to the left by K+-evoked stimulation. The critical concentration of ryanodine in GABA release was lower than that in glutamate release. During the resting stage, the critical concentrations of ryanodine were unaffected by inhibition of L-type, N-type and P-type voltage-sensitive Ca2+ channels (VSCCs) but were prevented by CBZ; however, during the neuronal hyperexcitable stage, the critical concentration was increased by CBZ, L-type and P-type VSCC inhibitors but not the N-type VSCC inhibitor. Therefore, a therapeutically relevant concentration of CBZ protects against the breakdown of the neurotransmitter release mechanism induced by hyperactivation of Ryr via inhibition of L-type and P-type VSCCs as well as inhibition of Ryr-sensitive CICR. These actions of CBZ appear to be involved, at least partially, in its anti-seizure mechanisms. Crown Copyright (c) 2007 Published by Elsevier Ltd. All rights reserved.