A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam
A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam
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DOI：
10.1152/jn.00279.2011
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发表时间：
2011-09-01
影响因子：
2.5
通讯作者：
Rothman, Steven M.
中科院分区：
文献类型：
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作者：
Meehan, Anna L.;Yang, Xiaofeng;Rothman, Steven M.
Meehan AL，Yang XF，McAdams BD，Yuan L，Rothman SM.抗癫痫药物作用的一种新机制：左乙拉西坦的作用可能介导囊泡进入。J Neurophysiol 106：1227-1239，2011.首次发表于2011年6月8日; doi：10.1152/jn.00279.2011。左乙拉西坦（LEV）是最常用的抗癫痫药物之一，但其作用机制尚不清楚。基于LEV结合囊泡蛋白突触囊泡蛋白2A并减少突触前神经递质释放的先前信息，我们希望更严格地表征其对递质释放的影响，并解释其充分发挥作用所需的延长潜伏期。在离体大鼠海马锥体神经元的全细胞贴片记录过程中，我们发现LEV以频率依赖性方式降低突触电流，并减少了易于释放的囊泡池。当我们操纵自发活动和刺激范例时，我们发现LEV孵育期间的突触活动改变了LEV效应出现的时间及其幅度。我们认为，突触活动和伴随的囊泡释放允许LEV进入回收囊泡到达其结合位点，突触囊泡蛋白2A。为了支持这一假设，囊泡“加载-卸载”协议使用高渗蔗糖在LEV的存在下迅速诱导LEV的效果。在没有LEV的情况下，这种效应在卸载后迅速消失。这些发现与LEV作用于囊泡内结合位点以调节递质的释放以及其对快速放电神经元的最显著作用是一致的。我们的研究结果确定了一个独特的神经生物学解释LEV的高选择性抗癫痫作用，并建议突触囊泡蛋白可能是适当的目标，为其他神经活性药物的发展。
Meehan AL, Yang XF, McAdams BD, Yuan L, Rothman SM. A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227-1239, 2011. First published June 8, 2011; doi:10.1152/jn.00279.2011.-Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.