Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie, Japan.
Neurosci Lett. 2012 Jun 19;518(2):69-74. doi: 10.1016/j.neulet.2012.03.056. Epub 2012 Mar 28.
To define the antiepileptic mechanisms of levetiracetam (LEV), the present study determined the concentration-dependent effects of locally perfused LEV on the releases of norepinephrine, dopamine, serotonin, l-glutamate and GABA induced by 50 mMK(+)-evoked stimulation and agonists of ryanodine receptor (RyR) and inositol-triphosphate receptor (IP3R) in the median prefrontal cortex (mPFC) using in vivo microdialysis. Local perfusion with LEV (10, 30 and 100 μM) alone did not affect the extracellular levels of all neurotransmitters in the mPFC. The release of neurotransmitters induced by K(+)-evoked stimulation was inhibited by perfusion with LEV in a concentration-dependent manner, and those induced by agonists of RyR and IP3R were also inhibited by LEV. Specifically, the RyR-induced release was inhibited by 10 μM LEV, whereas the IP3R-induced release was inhibited by 100 μM LEV, but not by 10 or 30 μM LEV. The above results suggest that LEV has little effect on the components of normal synaptic transmission but selectively inhibits transmission induced by neuronal hyperactivation. Thus, the mechanisms of the antiepileptic and neuroprotective actions of LEV seem to be mediated, at least in part, through the combination of these two inhibitory effects on depolarization-induced and CICR-associated neurotransmitter releases.
为了明确左乙拉西坦（LEV）的抗癫痫机制，本研究采用在体微透析技术，观察了局部灌流不同浓度的 LEV 对 50mM K+诱导刺激和兰尼碱受体（RyR）及三磷酸肌醇受体（IP3R）激动剂诱发的去甲肾上腺素、多巴胺、5-羟色胺、L-谷氨酸和 GABA 释放的浓度依赖性影响。单独局部灌流 10、30 和 100μM LEV 并不影响 mPFC 中外源神经递质的水平。LEV 以浓度依赖性方式抑制 K+诱导刺激引起的神经递质释放，也抑制 RyR 和 IP3R 激动剂引起的神经递质释放。具体而言，10μM LEV 抑制 RyR 诱导的释放，而 100μM LEV 抑制 IP3R 诱导的释放，但 10μM 和 30μM LEV 无此作用。上述结果表明，LEV 对正常突触传递的组成部分影响较小，但选择性抑制神经元过度兴奋引起的传递。因此，LEV 的抗癫痫和神经保护作用机制似乎至少部分是通过对去极化诱导和 CICR 相关神经递质释放的这两种抑制作用的结合来介导的。
