The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata
The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata
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DOI：
10.1016/0006-8993(96)00587-2
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发表时间：
1996-10-07
期刊：
影响因子：
2.9
通讯作者：
BlomsFunke, P
中科院分区：
文献类型：
--
作者：
Loscher, W;Honack, D;BlomsFunke, P
左乙拉西坦（(S)- α -乙基-2-氧-吡咯烷乙酰胺，ucb L059）是目前临床开发的一种新型抗惊厥药物。它的作用机制尚不清楚，尽管最近报道了一种新的[H-3]左乙拉西坦的特异性结合位点，可能与大脑特有的结合位点有关。该结合位点尚未被表征，但一些证据表明可能与GABA系统间接相互作用。因此，我们研究了在全身给药抗惊厥剂量后，左乙拉西仑对几个大鼠大脑区域GABA代谢和转换的影响。此外，为了研究左乙拉西坦对一个明确的gaba能神经元系统的功能影响，该系统在抗惊厥药物作用中起关键作用，我们研究了左乙拉西坦对麻醉大鼠网状部（SNR）神经元自发放电的作用。虽然左乙西坦在体外没有改变GABA合成和降解酶谷氨酸脱羧酶（GAD）和GABA氨基转移酶（GABA- t）的活性，但全身给药诱导了几个脑区这些酶的显著改变，这表明这些酶的改变不是直接的药物作用，而是GABA能或其他神经递质相关系统突触后改变的结果。在纹状体中，左乙乙胺170 mg/kg i.p诱导GABA-T活性显著升高，GAD活性显著降低。当氨基乙酸乙酯（AOAA）抑制GABA- t后估计GABA的转化时，左乙乙坦（在注射AOAA前15分钟给予）显著降低纹状体中GABA的转化。由于黑质网状部（SNR）接收来自纹状体的强GABA能输入，我们通过记录左乙西坦注射后SNR神经元的单单位活性，研究纹状体中GABA代谢和转换的改变是否导致了SNR神经元活性的功能改变。左乙拉西坦给药后神经元自发放电明显减少，但对信噪比神经元活动无明显影响。由于大量证据表明，SNR是神经元放电减少的关键部位，可以防止各种类型的癫痫发作，因此左乙拉西坦对SM活性的抑制作用可能有助于该药物的抗惊厥作用。
Levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently reported novel specific binding site for [H-3]levetiracetam, unique to brain, may be involved. This binding site has not yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiraceram's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia ni,ora pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetiracetam 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic rid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SM activity may contribute to the anticonvulsant action of this drug.