Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., Insurgentes Sur 3877, 14269, Mexico City, Mexico.
Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
Neurotox Res. 2018 May;33(4):837-845. doi: 10.1007/s12640-017-9836-4. Epub 2017 Nov 9.
Levetiracetam (LVT) is a relatively novel antiepileptic drug (AED) known to act through binding with the synaptic vesicular 2A (SV2A) protein, thus modulating the presynaptic neurotransmitter release. The tryptophan metabolite quinolinic acid (QUIN) acts as an excitotoxin when its brain concentrations reach toxic levels under pathological conditions. Since increased neuronal excitability induced by QUIN recruits degenerative events in the brain, and novel AED is also expected to exert neuroprotective effects in their pharmacological profiles, in this work the effect of LVT (54 mg/kg, i.p., administered for seven consecutive days) was tested as a pretreatment against the toxicity evoked by the bilateral intrastriatal injection of QUIN (60 nmol/μl) to adult rats. QUIN increased the striatal levels of peroxidized lipids and carbonylated proteins as indexes of oxidative damage 24 h after its infusion. In addition, in synaptosomal fractions isolated from QUIN-lesioned rats 24 h after the toxin infusion, γ-aminobutyric acid (GABA) release was decreased, whereas glutamate (Glu) release was increased. QUIN also decreased motor activity and augmented the rate of cell damage at 7 days post-lesion. All these alterations were significantly prevented by pretreatment of rats with LVT. The results of this study show a neuroprotective role and antioxidant action of LVT against the brain damage induced by excitotoxic events.
左乙拉西坦（LVT）是一种相对新颖的抗癫痫药物（AED），已知其通过与突触小泡 2A（SV2A）蛋白结合来发挥作用，从而调节突触前神经递质的释放。色氨酸代谢产物喹啉酸（QUIN）在病理条件下其脑浓度达到毒性水平时作为一种兴奋性毒素发挥作用。由于 QUIN 引起的神经元兴奋性增加会招募大脑中的退行性事件，因此新型 AED 也有望在其药理学特征中发挥神经保护作用，因此在这项工作中，LVT（54mg/kg，ip，连续 7 天给药）的作用作为预处理，对抗双侧纹状体注射 QUIN（60nmol/μl）对成年大鼠引起的毒性进行了测试。QUIN 输注后 24 小时，作为氧化损伤指标的纹状体过氧化物脂质和羰基化蛋白水平增加。此外，在 QUIN 损伤大鼠的突触体分离物中，24 小时后 GABA 释放减少，而 Glu 释放增加。QUIN 还降低了运动活性并在损伤后 7 天增加了细胞损伤率。所有这些改变均被 LVT 预处理显著预防。这项研究的结果表明，LVT 对兴奋性毒性引起的脑损伤具有神经保护作用和抗氧化作用。
