The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kiev 01030, Ukraine.
Brain Res. 2018 Nov 15;1699:69-78. doi: 10.1016/j.brainres.2018.06.032. Epub 2018 Jul 3.
A combination of a beneficial neuroprotectant, hypothermia, with targeted medication is a perspective therapeutic approach. Here, we analyzed both non-specific (deep and profound hypothermia, 27 °C and 17 °C, respectively) and targeted (anticonvulsant drug levetiracetam) modulation of l-[C]glutamate release induced by activation of presynaptic NMDA, AMPA, and kainate receptors in rat brain nerve terminals (synaptosomes). Gradual dynamics of hypothermia-mediated decrease in synaptosomal l-[C]glutamate release evoked by the receptor agonists NMDA-, AMPA-, and kainate (250 μM) has been demonstrated that can be of value for the justification of optimal temperature regimes in therapeutic hypothermia. 250 μM NMDA-induced l-[C]glutamate release from nerve terminals was higher in the presence of levetiracetam (100 μM) as compared to that without the drug. Despite levetiracetam effects decreased in hypothermia, combined application of hypothermia and levetiracetam resulted in higher NMDA-induced l-[C]glutamate release from nerve terminals as compared to that without the drug. These effects were not revealed for synaptosomal AMPA- and kainate-induced l-[C]glutamate release in the presence of levetiracetam at the similar concentration. Therefore, levetiracetam administration significantly mitigated a hypothermia-induced decrease in NMDA receptor response at the presynaptic level and can be used for the targeted neurocorrection to reduce side effects of hypothermia in cardiac surgery. However, levetiracetam-mediated improvement of NMDA receptor response is not applicable in stroke, brain trauma and neonatal asphyxia therapies, where the main neuroprotective action of hypothermia is associated with prevention of damaging consequence of pre-existing acute glutamate exitotoxicity.
一种有益的神经保护剂、低温与靶向药物相结合是一种有前景的治疗方法。在这里，我们分析了非特异性（深度和深度低温，分别为 27°C 和 17°C）和靶向（抗惊厥药物左乙拉西坦）调节大鼠脑神经末梢（突触体）中 NMDA、AMPA 和 kainate 受体激活诱导的 l-[C]谷氨酸释放。低温介导的突触体 l-[C]谷氨酸释放的逐渐动态变化由受体激动剂 NMDA、AMPA 和 kainate（250µM）诱发，这可能有助于为治疗性低温中的最佳温度范围提供依据。与无药物相比，神经末梢中 250µM NMDA 诱导的 l-[C]谷氨酸释放在存在左乙拉西坦（100µM）时更高。尽管左乙拉西坦的作用在低温下降低，但低温与左乙拉西坦的联合应用导致神经末梢中 NMDA 诱导的 l-[C]谷氨酸释放高于无药物。在类似浓度下，在左乙拉西坦存在的情况下，突触体 AMPA 和 kainate 诱导的 l-[C]谷氨酸释放没有显示出这些作用。因此，左乙拉西坦的给药显著减轻了低温对 NMDA 受体反应的抑制作用，并可用于靶向神经矫正，以减少心脏手术中低温的副作用。然而，左乙拉西坦介导的 NMDA 受体反应的改善不适用于中风、脑外伤和新生儿窒息的治疗，其中低温的主要神经保护作用与预防预先存在的急性谷氨酸释放毒性的破坏性后果有关。
