Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity
Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity
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新型易位蛋白 (18 kDa) 配体 ZBD-2 对局灶性脑缺血和 NMDA 诱导的神经毒性的神经保护作用
DOI：
10.1111/1440-1681.12460
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发表时间：
2015-10-01
影响因子：
2.9
通讯作者：
Zhao, Ming-Gao
中科院分区：
文献类型：
--
作者：
Li, Xu-Bo;Guo, Hong-Liang;Zhao, Ming-Gao
转运蛋白（18kda） （TSPO）的配体在应激反应和应激相关疾病中表现出快速的抗焦虑作用。该蛋白参与内源性神经类固醇的合成，包括孕烯醇酮、脱氢表雄酮和黄体酮。这些神经类固醇促进中枢神经系统（CNS）中c-氨基丁酸介导的神经传递。最近合成了一种TSPO配体n-苄基- n-乙基-2-（7,8-二氢-7-苄基-8-氧-2-苯基- 9h -嘌呤-9-基）乙酰胺（ZBD-2）。本研究的目的是探讨ZBD-2和ZBD-2的神经保护作用。在培养的皮质神经元中，ZBD-2处理可减轻n -甲基- d -天冬氨酸（NMDA）暴露引起的兴奋毒性。通过下调glun2b含NMDA受体（NMDARs）、Bax/Bcl-2比值、pro-caspase-3水平，显著减少凋亡细胞数量。全身治疗ZBD-2对大脑中动脉闭塞小鼠具有明显的神经保护作用。这些发现提供了直接证据，证明ZBD-2的神经保护作用部分是通过抑制glun2b - NMDA受体介导的兴奋性毒性介导的。
Ligands of the translocator protein (18 kDa) (TSPO) have demonstrated rapid anxiolytic efficacy in stress responses and stress-related disorders. This protein is involved in the synthesis of endogenous neurosteroids including pregnenolone, dehydroepiandrosterone, and progesterone. These neurosteroids promote c-aminobutyric acid-mediated neurotransmission in the central neural system (CNS). A TSPO ligand, N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide (ZBD-2) was recently synthesized. The purpose of the present study was to investigate the neuroprotective effects of ZBD-2 and. In cultured cortical neurons, treatment with ZBD-2 attenuated excitotoxicity induced by N-methyl-D-aspartate (NMDA) exposure. It significantly decreased the number of apoptotic cells by downregulating GluN2B-containing NMDA receptors (NMDARs), the ratio of Bax/Bcl-2, and levels of pro-caspase-3. Systemic treatment of ZBD-2 provided significant neuroprotection in mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that neuroprotection by ZBD-2 is partially mediated by inhibiting GluN2B-containing NMDA receptor-mediated excitotoxicity.