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Neuroprotective effects of a novel translocator protein (18 kD a) ligand, ZBD ‐2, against focal cerebral ischemia and NMDA ‐induced neurotoxicity
Author(s) -
Li XuBo,
Guo HongLiang,
Shi TianYao,
Yang Le,
Wang Min,
Zhang Kun,
Guo YanYan,
Wu YuMei,
Liu ShuiBing,
Zhao MingGao
Publication year - 2015
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12460
Subject(s) - neuroprotection , excitotoxicity , neuroactive steroid , nmda receptor , pregnenolone , translocator protein , pharmacology , chemistry , glutamate receptor , neurotoxicity , receptor , biochemistry , medicine , gabaa receptor , neuroinflammation , steroid , inflammation , organic chemistry , toxicity , hormone
Summary Ligands of the translocator protein (18 kD a) ( 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 γ ‐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 ( NMDAR s), 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.