title: Neuroprotective effects of a novel translocator protein (18 kDa) ligand, ZBD-2, against focal cerebral ischemia and NMDA-induced neurotoxicity.
abstract: 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 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 (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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xu-Bo
authors.initials: XB
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Guo
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Tian-Yao
authors.initials: TY
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Le
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008024:Ligands; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011688:Purinones / Q000378:metabolism / Q000494:pharmacology*; D018079:Receptors, GABA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000081:Acetamides; D053148:Caspase 3; D008024:Ligands; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011688:Purinones; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D051028:bcl-2-Associated X Protein; C463819:Bzrp protein, mouse; C000605004:N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; C121001:NR2B NMDA receptor
keywords: excitotoxicity; middle cerebral artery occlusion; neuroprotection; translocator protein (18 kDa)