title: Antidepressant-Like and Anxiolytic-Like Effects of ZBD-2, a Novel Ligand for the Translocator Protein (18 kDa).
abstract: Activation of translocator protein (18 kDa) (TSPO) plays an important role to mediate rapid anxiolytic efficacy in stress response and stress-related disorders by the production of neurosteroids. However, little is known about the ligand of TSPO on the anxiety-like and depressive behaviors and the underlying mechanisms in chronic unpredictable mild stress (UCMS) mice. In the present study, a novel ligand of TSPO, ZBD-2 [N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl) acetamide] synthesized by our laboratory, was used to evaluate the anxiolytic and antidepressant efficacy and to elucidate the underlying mechanisms. ZBD-2 (3 mg/kg) significantly attenuated anxiety-like and depressive behaviors in the UCMS mice, which was blocked by TSPO antagonist PK11195 (3 mg/kg). Treatment of ZBD-2 reversed the decrease in biogenic amines (norepinephrine, dopamine, and serotonin) in the brain region of hippocampus in the UCMS mice. The decreases in TSPO, GluN2B-containing N-methyl-D-aspartate (NMDA) receptors, GluA1, p-GluA1-Ser831, p-GluA1-Ser845, PSD-95, and GABAA-a2 were integrated with the increases of CaMKII and iNOS levels in the hippocampus of the UCMS mice. ZBD-2 significantly reversed the changes of above proteins. However, ZBD-2 or PK11195 treatment did not affect the levels of GluN2A-containing NMDA receptors and the total levels of GAD67. Our study provides strong evidences that ZBD-2 has a therapeutic effect on chronic stress-related disorders such as depression and anxiety through regulating the biogenic amine levels and the synaptic proteins in the hippocampus.
authors.affiliation: Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Nanjing University, Nanjing, 210002, China.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Nanjing University, Nanjing, 210002, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Nanjing University, Nanjing, 210002, China.
authors.forename: Jian-Ning
authors.initials: JN
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, Nanjing General Hospital of Nanjing Military Command, Nanjing University, Nanjing, 210002, China. liugene@hotmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China. liushb1974@aliyun.com.
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China. minggao@fmmu.edu.cn.
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology; D003863:Depression / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005968:Glutamate Decarboxylase / Q000032:analysis; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis; D018377:Neurotransmitter Agents / Q000032:analysis; D011688:Purinones / Q000494:pharmacology / Q000627:therapeutic use*; D018079:Receptors, GABA / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis; D013315:Stress, Psychological / Q000188:drug therapy / Q000523:psychology
chemical_list: D000081:Acetamides; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D005968:Glutamate Decarboxylase; D007546:Isoquinolines; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D011688:Purinones; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; C463819:Bzrp protein, mouse; C000605004:N-benzyl-N-ethyl-2-(7,8-dihydro-7-benzyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; C402565:glutamate decarboxylase 1; C037850:PK 11195
keywords: Anxiety; Chronic unpredictable mild stress; Depression; Translocator protein (18 kDa); ZBD-2