title: Antidepressant-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in chronically stressed rats.
abstract: The present study aimed to examine the molecular and cellular mechanisms underlying the antidepressant-like effect of YL-IPA08, a novel TSPO ligand designed and synthesized at our institute. We firstly used the chronic unpredictable stress (CUS) procedure of rats, a well validated stress-related animal model of depression, to further determine the antidepressant-like of YL-IPA08. And we found that YL-IPA08 caused significant suppression of inhibiting of locomotor activity, reducing the sucrose preference and increasing the latency to eat induced by CUS. In addition, YL-IPA08 treatment increased the levels of progesterone and allopregnanolone in the hippocampus and prefrontal cortex of post- CUS rats. Furthermore, long-term YL-IPA08 administration reversed dendritic shrinkage, down-regulation of neurotrophic signaling pathway within the hippocampus, as well as HPA dysfunctions simultaneously observed in the CUS rats. Collectively, the evidence presented above supports the notion that binding to TSPO and the subsequent synthesis of neurosteroid, maintenance of hippocampal morphologic and functional plasticity, and preventing HPA axis dysfunction, may account for the profound molecular and cellular mechanism underlying the antidepressant-like effect of YL-IPA08.
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
authors.forename: Yu-Lu
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Yan-Qin
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: yangrf215@163.com.
authors.forename: Ri-Fang
authors.initials: RF
authors.lastname: Yang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: lyf619@aliyun.com.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; C463819:Bzrp protein, mouse; D007093:Imidazoles; C000598174:N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-chlorophenyl)-7-methylimidazo(1,2-a)pyridine-3-acetamide; D011725:Pyridines; D018079:Receptors, GABA
keywords: Chronic unpredictable stress; Major depressive disorder; Neuroplasticity; Neurosteroid; Translocator protein 18 kDa (TSPO)