title: Acute Treatment with a Novel TRPC4/C5 Channel Inhibitor Produces Antidepressant and Anxiolytic-Like Effects in Mice.
abstract: Transient receptor potential canonical (TRPC) channels are widely expressed in brain and involved in various aspects of brain function. Both TRPC4 and TRPC5 have been implicated in innate fear function, which represents a key response to environmental stress. However, to what extent the TRPC4/C5 channels are involved in psychiatric disorders remains unexplored. Here, we tested the antidepressant and anxiolytic-like effects of a newly identified TRPC4/C5 inhibitor, M084. We show that a single intraperitoneal administration of M084 at 10 mg/kg body weight to C57BL/6 male mice significantly shortened the immobility time in forced swim test and tail suspension test within as short as 2 hours. The M084-treated mice spent more time exploring in illuminated and open areas in light/dark transition test and elevated plus maze test. In mice subjected to chronic unpredictable stress, M084 treatment reversed the enhanced immobility time in forced swim test and decreased the latency to feed in novelty suppressed feeding test. The treatment of M084 increased BDNF expression in both mRNA and protein levels, as well as phosphorylation levels of AKT and ERK, in prefrontal cortex. Our results indicate that M084 exerts rapid antidepressant and anxiolytic-like effects at least in part by acting on BDNF and its downstream signaling. We propose M084 as a lead compound for further druggability research.
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100039, China; Yunnan Institute of Traditional Chinese Medicine and Materia Medica, Kunming, Yunnan 650223, China.
authors: Li-Ping
authors: LP
authors: Yang
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China; University of Chinese Academy of Sciences, Beijing 100039, China.
authors: Fang-Jie
authors: FJ
authors: Jiang
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
authors: Gui-Sheng
authors: GS
authors: Wu
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
authors: Ke
authors: K
authors: Deng
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
authors: Meng
authors: M
authors: Wen
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
authors: Xiaoju
authors: X
authors: Zhou
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
authors: Xuechuan
authors: X
authors: Hong
authors: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, 77030, United States of America.
authors: Michael X
authors: MX
authors: Zhu
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
authors: Huai-Rong
authors: HR
authors: Luo
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases