title: Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia.
abstract: Cognitive deficits are the core symptoms of schizophrenia and major contributors to disability in schizophrenic patients, but effective treatments are still lacking. Previous studies have demonstrated that impaired BDNF/TrkB signaling is associated with the cognitive impairments of schizophrenia. 7,8-Dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The present study aimed to assess the effect of 7,8-DHF on the cognitive and synaptic impairments of schizophrenia. A brief disruption of NMDA receptors with MK-801 during early development serves as an animal model for cognitive deficits of schizophrenia. We found that MK-801-treated rats showed significant deficits in working learning ability and hippocampal synaptic plasticity, as well as reduction of BDNF, TrkB, and phosphorylated TrkB in the hippocampus. After intraperitoneal administration with 7,8-DHF (5 mg/kg) once daily for a consecutive 14days, we found that chronic 7,8-DHF treatment significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased the phosphorylation levels of TrkB downstream signal cascades including ERK1/2, CaMKII, CREB and GluR1, and promoted hippocampal synaptic plasticity, which in turn rescued performance in spatial working learning. Our results thus demonstrate that activation of TrkB signaling can reverse the cognitive deficits of schizophrenia and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in treating schizophrenia-related cognitive impairments.
authors.affiliation: Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, P.R. China.
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Hubei University of Science and Technology, Xianning 437100, P.R. China.
authors.forename: Yan-Kun
authors.initials: YK
authors.lastname: Li
authors.affiliation: Department of Neurology, The Second Affiliated Hospital To Nanchang University, Nanchang University, Nanchang 330025, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, P.R. China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wan
authors.affiliation: Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, P.R. China.
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Jiangxi Mental Hospital, Nanchang 330029, P.R. China. Electronic address: jxmh_hb@126.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C485383:6,7-dihydroxyflavone; D047309:Flavones; D016291:Dizocilpine Maleate; D020813:Receptor, trkB
keywords: 7,8-Dihydroxyflavone (7,8-DHF); Cognitive deficits; Schizophrenia; Synaptic plasticity; Tyrosine kinase receptor B (TrkB)