title: O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity.
abstract: 7,8-Dihydroxyflavone (7,8-DHF) acts as a TrkB receptor-specific agonist. It mimics the physiological actions of brain-derived neurotrophic factor (BDNF) and demonstrates remarkable therapeutic efficacy in animal models of various neurological diseases. Nonetheless, its in vivo pharmacokinetic profiles and metabolism remain unclear. Here we report that 7,8-DHF and its O-methylated metabolites distribute in mouse brain after oral administration. Both hydroxy groups can be mono-methylated, and the mono-methylated metabolites activate TrkB in vitro and in vivo. Blocking methylation, using COMT inhibitors, diminishes the agonistic effect of TrkB activation by 7,8-DHF or 4'-dimethylamino-7,8-DHF, supporting the contribution of the methylated metabolite to TrkB activation in mouse brain. Moreover, we have synthesized several methylated metabolite derivatives, and they also potently activate the TrkB receptor and reduce immobility in both forced swim test and tail suspension test, indicating that these methylated metabolites may possess antidepressant activity. Hence, our data demonstrate that 7,8-DHF is orally bioavailable and can penetrate the brain-blood barrier. The O-methylated metabolites are implicated in TrkB receptor activation in the brain.
authors: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Xia
authors: X
authors: Liu
authors: Qi
authors: Q
authors: Qi
authors: Ge
authors: G
authors: Xiao
authors: Jingyu
authors: J
authors: Li
authors: Hongbo R
authors: HR
authors: Luo
authors: Keqiang
authors: K
authors: Ye
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002478:Cells, Cultured; D047309:Flavones / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020813:Receptor, trkB / Q000819:agonists*
chemical_list: C485383:6,7-dihydroxyflavone; D000928:Antidepressive Agents; D047309:Flavones; D020813:Receptor, trkB