PMID- 23445871 OWN - NLM STAT- MEDLINE DCOM- 20131217 LR - 20211021 IS - 1423-0313 (Electronic) IS - 0031-7012 (Print) IS - 0031-7012 (Linking) VI - 91 IP - 3-4 DP - 2013 TI - O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. PG - 185-200 LID - 10.1159/000346920 [doi] AB - 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. CI - Copyright (c) 2013 S. Karger AG, Basel. FAU - Liu, Xia AU - Liu X AD - Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. FAU - Qi, Qi AU - Qi Q FAU - Xiao, Ge AU - Xiao G FAU - Li, Jingyu AU - Li J FAU - Luo, Hongbo R AU - Luo HR FAU - Ye, Keqiang AU - Ye K LA - eng GR - R01 DC010204/DC/NIDCD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20130221 PL - Switzerland TA - Pharmacology JT - Pharmacology JID - 0152016 RN - 0 (6,7-dihydroxyflavone) RN - 0 (Antidepressive Agents) RN - 0 (Flavones) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Antidepressive Agents/blood/*pharmacology MH - Behavior, Animal/drug effects MH - Brain/metabolism MH - Caco-2 Cells MH - Cells, Cultured MH - Flavones/blood/*pharmacology MH - Humans MH - Male MH - Methylation MH - Mice MH - Mice, Inbred C57BL MH - Neurons/drug effects/metabolism MH - Receptor, trkB/*agonists PMC - PMC4793717 MID - NIHMS763634 EDAT- 2013/03/01 06:00 MHDA- 2013/12/18 06:00 PMCR- 2016/03/16 CRDT- 2013/03/01 06:00 PHST- 2012/10/05 00:00 [received] PHST- 2013/01/07 00:00 [accepted] PHST- 2013/03/01 06:00 [entrez] PHST- 2013/03/01 06:00 [pubmed] PHST- 2013/12/18 06:00 [medline] PHST- 2016/03/16 00:00 [pmc-release] AID - 000346920 [pii] AID - 10.1159/000346920 [doi] PST - ppublish SO - Pharmacology. 2013;91(3-4):185-200. doi: 10.1159/000346920. Epub 2013 Feb 21.