Liu X, Qi Q, Xiao G, Li J, Luo HR, Ye K. O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. Pharmacology 91: 185-200

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Ga., USA.
Pharmacology (Impact Factor: 1.67). 02/2013; 91(3-4):185-200. DOI: 10.1159/000346920
Source: PubMed


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.

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    • "Our pharmacokinetic experiments found that the oral bioavailablity of 7,8-DHF is about 5%, and its half-life is about 134 min in the plasma after oral gavage of 50 mg/kg. Furthermore, it can penetrate the blood–brain barrier (Liu et al, 2013). Remarkably, systemic administration of 7,8- DHF can activate TrkB receptors in the brain as evidenced by increases in phosphorylated TrkB in rodents (Andero et al, 2012; Andero et al, 2011; Choi et al, 2010; Jang et al, 2010; Liu et al, 2010). "
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