O-Methylated Metabolite of 7,8-Dihydroxyflavone Activates TrkB Receptor and Displays Antidepressant Activity

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Ga., USA.
Pharmacology (Impact Factor: 1.58). 02/2013; 91(3-4):185-200. DOI: 10.1159/000346920
Source: PubMed

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.

Download full-text


Available from: Qi Qi, Jun 30, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor (BDNF)/tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Aβ-induced toxicity, and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Aβ deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.Neuropsychopharmacology accepted article preview online, 11 September 2013. doi:10.1038/npp.2013.243.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2013; DOI:10.1038/npp.2013.243 · 7.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems. Molecular techniques using synapatosomes in previous studies have suggested that BDNF's receptor, tyrosine kinases (Trk), can quickly regulate dopamine release and transporter dynamics. Our main objective in this study is to determine whether slice fast scan cyclic voltammetry can be used to investigate the role of the TrkB receptor on dopamine release and uptake processes in the caudate-putamen. Fast scan cyclic voltammetry measured dopamine release and uptake rates in the presence of BDNF, or its agonist 7,8-dihydroxyflavone, or a TrkB inhibitor K252a. Superfusion of BDNF led to partial recovery of the electrically-stimulated dopamine release response in BDNF+/- mice which is blunted compared to wildtype mice, with no effect in wildtype mice. Conversely, infusion of 7,8-dihydroxyflavone increased electrically-stimulated dopamine release in wildtype mice with no difference in BDNF+/- mice. Overall, BDNF and 7,8-dihydroxyflavone had no effect on dopamine uptake rates. Concentrations greater than 3 μM 7,8-dihydroxyflavone affected DA uptake rates in BDNF+/- mice only. To demonstrate that BDNF and 7,8-dihydroxyflavone modulate DA release by activating the TrkB receptor, both genotypes were pretreated with K252a. K252a was able to block BDNF and 7,8-DHF induced increases during stimulated dopamine release in BDNF+/- and wildtype mice, respectively. Fast scan cyclic voltammetry demonstrates that acute TrkB activation potentiates dopamine release in both genotypes.
    ACS Chemical Neuroscience 05/2013; 4(5). DOI:10.1021/cn4000742 · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuronal survival and neuroplasticity in the central nervous system (CNS). As a result, there has been a growing interest in the role of BDNF in neuropsychiatric disorders associated with neurodegeneration, including depression and dementia. However, until now, BDNF-targeting therapies have yielded disappointing results. BDNF is thought to exert its beneficial effects on synaptic and neuronal plasticity mainly through binding to the tyrosine kinase B (TrkB) receptor. Recently, 7,8-dihydroxyflavone (7,8-DHF) was identified as the first selective TrkB agonist. In the present study the effect of 7,8-DHF on memory consolidation processes was evaluated. In healthy rats, 7,8-DHF improved object memory formation in the object recognition task when administered both immediately and 3hours after learning. In a transgenic mouse model of Alzheimer's disease, i.e. APPswe/PS1dE9 mice, spatial memory as measured in the object location task was improved after administration of 7,8-DHF. A similar memory improvement was found when their wild-type littermates were treated with 7,8-DHF. The acute beneficial effects in healthy mice suggest that effects might be symptomatic rather than curing. Nevertheless, this study suggests that 7,8-DHF might be a promising therapeutic target for dementia.
    Behavioural brain research 09/2013; 257. DOI:10.1016/j.bbr.2013.09.029 · 3.39 Impact Factor