O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity.
O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity.
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作者：
Liu X;Qi Q;Xiao G;Li J;Luo HR;Ye K
7，8-二羟基黄酮（7，8-DHF）作为TrkB受体特异性激动剂。它模拟脑源性神经营养因子（BDNF）的生理作用，并在各种神经系统疾病的动物模型中显示出显着的治疗效果。尽管如此，其体内药代动力学特征和代谢仍不清楚。本文报道了7，8-DHF及其O-甲基化代谢产物经口给药后在小鼠脑内的分布。两个羟基都可以被单甲基化，并且单甲基化的代谢物在体外和体内激活TrkB。使用COMT抑制剂阻断甲基化，减少了7，8-DHF或4′-二甲氨基-7，8-DHF对TrkB激活的激动作用，支持甲基化代谢物对小鼠脑中TrkB激活的贡献。此外，我们还合成了几种甲基化代谢物衍生物，它们在强迫游泳试验和悬尾试验中也有效地激活TrkB受体并减少不动性，表明这些甲基化代谢物可能具有抗抑郁活性。因此，我们的数据表明，7，8-DHF是口服生物利用度，可以穿透脑血屏障。0-甲基化代谢物与脑中的TrkB受体活化有关。
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.