7,8-ジヒドロキシフラボン, abbreviated as 7,8-DHF, also known as tropoflavin, is a natural flavone, which exists in plants such as Tridax procumbens , BDNF mimetic compound 7,8-dihydroxyflavone (7,8-dhf) is an effective small-molecule TrkB agonist with a significant therapeutic effect on Alzheimer's disease (AD). However, 7,8-dhf had only moderate oral bioavailability and moderate pharmacokinetics (PK) curve. In order to alleviate these preclinical obstacles, we used prodrug strategies to improve the oral bioavailability and brain exposure of 7,8-dhf and found that the best prodrug R13 has good characteristics and reverses cognitive defects in the AD mouse model in a dose-dependent manner.
7,8-ジヒドロキシフラボンとは何ですか？
7,8 -ジヒドロキシフラボン（7,8-dhf）は、植物に含まれるフラボンです。 脳由来神経栄養因子（BDNF）の機能を模倣する分子を探しているときに発見されました。
BDNF promotes the growth of neurons and synapses (synaptogenesis), which is very important for normal brain function. A small amount of BDNF was observed in depression, Alzheimer's disease, Parkinson's disease, and schizophrenia.
動物実験では、7,8 - DHFが脳の修復、長期記憶、うつ病、神経変性疾患に寄与する可能性があることが示されています。 しかし、人体実験はまだ始まっていません。
7,8-dhfの作用機序は何ですか？
7,8 - dhfは、トロポミオシン関連キナーゼB（TrkB）受容体（BDNFの典型的な標的）を活性化することにより、脳細胞における脳-由来神経栄養因子（BDNF）の役割をシミュレートします。
BDNFの治療の可能性は、その半減期が短い-（10分未満）ため、またその容量が大きいために血液-脳関門を通過できないために制限されます。 BDNFとは異なり、7,8 - dhfは血液脳関門を通過し、中枢神経系（CNS）に入ることができます。
7,8-dhf also increased Nrf2 production. Nrf2 increases antioxidant enzymes such as heme oxygenase-1 (HO-1) and DNA repair enzymes (8-oxguanine DNA glycosylase-1 – O&1)
7,8-dhfは、酸化ストレスによって引き起こされる損傷や死から細胞を保護します。 細胞は保護されたTrkB受容体を持っている必要はありません。
この場合、7,8-dhfは活性酸素種（ROS）を除去します。 Nrf2が増加しました。 これにより、いくつかの抗酸化酵素の生成が増加します。 グルタチオン（GSH）、グルタチオンペルオキシダーゼ（GPX）、およびスーパーオキシドジスムターゼ（SOD）のレベルを上げます。
7,8-dhfの研究結果に関する議論
In the present report, we show that 7,8-dhf can penetrate BBB, and its main metabolites in plasma are o-monomethylated and o-glucuronide metabolites. 7,8-dhf and a monomethylated metabolite (7-hydroxy-8-methoxy flavone) were also detected in the brain. Interestingly, blocking COMT with two different inhibitors reduced the TrkB spike activation of 7,8-dhf or lead compound 4 '- DMA-7,8-dhf in the mouse brain, suggesting that methylated metabolites contribute to the activation of TrkB receptors during oral administration of 7,8-dhf. Interestingly, - The methylated metabolite h428 activates TrkB receptors in primary neurons and mouse brain after oral administration, emphasizing the observation that methylated metabolites trigger TrkB receptor activation. As expected, 3 weeks of chronic treatment with methylated metabolite h428 or its synthetic derivatives significantly reduced immobility in two types of antidepressant behavior tests, accompanied by significant TrkB phosphorylation and demonstrable neurogenesis in the hippocampus. These observations support the view that active methylated metabolites induce chronic TrkB activation and significant neurogenesis, resulting in strong antidepressant effects.
Since oral administration of 7,8-dhf or its synthetic derivative 4 '- DMA-7,8-dhf can cause TrkB activation at 1-2 hours, and the stimulating effect can be proved even at 4 hours in the mouse brain, we studied its pharmacokinetic characteristics in vivo. The peak value of 7,8-dhf in plasma reached 70 ng/ml at 10 minutes, but slowly decreased to 24 ng/ml after 4 hours, and even 5 ng/ml of 7,8-dhf was detected at 8 hours, indicating that it is available for oral bioavailability. Although its bioavailability is very low, its metabolic rate is much slower when its concentration is low. On the other hand, the concentrations of both methylated metabolites were relatively low compared with the parent 7,8-dhf, suggesting that glucuronidation rather than methylation may be the main metabolite. Interestingly, the half-life of 8-methoxy metabolite in plasma is 148 minutes, while that of the 7-methoxy metabolite is 92 minutes, indicating that 8-methoxy-7-hydroxy flavone is more metabolically stable than 8-hydroxy-7-methoxy flavone. H428). In brain samples, 7,8-dhf also peaked at about 52 ng / g in 10 minutes and decreased to 18 ng / g in 30 minutes, after which it remained relatively stable until 240 minutes (7 ng / g). Surprisingly, the 7-methoxy metabolite (h428) was below the quantification limit in the brain, while the 8-methoxy metabolite was observed 3 minutes after oral administration, even at 240 minutes (Fig. 2). 1 ). It is conceivable that if the methylated metabolite promotes TrkB activation in vivo through 7,8-dhf, it may mainly come from the metabolite of 8-methoxy-7-hydroxy flavone. Nevertheless, the concentration of the parent compound in the brain is about 30 times higher than that of the methylated metabolite, suggesting that the main contribution to triggering TrkB activation comes from the parent compound. It should be noted that TrkB activation in the mouse brain was significant 4 hours or more after oral administration of 7,8-dhf, suggesting that TrkB activation may be mainly triggered by 7,8-dhf itself at a later time point. At early time points, such as 1-2 hours, the methylated metabolite 8-methoxy-7-hydroxy flavone may also contribute to TrkB activation in the brain, which is supported by COMT inhibitor data, and they show partial blocking of agonistic effects in the mouse brain through 7,8-dhf. After oral administration, part of 7,8-dhf is metabolized through o-glucuronidation in the circulatory system (much lower o-sulfation concentration on 7,8-dhf is also detected in plasma), thus reducing its concentration in the central nervous system. The parent drug and methylated metabolites penetrate the BBB, where they both activate the TrkB receptor. Blocking o-monomethylation of 7,8-dhf by inhibiting COMT will reduce the effect of 7,8-dhf on TrkB activation