7,8-dihydroxyflavone, 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.
Qu'est-ce que la 7,8-dihydroxyflavone ?
La 7,8-dihydroxyflavone (7,8-dhf) est une flavone présente dans les plantes. Il a été découvert lors de la recherche de molécules qui imitent la fonction des facteurs neurotrophiques dérivés du cerveau (BDNF).
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.
Des études animales ont montré que le 7,8-DHF peut contribuer à la réparation du cerveau, à la mémoire à long terme, à la dépression et aux maladies neurodégénératives. Cependant, la recherche humaine n'a pas encore commencé.
Quel est le mécanisme d'action du 7,8-dhf ?
Le 7,8-dhf simule le rôle du facteur neurotrophique dérivé du cerveau (BDNF) dans les cellules cérébrales en activant le récepteur de la kinase B associée à la tropomyosine (TrkB) (une cible typique du BDNF).
Le potentiel thérapeutique du BDNF est limité en raison de sa courte demi-vie-(moins de 10 minutes) et de son incapacité à traverser la barrière hémato-encéphalique en raison de son volume important. Contrairement au BDNF, le 7,8-dhf peut traverser la barrière hémato-encéphalique et pénétrer dans le système nerveux central (SNC).
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)
Le 7,8-dhf préserve les cellules des dommages et de la mort causés par le stress oxydatif. Les cellules n'ont pas besoin d'avoir des récepteurs TrkB protégés.
Dans ce cas, le 7,8-dhf élimine les espèces réactives de l'oxygène (ROS). Nrf2 augmenté. Cela augmente la production de plusieurs enzymes antioxydantes. Augmentez les niveaux de glutathion (GSH), de glutathion peroxydase (GPX) et de superoxyde dismutase (SOD).
Discussion sur les résultats de la recherche sur le 7,8-dhf
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