Small molecule TrkB agonists and their potential therapeutic role in mental health A variety of natural products act on brain-derived neurotrophic factor's (BDNF) receptor, to tropomyosin-related kinase receptor B, TrkB. One of these, 7,8-dihydroxyflavone found in several plants such as Tridax procumbens , Godmania aesculifolia and Primula sp. has been selected as a potent and selective agonist for this receptor. Some polyphenols showing promise include dihydromyricetin, amentoflavone, apigenin, chlorogenic acid, curcumin, ferulic acid, hesperidin, rutin, quercetin, naringenin, resveratrol, ellagic acid, nobiletin, anthocyanins and proanthocyanidins. Polyphenols with noted effects on human serum BDNF: Green tea catechins Coffee extracts Ginkgo flavonoids Curcumin The clinical implications of TrkB agonists are diverse as a range on CNS conditions have been suggested to involve deficient BDNF-TrkB signalling Research efforts have led to analogues such as 4'-dimethylamino-7,8-dihydroxyflavone or 7,8-dihydroxyflavone prodrugs, the latter of which are gradually metabolised in the liver to release the parent compound. The 4'-dimethylamino analogue is more potent and seems to have favourable bioavailability and pharmacokinetics. Natural products can act a variety of ways on BDNF and TrkB, including BDNF mRNA level 1 upregulation, protein level upregulation, both in combination or as direct agonists of TrkB. Other natural products with direct TrkB agonist effects include deoxygedunin from Azadirachta indica (Neem). Small molecule TrkB agonists act as BDNF-mimetics, promoting signalling cascades that evoke neuroplasticity, neurogenesis and neuroprotection. Activation of BDNF signaling pathways has been considered as a disease-modifying strategy for neurological and psychiatric diseases Flavonoids have various effects on the CNS with the ability to improve human memory and neurocognitive performance - protection of vulnerable neurons - enhancement of existing neuronal function - stimulate neuronal regeneration - effects on LTP - modulation of signalling pathways 7,8-Dihydroxyflavone is a specific TrkB agonist which activates its downstream PI3K/Akt and Erk signaling cascades, and crosses the BBB after peripheral administration. It has been shown to exert therapeutic effects in various animal disease models related to deficient BDNF signaling. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a crucial role in promoting neuronal survival by specifically binding to tropomyosin-related kinase receptor B (TrkB). This binding results in the autophosphorylation and dimerization of the TrkB receptor, which triggers the activation of downstream phosphatidylinositol 3-kinase (PI3K)/Akt, MAPK/Erk, or PLC-γ survival signaling. The PI3K/Akt signaling pathway is the major TrkB-mediated survival pathway that promotes neuronal survival and protects against apoptosis. 2 The 4'-dimethylamino analogue exerts more potent and sustained TrkB agonism, with initial research indicating robust antidepressant effects and increases in hippocampal neurogenesis. Their initial data suggests the compound is not toxic to the mice at 5 mg/kg dose over the 3-week chronic treatment. Researchers indicate there may be a parallel to other flavonoids in the CNS effects where higher doses may not provide greater therapeutic responses. For the lead compound 7,8- dihydroxyflavone, lower doses promoted recovery in brain injury models while a higher dose did not: The reduced efficiency of the higher dose of 7,8-DHF ( may be attributed to the pharmacological profiles of flavonoids (which have different pharmacological effects depending on their concentration). For example, Akt activation ... induced by lower concentrations of the flavonoid quercetin and inhibited by higher concentrations. An alternate explanation is that 7,8-DHF, acting as a potent BDNF agonist, may have dose-dependent neuroprotective activity similar to that of BDNF. Previous studies have reported that high concentrations of BDNF or other TrkB ligands resulted in a downregulation of the TrkB response and a decrease in the BDNF-mediated neuroprotection. Our findings underscore the importance of addressing the possibility of ligand-induced down-regulation of the receptor response when considering TrkB agonists for treatment of neurological diseases. 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