Tropoflavin Explained

Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves.[1] [2] [3] It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB) (Kd ≈ 320 nM), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF).[4] [5] [6] Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier.[7] [8] A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13 (and, formerly, R7), is under development for the treatment of Alzheimer's disease.[9] [10]

Tropoflavin has demonstrated therapeutic efficacy in animal models of a variety of central nervous system disorders,[6] including depression, Alzheimer's disease,[11] [12] [13] cognitive deficits in schizophrenia,[14] Parkinson's disease, Huntington's disease,[15] amyotrophic lateral sclerosis,[16] traumatic brain injury,[17] cerebral ischemia,[18] [19] fragile X syndrome,[20] and Rett syndrome.[21] Tropoflavin also shows efficacy in animal models of age-associated cognitive impairment[22] and enhances memory consolidation and emotional learning in healthy rodents.[23] [24] In addition, tropoflavin possesses powerful antioxidant activity independent of its actions on the TrkB receptor,[25] and protects against glutamate-induced excitotoxicity,[26] 6-hydroxydopamine-induced dopaminergic neurotoxicity,[27] and oxidative stress-induced genotoxicity.[28] It was also found to block methamphetamine-induced dopaminergic neurotoxicity, an effect which, in contrast to the preceding, was found to be TrkB-dependent.[29]

In 2017, evidence was published suggesting that tropoflavin and various other reported small-molecule TrkB agonists might not actually be direct agonists of the TrkB and might be mediating their observed effects by other means.[30] [31]

Tropoflavin has been found to act as a weak aromatase inhibitor in vitro (Ki = 10 μM),[32] though there is evidence to suggest that this might not be the case in vivo. In addition, it has been found to inhibit aldehyde dehydrogenase and estrogen sulfotransferase in vitro (Ki = 35 μM and 1–3 μM, respectively), although similarly to the case of aromatase, these activities have not yet been confirmed in vivo. Unlike many other flavonoids, tropoflavin does not show any inhibitory activity on 17β-hydroxysteroid dehydrogenase.[33] Tropoflavin has also been observed to possess in vitro antiestrogenic effects at very high concentrations (Ki = 50 μM).[34] [35]

A variety of close structural analogues of tropoflavin have also been found to act as TrkB agonists in vitro, including diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone), norwogonin (5,7,8-trihydroxyflavone), eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone), 7,8,3'-trihydroxyflavone, 7,3'-dihydroxyflavone, 7,8,2'-trihydroxyflavone, 3,7,8,2'-tetrahydroxyflavone, and 3,7-dihydroxyflavone.[36] The highly hydroxylated analogue gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be an antagonist of TrkB in vitro.

Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level of orexin A, but not orexin B, in mice.[37]

See also

Notes and References

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  2. Colombo PS, Flamini G, Christodoulou MS, Rodondi G, Vitalini S, Passarella D, Fico G . Farinose alpine Primula species: phytochemical and morphological investigations . Phytochemistry . 98 . 151–9 . February 2014 . 24345641 . 10.1016/j.phytochem.2013.11.018 . 2014PChem..98..151C . free . 2434/233766 .
  3. Web site: Molecule found in tree leaves helps female mice combat weight gain; males unaffected . 2015-03-19 . Cell Press . ScienceDaily . 2015.
  4. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K . A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone . Proc. Natl. Acad. Sci. U.S.A. . 107 . 6 . 2687–92 . 2010 . 20133810 . 2823863 . 10.1073/pnas.0913572107 . 2010PNAS..107.2687J . free .
  5. Liu X, Obianyo O, Chan CB, Huang J, Xue S, Yang JJ, Zeng F, Goodman M, Ye K . Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor . J. Biol. Chem. . 289 . 40 . 27571–84 . 2014 . 25143381 . 10.1074/jbc.M114.562561 . 4183797. free .
  6. Zeng Y, Wang X, Wang Q, Liu S, Hu X, McClintock SM . Small molecules activating TrkB receptor for treating a variety of CNS disorders . CNS Neurol Disord Drug Targets . 12 . 7 . 1066–77 . 2013 . 23844685 . 10.2174/18715273113129990089.
  7. Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K . A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect . J. Med. Chem. . 53 . 23 . 8274–86 . 2010 . 21073191 . 3150605 . 10.1021/jm101206p .
  8. Liu X, Chan CB, Qi Q, Xiao G, Luo HR, He X, Ye K . Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression . J. Med. Chem. . 55 . 19 . 8524–37 . 2012 . 22984948 . 3491656 . 10.1021/jm301099x .
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  17. Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY, Chen SF . Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling . PLOS ONE . 9 . 11 . e113397 . 2014 . 25415296 . 4240709 . 10.1371/journal.pone.0113397 . 2014PLoSO...9k3397W . free .
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