Neuroscience Research Compound · For laboratory research use only
Also known as 7,8-Dihydroxyflavone
7,8-Dihydroxyflavone (7,8-DHF) is a flavone reported in 2010 as a high-affinity small-molecule agonist of tropomyosin receptor kinase B (TrkB), the receptor for brain-derived neurotrophic factor (BDNF)1. It has since been studied in rodent models of excitotoxicity, stroke, Parkinson's disease, depression and Alzheimer's disease1,2,3,4, and a carbamate prodrug, R13, was developed to improve its bioavailability5.
Its standing as a direct TrkB agonist is contested. A 2017 study that set up multiplex quantitative assays of TrkB activation, downstream signalling and gene expression could not reproduce the activity of previously reported small-molecule TrkB agonists, a group to which 7,8-DHF belongs, and its authors advised careful interpretation of results obtained with them6.
As described in the research literature
As described in the research literature, 7,8-DHF was reported to provoke TrkB dimerisation and autophosphorylation and to activate downstream signalling. It protected wild-type but not TrkB-deficient neurons from apoptosis, and its effects on infarct volume in a mouse stroke model were described as TrkB-dependent1.
Metabolism studies in mice reported that 7,8-DHF and its O-methylated metabolites distribute to the brain, that either hydroxy group can be mono-methylated, and that the methylated metabolites also activate TrkB; blocking methylation with COMT inhibitors diminished the TrkB activation observed2. These findings should be read alongside the 2017 multiplex assay study, in which BDNF produced robust receptor activation but the reported small-molecule agonists did not6.
What published studies have examined
The 2010 study examined receptor dimerisation and phosphorylation, apoptosis in wild-type and TrkB-deficient neurons, kainic acid toxicity, infarct volume in a stroke model and a Parkinson's disease model in mice1.
Sources [1]
In 5XFAD transgenic mice, studies examined Y-maze spontaneous alternation, hippocampal BDNF-TrkB signalling, BACE1 levels and amyloid-beta generation3, and hippocampal synapse number, synaptic plasticity and amyloid deposition alongside amyloid-beta toxicity in primary neurons4.
Brain distribution of 7,8-DHF and its O-methylated metabolites was examined in mice, with synthetic methylated derivatives tested in forced swim and tail suspension tests2. Ester and carbamate derivatives were screened with in vitro ADME assays and in vivo pharmacokinetic studies, leading to the prodrug R13, which was then examined in 5XFAD mice5.
Complementary quantitative assays of TrkB receptor activation, TrkB-dependent signalling and gene expression in different cellular contexts were used to re-examine reported small-molecule TrkB agonists, without reproducing their reported activity6.
Sources [6]
A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone.
Jang SW, Liu X, Yepes M, et al. Proceedings of the National Academy of Sciences of the United States of America, 2010.
O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity.
Liu X, Qi Q, Xiao G, et al. Pharmacology, 2013.
7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's disease.
Devi L, Ohno M Neuropsychopharmacology, 2012.
7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease.
Zhang Z, Liu X, Schroeder JP, et al. Neuropsychopharmacology, 2014.
The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease.
Chen C, Wang Z, Zhang Z, et al. Proceedings of the National Academy of Sciences of the United States of America, 2018.
Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists.
Boltaev U, Meyer Y, Tolibzoda F, et al. Science Signaling, 2017.
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