7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders

Du, Xin; Hill, Rachel Anne

doi:10.1016/j.neuint.2015.07.021

Cited by 43 publications

(28 citation statements)

References 212 publications

(204 reference statements)

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“…The molecular mechanism of 7,8‐DHF has not been understood until recently. 7,8‐DHF has been revealed to be an agonist specific for TrkB and the first drug which can simulate the biological effect of BDNF . Its interaction with TrkB activates PLC‐γ, AKT and ERK1/2 signaling pathways, plays roles in neural protection and leads to behavioral changes, for instance, improving memory and counteracting depression .…”

Section: Introductionmentioning

confidence: 99%

“…7,8‐DHF has been revealed to be an agonist specific for TrkB and the first drug which can simulate the biological effect of BDNF . Its interaction with TrkB activates PLC‐γ, AKT and ERK1/2 signaling pathways, plays roles in neural protection and leads to behavioral changes, for instance, improving memory and counteracting depression . Besides the nervous system, since TrkB receptors are also widely distributed in the gastrointestinal tract, it is presumed that 7,8‐DHF is probably capable of activating TrkB and exerts biological effect on gastrointestinal dynamics.…”

Section: Introductionmentioning

confidence: 99%

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7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

Tian

et al. 2018

Clin Exp Pharma Physio

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Although 7,8-dihydroxyflavone (7,8-DHF), a synthetic agonist specific for tyrosine kinase receptor B (TrkB), has been reported to promote intestinal dynamics, its effect on gastric dynamics has not been studied as yet. In this study, we explored how 7,8-DHF affected the carbachol (CCh)-induced contraction of rat gastric muscle by way of measuring the contractile tension of muscular strips. We found that although 7,8-DHF did not directly cause contraction of gastric muscle, it enhanced CCh-induced, instead of substance P- or high K -induced, contraction. The enhancing role of 7,8-DHF was partially blocked by ANA-12, a blocker specific for TrkB the activation of which in the gastric strips was evidenced by its phosphorylation. Although 7,8-DHF alone did not activate : phospholipase C (PLC)-γ in gastric muscle, CCh did, and importantly, the combined treatment with CCh + 7,8-DHF activated more PLC-γ. U73122, an antagonist to PLC-γ blocked both the CCh-induced and the 7,8-DHF-enhanced/CCh-induced contraction by ~30%. To pursue how 7,8-DHF could augment CCh-activated PLC-γ phosphorylation, we first examined the effect of 7,8-DHF on the expression of muscarinic receptors in gastric muscle and found that 7,8-DHF specifically increased M3 but not M2 receptor expression possibly through TrkB/Akt (protein kinase B) pathway because the Akt antagonist, LY294002 significantly suppressed the 7,8-DHF-augmemted M3 expression and completely blocked the 7,8-DHF-enhanced cholinergic contraction. Supporting the result, Akt phosphorylation in the gastric muscle was enhanced by 7,8-DHF treatment. The in vivo experiment showed that orally fed 7,8-DHF increased gastric emptying rate. The results imply a possibility that 7,8-DHF may be developed into a drug in the future for enhancing gastric dynamics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

Tian

et al. 2018

Clin Exp Pharma Physio

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“…Moreover, BDNF protects hippocampal neurons from glutamate toxicity [ 9 ], rescues cerebellar neurons from programmed cell death [ 10 ], reduces ischemic neuronal injury [ 11 , 12 ] and improves functional recovery from postinjury regeneration [ 13 ]. Thus, BDNF may represent a beneficial therapeutic agent against a variety of human disorders such as ALS, AD, PD, fetal alcohol exposure, autism and schizophrenia [ 14 ]. However, the outcomes of several clinical trials using recombinant BDNF are disappointing [ 15 , 16 ], possibly because of the poor delivery and short in vivo half-life of BDNF.…”

Section: Introductionmentioning

confidence: 99%

7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders

Liu

Chan

2016

Transl Neurodegener

153

103

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Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone (7,8-DHF) is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases.

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“…As potential dietary supplements their multi-target properties may be beneficial in prevention and treatment of the age-associated neurodegenerative diseases (Williams et al, 2015). Neurobiological perspectives on some individual flavonoids can be found in the first volume of this Special Issue (Blasina et al, 2015;Dajas et al, 2015;Du and Hill, 2015;Johnston, 2015;Krasieva et al, 2015). Wadhwa et al also contextualise the holistic, multifunctional drug/multi-target approach which may alleviate the diverse pathological consequences inflicted by the multifactorial nature of brain disorders.…”

Section: Dietary Supplements: Benefits Of Multi-target Approachesmentioning

confidence: 99%

Neuro-nutraceuticals: Further insights into their promise for brain health

Williams

Mohanakumar

Beart

2016

Neurochemistry International

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In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address key emergent issues such as bioavailability, neuronal health, inflammation and the holistic benefit of multi-targeted actions that impact upon how nutraceuticals ultimately leverage the brain to function better. In terms of the benefit of nutraceuticals it is clear that some naturally occurring molecules can be advantageous to both the young and aged brain, and that they have actions that ultimately can be directed to aid either in the improvement of cognition or in the management of debilitating neurodegenerative and neuropsychiatric conditions.

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7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders

Cited by 43 publications

References 212 publications

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders

Neuro-nutraceuticals: Further insights into their promise for brain health

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