Flavones for improved synaptic plasticity

Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor and thus mediates neuronal differentiation and survival, synaptic plasticity and neurogenesis. 

The therapeutic potential of BDNF is limited by its poor pharmacokinetic profile. 7,8-dihydroxyflavone (7,8 DHF) is a bioactive high-affinity TrkB agonist that provokes receptor dimerization, autophosphorylation and activation of downstream signaling.

7,8-DHF is a member of the flavonoid family, that has been demonstrated to rescue in vitro long-term synaptic plasticity in the hippocampus of aged rats and in vivo rescues aging-related cognitive impairment in rats (Journal of Neurochemistry, 122: 800–811, 2012). 

The neurotrophic effects of 7,8-DHF have been identified in various neurological diseases such as ischemic stroke and Parkinson’s disease. 7,8-DHF protected wild-type, but not TrkB-deficient, neurons from apoptosis  and administration of 7,8-DHF to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB dependent manner, and was neuroprotective in an animal model of Parkinson disease (Sung-Wuk Jang et al., PNAS, 107.6: 2687–2692, 2010). 

The angiogeneic effect of 7,8-DHF has been observed in endothelial cells derived from resistance vessel of the brain. Angiogenesis by 7,8-DHF is an important factor that helps prevent and treat various ischemic diseases (Jeremy Williams et al., 2011).

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have also emerged as mediators in the pathophysiology of post-traumatic stress disorder, where patients show cognitive deficits. In this context, 7,8-DHF blocks long-term spatial memory impairment caused by immobilization stress in rats hippocampus (Andero et al., hippocampus, 22: 399–408, 2012).

It has also been shown that 7,8-DHF exhibits therapeutic efficacy in a mouse model of Rett syndrome (Johnson et al., Journal of Applied Physiology, 112: 704–710, 2012).

Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer’s disease (AD). 7,8-DHF reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s Disease (Latha Devi and Masuo Ohno, Neuropsychopharmacology 37: 434–444, 2012).

Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases. Current findings about 7,8-DHF and other functional mimetics of BDNF could evolve into a new class of drugs for cognitive aging and aging-related neurodegenerative diseases. The project is carried out by Ph.D. student Sarah Afshordel in cooperation with Prof. W. Gibson Wood, University of Minnesota, Minnapolis, USA.

© Prof. Dr. Gunter P. Eckert 2018