7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease

Abstract

Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/ tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Abinduced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Ab deposition in transgenic mice that coexpress five familial Alzheimer's disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.

7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome

“…This strategy has shown promise in preclinical studies (Jang et al, 2010;Liu et al, 2012;Zeng et al, 2013;Zhang et al, 2014). During the course of this study, several groups (Liu et al, 2012;Zeng et al, 2013;Jiang et al, 2013;Zhang et al, 2014) confirmed the effects with oral 7, 8-DHF application. However, to date, there is no information regarding the therapeutic role of 7, 8-DHF in FXS phenotypes.…”

“…Ye's group showed that 7, 8-DHF can binds to TrkB receptors with high affinity and activates TrkB downstream signaling cascades (Jang et al, 2010;Liu et al, 2012). This strategy has shown promise in preclinical studies (Jang et al, 2010;Liu et al, 2012;Zeng et al, 2013;Zhang et al, 2014). During the course of this study, several groups (Liu et al, 2012;Zeng et al, 2013;Jiang et al, 2013;Zhang et al, 2014) confirmed the effects with oral 7, 8-DHF application.…”

TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination

“…Towards this end, several small molecule TrkB agonists have recently been developed, including 7, and adenosine A2A receptor agonists (Wehrman et al, 2007). LM22A-4 and 7,8-DHF have been shown to prevent neural cell death in a TrkB dependent manner in vitro, and also exert neuroprotective effects and promote functional recovery in a number of animal models of neurodegenerative disease (Simmons et al, 2013;Jiang et al, 2013;Zhang et al, 2014;Chang et al, 2002;Trapp and Nave, 2008;Massa et al, 2010;Jang et al, 2010). Interestingly, several recent studies have implicated BDNF in reducing the extent of demyelination and promoting remyelination using different animal models of CNS demyelination (VonDran et al, 2011;Linker et al, 2010), suggesting that activating BDNF signalling with small molecule BDNF mimetics is a potential therapeutic strategy to enhance CNS remyelination following a demyelinating insult.…”

Oroxylin A enhances memory consolidation through the brain-derived neurotrophic factor in mice

“…Moreover, we and others have found that an increase of mature BDNF (mBDNF) in specific time period is crucial for its action on memory consolidation Kim et al, 2012). According to these findings, BDNF releasing agents or TrkB receptor agonists would be candidates for various brain disorders that show learning and memory disturbances (Shin et al, 2014;Zhang et al, 2014). Oroxylin A (5,7-dihydroxy-6-methoxyflavone) is a flavonoid compound isolated from the root of Scutellaria baicalensis Georgi.…”