7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Abstract

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). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the b-secretase enzyme (BACE1) that initiates amyloid-b (Ab) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the b-secretasecleaved C-terminal fragment of amyloid precursor protein (C99), Ab40, and Ab42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and b-amyloidogenesis.

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

“…Interestingly, more complete rescue is achieved with DHF (47). This TrkB agonist is also reported to enhance acquisition and prolong extinction of fear conditioning in C57BL/6 mice (29) and to reverse some of the Alzheimer's disease-associated memory loss (48). It should, however, be emphasized that our DHF results are based on a single pharmacological approach, and that although DHF is efficacious in activating TrkB in cells (29), the specificity of this compound in vivo has not been fully established.…”

Protection of Spiral Ganglion Neurons from Degeneration Using Small-Molecule TrkB Receptor Agonists

“…Previous studies revealed that 7,8-DHF has no detectable toxicities, even when given at high dosages in animal studies (Payá et al, 1993;Tasdemir et al, 2006), suggesting that it has negligible systemic side effects. A number of recent studies using 7,8-DHF have shown promising therapeutic effects for numerous neurological diseases (Choi et al, 2010;Liu et al, 2010;Devi and Ohno, 2012). Studies show that 7,8-DHF fully mimics BDNF and exhibits promising therapeutic effects in animal models of depression (Blugeot et al, 2011), Alzheimer's disease (Devi and Ohno, 2012), and Rett syndrome .…”

“…A number of recent studies using 7,8-DHF have shown promising therapeutic effects for numerous neurological diseases (Choi et al, 2010;Liu et al, 2010;Devi and Ohno, 2012). Studies show that 7,8-DHF fully mimics BDNF and exhibits promising therapeutic effects in animal models of depression (Blugeot et al, 2011), Alzheimer's disease (Devi and Ohno, 2012), and Rett syndrome . Compared with intracochlear infusion of BDNF, the local or systematic application of 7,8-DHF or 7,8,3Ј-THF should also be advantageous in terms of better pharmacokinetic properties than those observed with polypeptides.…”

“…These compounds readily crossed the blood-brain barrier and activate TrkB receptors in neurons with a half-effective concentration (EC 50 ) below 50 nM (Jang et al, 2010). 7,8-Dihydroxyflavone (7,8-DHF) was tested in a number of neurodegenerative animal models and show promising results (Blugeot et al, 2011;Devi and Ohno, 2012). However, the effect of 7,8-DHF has not been examined for auditory neuroprotection.…”

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

“…Because they are small enough to pass the blood-brain (or blood-nerve) barrier, they have been used systemically, even by oral administration (18). One or both of these molecules have been applied to the study of a wide range of different neurological model systems, including learning (21), memory loss (22), excitotoxic stress (23), depression (24,25), fear conditioning (19), neuromuscular synaptic transmission (26), and age-related synaptic plasticity (27). If treatments with these molecules, especially systemically, proved effective in enhancing axon regeneration in injured peripheral nerves, such a result could form the basis for the development of a novel treatment strategy for peripheral nerve injuries.…”