The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease

Abstract

The BDNF mimetic compound 7,8-dihydroxyflavone (7,8-DHF), a potent small molecular TrkB agonist, displays prominent therapeutic efficacy against Alzheimer's disease (AD). However, 7,8-DHF has only modest oral bioavailability and a moderate pharmacokinetic (PK) profile. To alleviate these preclinical obstacles, we used a prodrug strategy for elevating 7,8-DHF oral bioavailability and brain exposure, and found that the optimal prodrug R13 has favorable properties and dose-dependently reverses the cognitive defects in an AD mouse model. We synthesized a large number of 7,8-DHF derivatives via ester or carbamate group modification on the catechol ring in the parent compound. Using in vitro absorption, distribution, metabolism, and excretion assays, combined with in vivo PK studies, we identified a prodrug, R13, that prominently up-regulates 7,8-DHF PK profiles. Chronic oral administration of R13 activated TrkB signaling and prevented Aβ deposition in 5XFAD AD mice, inhibiting the pathological cleavage of APP and Tau by AEP. Moreover, R13 inhibited the loss of hippocampal synapses and ameliorated memory deficits in a dose-dependent manner. These results suggest that the prodrug R13 is an optimal therapeutic agent for treating AD.

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

“…To assess the role of gut microbiota alteration in AD pathogenesis, we used the 5XFAD transgenic (Tg) mouse model, which is widely used in AD study for faithfully recapitulating AD-associated pathological features including the severely accelerated cognitive impairment, amyloid deposition in the 2 nd postnatal month, synaptic degeneration in the 4 th postnatal month, and behavioural changes in the 6 th month. [20][21][22][23] Consistent with these reports, [24][25][26][27] we observed rapid accumulation of Aβ plaque deposition in the cortex and hippocampus beginning from the 3 rd postnatal month in Tg mice compared to the age-paired wild-type (WT) mice (Supplementary information, Fig. S1a).…”

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

“…This failure in fl-TrkB localization from non-MLR subcellular regions to buoyant MLRs may explain the lack of efficacy of exogenous neurotrophin delivery in several failed clinical trials. The current study suggests that preservation of MLR-associated fl-TrkB expression in PSAPP-SynCav1 mice may potentially increase the efficacy of endogenous (BDNF) or exogenous agonists (e.g., dihydroxyflavone [28,35,36]) that specifically target TrkB activation. AD brains exhibit anatomical and ultrastructural changes (i.e., reduced synapses) in hippocampal and cortical brain regions [37].…”

Regulation of BDNF-TrkB Signaling and Potential Therapeutic Strategies for Parkinson’s Disease

“…It has a very long half-life and improved oral bioavailability. These effects of pro-drug R13 can block synaptic loss though the sustainable induction of TrkB and its downstream signals [120].…”