New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

Abstract

Synapse loss in the brain of Alzheimer’s disease patients correlates with cognitive dysfunctions. Drugs that limit synaptic loss are promising pharmacological agents. The transient receptor potential cation channel, subfamily C, member 6 (TRPC6) regulates the formation of an excitatory synapse. Positive regulation of TRPC6 results in increased synapse formation and enhances learning and memory in animal models. The novel selective TRPC6 agonist, 3-(3-,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one, has recently been identified. Here we present in silico, in vitro, ex vivo, pharmacokinetic and in vivo studies of this compound. We demonstrate that it binds to the extracellular agonist binding site of the human TRPC6, protects hippocampal mushroom spines from amyloid toxicity in vitro, efficiently recovers synaptic plasticity in 5xFAD brain slices, penetrates the blood–brain barrier and recovers cognitive deficits in 5xFAD mice. We suggest that C20 might be recognized as the novel TRPC6-selective drug suitable to treat synaptic deficiency in Alzheimer’s disease-affected hippocampal neurons.

Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer’s Disease Mice Model

“…There are several paradigms of FC testing [90,91]. Here, we used an auditory one because it corresponds well with changes observed in the downstream of Alzheimer's disease and other neurodegenerative diseases [92,93]. We used optogenetics to evaluate the positive effect of hippocampal astrocytic OPTO-α1AR activation that was expressed in the increase in the context and cued freezing time.…”

Design, synthesis and the evaluation of cholinesterase inhibition and blood‐brain permeability of daidzein derivatives or analogs

“…The experiment was conducted according to previous reports with slightly modification (Xiao et al, 2016; Zernov et al, 2022). ICR mice randomly divided into 11 groups of eight males and eight females per time point, fasted for 12 h before dosing.…”

Benzopyran derivative penetrates the blood–brain barrier, eliminates synaptic deficiency and restores memory deficit in 5xFAD mice

“…С20 эффективно проникал через ГЭБ, не вызывая острую и хроническую токсичность в диапазоне доз 10-100 мг/кг. Внутрибрюшинные инъекции 10 мг/кг C20 в течение 14 дней усиливают как зависимую от гиппокампа контекстную, так и независимую от гиппокампа память о страхе у мышей 5xFAD [3]. Таким образом, C20 может быть признан перспективным соединением, специфичным для TRPC6, которое может уменьшить снижение когнитивных функций.…”

“…C20 effectively passes through the BBB without causing acute or chronic toxicity in dosages ranging from 10-100 mg/kg. In a 14-day treatment of intraperitoneal injections with a 10 mg/kg dosage of C20, hippocampus-dependent context and hippocampus-independent cued fear memory improved in 5xFAD mice [3]. Therefore, C20 is a promising TRPC6-specific compound that may aid in reducing cognitive decline.…”