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

Author:

Zernov NikitaORCID,Veselovsky Alexander V.ORCID,Poroikov Vladimir V.ORCID,Melentieva Daria,Bolshakova Anastasia,Popugaeva ElenaORCID

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.

Funder

Russian Science Foundation

Program for Basic Research in the Russian Federation for a long-term period

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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