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

Summary

Researchers developed a new drug candidate called C20 that activates TRPC6 proteins in the brain. In studies with Alzheimer’s disease mouse models, C20 protected nerve connections from damage, restored memory function, and successfully crossed the blood-brain barrier. The compound shows promise as a potential treatment for Alzheimer’s disease by strengthening the connections between brain cells that are damaged in the disease.

Background

Synapse loss in Alzheimer’s disease correlates with cognitive dysfunction. TRPC6 channels regulate excitatory synapse formation, and positive regulation of TRPC6 enhances learning and memory. A novel selective TRPC6 agonist has been recently identified for potential therapeutic use.

Objective

To investigate the efficacy of the novel TRPC6 agonist C20 (3-(3,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one) in treating synaptic deficiency and memory impairment in Alzheimer’s disease models.

Results

C20 bound to the extracellular agonist binding site of TRPC6, protected hippocampal mushroom spines from amyloid toxicity, restored long-term potentiation in 5xFAD brain slices, efficiently penetrated the blood-brain barrier, and recovered contextual and cued fear memory deficits in 6-month-old 5xFAD mice.

Conclusion

C20 demonstrates potential as a TRPC6-selective drug candidate for treating synaptic deficiency in Alzheimer’s disease-affected hippocampal neurons through restoration of synaptic plasticity and cognitive function.
  • Published in:International Journal of Molecular Sciences,
  • Study Type:Preclinical Research Study,
  • Source: PMID: 36362339, DOI: 10.3390/ijms232113552
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