
Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease
Author(s) -
Jin LeeWay,
Lucente Jacopo Di,
Nguyen Hai M.,
Singh Vikrant,
Singh Latika,
Chavez Monique,
Bushong Trevor,
Wulff Heike,
Maezawa Izumi
Publication year - 2019
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.754
Subject(s) - microglia , neuroinflammation , medicine , hippocampal formation , pharmacology , proinflammatory cytokine , neuroscience , long term potentiation , hippocampus , pathology , immunology , inflammation , biology , disease , receptor
Objective Microglia play a pivotal role in the initiation and progression of Alzheimer's disease ( AD ). We here tested the therapeutic hypothesis that the Ca 2+ ‐activated potassium channel KC a3.1 constitutes a potential target for treating AD by reducing neuroinflammation. Methods To determine if KC a3.1 is relevant to AD , we tested if treating cultured microglia or hippocampal slices with A β oligomer (A β O) activated KC a3.1 in microglia, and if microglial KC a3.1 was upregulated in 5x FAD mice and in human AD brains. The expression/activity of KC a3.1 was examined by qPCR , Western blotting, immunohistochemistry, and whole‐cell patch‐clamp. To investigate the role of KC a3.1 in AD pathology, we resynthesized senicapoc, a clinically tested KC a3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, A β deposition and hippocampal long‐term potentiation ( hLTP ) in 5x FAD mice. Results We found markedly enhanced microglial KC a3.1 expression/activity in brains of both 5x FAD mice and AD patients. In hippocampal slices, microglial KC a3.1 expression/activity was increased by A β O treatment, and its inhibition diminished the proinflammatory and hLTP ‐impairing activities of A β O. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5x FAD mice, reduced neuroinflammation, decreased cerebral amyloid load, and enhanced hippocampal neuronal plasticity. Interpretation Our results prompt us to propose repurposing senicapoc for AD clinical trials, as senicapoc has excellent pharmacological properties and was safe and well‐tolerated in a prior phase‐3 clinical trial for sickle cell anemia. Such repurposing has the potential to expedite the urgently needed new drug discovery for AD .