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- W2897088564 abstract "KCa3.1, an intermediate-conductance Ca2+-activated K+ channel, is expressed mainly in immune cells and constitutes a promising target for modulating microglia in brain disorders. We have investigated the in vivo significance of KCa3.1 in Alzheimer's disease (AD). The functional expression of microglial KCa3.1 in the 5xFAD mouse model of AD and human AD brain tissue samples, compared with control brain samples, was studied using qPCR, immunohistochemistry, Western blotting, and whole-cell patch clamp techniques. A specific KCa3.1 inhibitor called Senicapoc was investigated for its pharmacokinetic (PK) properties and for its effects on rectifying AD-like deficits in Aβ oligomer-activated hippocampal slices and 5xFAD mice. Microglial KCa3.1 expression and channel activity were enhanced in the 5xFAD model and human AD brains. Aβ oligomer-activated hippocampal slices showed enhanced microglial activation, neuronal damage, and impaired long-term potentiation (LTP), which were mitigated by pharmacological KCa3.1 blockade. The small molecule KCa3.1 blocker Senicapoc showed excellent PK properties including oral availability and brain penetrance. Long-term treatment of 5xFAD mice with Senicapoc reduced microglial activation, mitigated hippocampal LTP deficits, and reduced cerebral Aβ load. Senicapoc was previously advanced to a Phase-3 clinical trial for sickle cell anemia and is a relatively safe drug. Our results provide a strong rationale to repurpose Senicapoc for the treatment of AD and/or mild cognitive impairment." @default.
- W2897088564 created "2018-10-26" @default.
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- W2897088564 date "2018-07-01" @default.
- W2897088564 modified "2023-10-16" @default.
- W2897088564 title "O5‐05‐05: REPURPOSING THE KCA3.1 INHIBITOR SENICAPOC AS A MICROGLIA‐TARGETED THERAPEUTIC CANDIDATE FOR ALZHEIMER'S DISEASE" @default.
- W2897088564 doi "https://doi.org/10.1016/j.jalz.2018.06.3023" @default.
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