Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease

Lee-Way Jin, Jacopo Di Lucente, Hai M. Nguyen, Vikrant Singh, Latika Singh, Monique Chavez, Trevor Bushong, Heike Wulff, Izumi Maezawa

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 KCa3.1 constitutes a potential target for treating AD by reducing neuroinflammation. Methods: To determine if KCa3.1 is relevant to AD, we tested if treating cultured microglia or hippocampal slices with Aβ oligomer (AβO) activated KCa3.1 in microglia, and if microglial KCa3.1 was upregulated in 5xFAD mice and in human AD brains. The expression/activity of KCa3.1 was examined by qPCR, Western blotting, immunohistochemistry, and whole-cell patch-clamp. To investigate the role of KCa3.1 in AD pathology, we resynthesized senicapoc, a clinically tested KCa3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, Aβ deposition and hippocampal long-term potentiation (hLTP) in 5xFAD mice. Results: We found markedly enhanced microglial KCa3.1 expression/activity in brains of both 5xFAD mice and AD patients. In hippocampal slices, microglial KCa3.1 expression/activity was increased by AβO treatment, and its inhibition diminished the proinflammatory and hLTP-impairing activities of AβO. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5xFAD 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.

Original languageEnglish (US)
Pages (from-to)723-738
Number of pages16
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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