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41. Repurposing the KCa3.1 Blocker Senicapoc for Ischemic Stroke.

Author

Chen, Yi-Je, Nguyen, Hai, Singh, Latika, Dietrich, Connor, Pyles, Benjamin, Cui, Yanjun, Weinstein, Jonathan, Wulff, Heike, and Lee, Ruth

Subjects
Ischemic stroke, KCa3.1, Microglia activation, Middle cerebral artery occlusion, Neuroinflammation, Senicapoc, Animals, Intermediate-Conductance Calcium-Activated Potassium Channels, Ischemic Stroke, Male, Mice, Inbred C57BL, Mice, Microglia, Drug Repositioning, Infarction, Middle Cerebral Artery, Acetamides, Potassium Channel Blockers, Trityl Compounds
Abstract

Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC50 of 7 nM, reduced Ca2+ signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.

Published
2024

43. Time for a Diagnostic Paradigm Shift From STEMI/NSTEMI to OMI/NOMI (DIFOCCULT-3)

Author

Ankara Etlik City Hospital, Antalya City Hospital, Bağcılar Training and Research Hospital, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Ataturk University, Eskisehir City Hospital, Kartal Kosuyolu High Speciality Training and Research Hospital, Marmara University Pendik Training and Research Hospital, Istanbul Mehmet Akif Ersoy Educational and Training Hospital, Muğla Sıtkı Koçman University, Necmettin Erbakan University, Meram Faculty of Medicine, Ordu State Hospital, Sanliurfa Mehmet Akif Inan Education and Research Hospital, Sirnak State Hospital, Tokat Gaziosmanpasa University, Umraniye Education and Research Hospital, Van Training and Research Hospital, Yuzuncu Yıl University, and Kutahya Health Sciences University

Published
2024

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