Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels

Abstract

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.

DOI: 10.1038/86546
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@article{Gribkoff2001TargetingAI, title={Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels}, author={Valentin K. Gribkoff and John E. Starrett and Steven I. Dworetzky and Piyasena Hewawasam and Christopher G. Boissard and Deborah A. Cook and Stephen W. Frantz and Karen L Heman and Jeffrey R. Hibbard and Kevin Huston and Graham Johnson and B. Santhana Krishnan and Gene G. Kinney and Lynn A. Lombardo and Nicholas A. Meanwell and Perry B. Molinoff and Robert A. Myers and Sandra L. Moon and Astrid A. Ortiz and Lorraine M Pajor and Rick L. Pieschl and Debra J. Post-Munson and Laura J. Signor and Nugehally Srinivas and Matthew T. Taber and George Thalody and Joanne T. Trojnacki and Harvey Wiener and Krishnaswamy Yeleswaram and Sarita W. Yeola}, journal={Nature Medicine}, year={2001}, volume={7}, pages={471-477} }