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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.

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Figure 1: Maxi-K channel opening by compound 1 and BMS-204352.
Figure 2: Ca++-sensitivity of the effects of BMS-204352.
Figure 3: Modulation of transmitter release and synaptic transmission by maxi-K channel openers.
Figure 4: BMS-204352 had no effect on blood pressure or cerebral blood flow.
Figure 5: Effects of compound 1 and BMS-204352 on infarct volume in rat models of permanent focal stroke.
Figure 6: Effects of a maxi-K channel opener with low brain penetration.

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Correspondence to Valentin K. Gribkoff.

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Gribkoff, V., Starrett, J., Dworetzky, S. et al. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nat Med 7, 471–477 (2001). https://doi.org/10.1038/86546

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