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

V K Gribkoff1, J E Starrett, S I Dworetzky

  • 1Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA. valentin.gribkoff@bms.com

Nature Medicine
|April 3, 2001
PubMed

Insights

Novel openers of large-conductance, calcium-activated potassium channels offer neuroprotection against ischemic stroke. This approach restricts calcium entry in at-risk neurons with minimal side effects.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cardiovascular Research

Background:

  • Ischemic stroke causes dangerous intracellular calcium (Ca++) buildup in neurons.
  • This calcium overload triggers a cascade leading to neuronal death.

Purpose of the Study:

  • To develop and evaluate novel openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels.
  • To investigate the neuroprotective potential of these openers in stroke models.

Main Methods:

  • Developed novel fluoro-oxindole compounds (BMS-204352 and racemic compound 1) as maxi-K channel openers.
  • Tested BMS-204352 in rat models of permanent large-vessel stroke.
  • Assessed neuroprotection, blood pressure, and cerebral blood flow.

Main Results:

  • BMS-204352 and compound 1 are potent, Ca++-sensitive maxi-K channel openers.
  • BMS-204352 demonstrated significant cortical neuroprotection when given 2 hours post-stroke onset.
  • No adverse effects on blood pressure or cerebral blood flow were observed.

Conclusions:

  • Maxi-K channel openers represent a promising therapeutic strategy for ischemic stroke.
  • This approach offers targeted neuroprotection by regulating Ca++ entry.
  • The developed compounds show potential for clinical application with a favorable safety profile.

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