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Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels

Zhi-Gang Xiong1, Xiao-Man Zhu, Xiang-Ping Chu

  • 1Robert S Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA. zxiong@downeurobiology.org

Cell
|September 17, 2004
PubMed

Insights

Acidosis activates acid-sensing ion channels (ASICs), causing calcium (Ca2+) overload and neuronal injury during ischemic stroke. Blocking these channels offers potent neuroprotection, revealing new therapeutic targets.

Area of Science:

  • Neuroscience
  • Cellular Biology
  • Biochemistry

Background:

  • Calcium (Ca2+) toxicity is central to ischemic brain injury.
  • Previous neuroprotective strategies targeting glutamate receptors have shown limited success.
  • The role of acidosis in ischemic brain injury remains poorly understood.

Purpose of the Study:

  • To elucidate the mechanism of acid-induced neuronal injury in the ischemic brain.
  • To investigate the role of acid-sensing ion channels (ASICs) in mediating this injury.
  • To evaluate ASIC blockers as potential neuroprotective agents for stroke.

Main Methods:

  • Investigated the effect of acidosis on neuronal injury in vitro and in vivo.
  • Utilized cell transfection and gene knockout models to study ASIC function.
  • Administered ASIC blockers and glutamate antagonists in a focal ischemia model.

Main Results:

  • Acidosis activates Ca2+-permeable ASICs, leading to Ca2+ influx and neuronal injury.
  • This injury mechanism is independent of glutamate receptors.
  • ASIC blockers significantly protected neurons from acid injury and ischemic brain damage.
  • ASIC antagonism proved more potent than glutamate antagonism in a focal ischemia model.

Conclusions:

  • Acidosis mediates neuronal injury in ischemic stroke through ASIC activation and subsequent Ca2+ toxicity.
  • ASICs represent novel therapeutic targets for stroke treatment.
  • ASIC blockers offer a promising neuroprotective strategy against ischemic brain injury.

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