A key role for connexin hemichannels in spreading ischemic brain injury

  • Davidson J
  • Green C
  • Bennet L
 et al. 
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Abstract

Brain damage resulting from cerebral ischemia remains a significant problem at all stages of life. In adults, ischemic stroke is the third leading cause of death and the leading cause of disability in the developed world. In term newborns, moderate to severe brain damage after hypoxia-ischemia (HI) occurs in 1-3 per 1000 live births. One of the most striking features of HI injury is that after initial recovery of cellular oxidative metabolism, there is a delayed, 'secondary' mitochondrial failure that spreads over time from the most severely damaged areas outwards, into previously undamaged regions. This secondary failure is accompanied by transient seizure activity and cytotoxic edema. The specific mechanisms of this spread are poorly understood, but it is at least partly associated with spreading waves of depression that can trigger cell death in neighboring uninjured tissues. The waves are propagated through cell-cell communication via gap junction channels (the so called "bystander effect"). It has recently been proposed that unopposed connexin hemichannels (connexons) also play a significant role by mediating release of paracrine molecules that in turn propagate cell death messages by releasing intracellular mediators such as ATP, NAD(+), or glutamate or by abnormally prolonged opening to allow cell edema. There is increasing evidence that connexin hemichannels contribute to injury after many neural insults and that it is possible to significantly reduce the spread of damage after injury by suppressing the induction or activity of the connexin proteins that form hemichannels.

Author-supplied keywords

  • Aging/metabolism/pathology
  • Animals
  • Astrocytes/metabolism/pathology
  • Blood-Brain Barrier/metabolism/pathology
  • Brain Ischemia/*metabolism/pathology/prevention &
  • Bystander Effect
  • Connexins/antagonists & inhibitors/*metabolism
  • Disease Progression
  • Gap Junctions/*metabolism/pathology
  • Humans
  • Ion Channel Gating
  • Ion Channels/antagonists & inhibitors/*metabolism
  • Molecular Targeted Therapy

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Authors

  • J O Davidson

  • C R Green

  • L Bennet

  • L F Nicholson

  • H Danesh-Meyer

  • S J O'Carroll

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