Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice

J Cereb Blood Flow Metab. 2001 Dec;21(12):1436-41. doi: 10.1097/00004647-200112000-00008.

Abstract

Cyclooxygenase-1 (COX-1), a rate-limiting enzyme in the synthesis of prostanoids, is involved in selected vasodilatatory responses of the cerebral circulation. Cyclooxygenase-1-null mice were used to determine whether COX-1 influences cerebral ischemic damage. The middle cerebral artery was occluded in COX-1 -/- and +/+ mice (n = 9/group), and lesion volume was determined in thionin-stained sections 24 or 96 hours later. Middle cerebral artery occlusion produced larger infarcts in COX-1 -/- mice, both at 24 (35 +/- 17%; P < 0.05) and 96 hours (41 +/- 16%; P < 0.05) after ischemia. The enlargement was not due to increased susceptibility to glutamate excitotoxicity, because microinjection of N-methyl-D-aspartate or kainate in the parietal cortex produced comparable lesions in COX-1 +/+ and -/- mice ( P > 0.05; n = 8/group). To examine the contribution of hemodynamic factors to the enlargement of the infarct, cerebral blood flow was monitored by laser-Doppler flowmetry in the ischemic territory (n = 6/group). Although the reduction in cerebral blood flow was comparable in the ischemic core ( P > 0.05), at the periphery of the ischemic territory the reduction was greater in COX-1 -/- mice (-58 +/- 4%) than in COX-1 +/+ mice (-34 +/- 5%; P < 0.05). It is concluded that mice lacking COX-1 are more susceptible to focal cerebral ischemia, an effect that can be attributed to a more severe cerebral blood flow reduction in vulnerable regions at the periphery of the ischemic territory. Thus, the vascular effects of COX-1 may contribute to maintain cerebral blood flow in the postischemic brain and, as such, play a protective role in ischemic brain injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / enzymology*
  • Brain / pathology
  • Brain Ischemia / genetics*
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Cerebrovascular Circulation
  • Cyclooxygenase 1
  • Disease Susceptibility
  • Excitatory Amino Acid Agonists
  • Female
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Isoenzymes / genetics*
  • Kainic Acid
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Methylaspartate
  • Neurotoxins
  • Parietal Lobe / pathology
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Prostaglandins / metabolism
  • Stroke / genetics
  • Stroke / metabolism
  • Stroke / pathology

Substances

  • Excitatory Amino Acid Agonists
  • Isoenzymes
  • Membrane Proteins
  • Neurotoxins
  • Prostaglandins
  • N-Methylaspartate
  • Cyclooxygenase 1
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Kainic Acid