Skip to main content
Article thumbnail
Location of Repository

Cyclooxygenase inhibition in ischemic brain injury.

By Dr. Eduardo Candelario-Jalil and Bernd L. Fiebich


Neuroinflammation is one of the key pathological events involved in the progression of brain damage caused by cerebral ischemia. Metabolism of arachidonic acid through cyclooxygenase (COX) enzymes is known to be actively involved in the neuroinflammatory events leading to neuronal death after ischemia. Two isoforms of COX, termed COX-1 and COX-2, have been identified. Unlike COX-1, COX-2 expression is dramatically induced by ischemia and appears to be an effector of tissue damage. This review article will focus specifically on the involvement of COX isozymes in brain ischemia. We will discuss issues related to the biochemistry and selective pharmacological inhibition of COX enzymes, and further refer to their expression in the brain under normal conditions and following excitotoxicity and ischemic cerebral injury. We will review present knowledge of the relative contribution of each COX isoform to the brain ischemic pathology, based on data from investigations utilizing selective COX-1/COX-2 inhibitors and genetic knockout mouse models. The mechanisms of neurotoxicity associated with increased COX activity after ischemia will also be examined. Finally, we will provide a critical evaluation of the therapeutic potential of COX inhibitors in cerebral ischemia and discuss new targets downstream of COX with potential neuroprotective ability

Topics: Neurochemistry
Publisher: Bentham Science Publishers
Year: 2008
OAI identifier:

Suggested articles


  1. (2000). 5-Lipoxygenase and cyclooxygenase mRNA expression in rat hippocampus:early response to glutamate receptor activation by kainate. Exp Gerontol
  2. (1998). A light and electron microscopic study of cytoplasmic phospholipase A2 and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res
  3. (1999). A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1.
  4. (2001). Acetylsalicylic acid reduces ischemiainduced proliferation of dentate cells in gerbils. Neuroreport doi
  5. (2006). Activation of cerebral peroxisome proliferator-activated receptors gamma promotes neuroprotection by attenuation of neuronal cyclooxygenase-2 overexpression after focal cerebral ischemia in rats. doi
  6. (2006). Anti-inflammatory drugs in the treatment of neurodegenerative diseases: current state. Curr Pharm Des
  7. (1989). Anti-ischaemic effects of indomethacin and ketamine on hippocampus neurones in Mongolian gerbils. Pharmacol Toxicol
  8. (2007). Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models.
  9. (1999). Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition.
  10. (2004). Arachidonic acid-induced carboncentered radicals and phospholipid peroxidation in cyclo-oxygenase-2-transfected PC12 cells.
  11. (1981). Are prostaglandins involved in experimental ischemic edema in gerbils? Stroke
  12. (2006). Bench to bedside: the quest for quality in experimental stroke research.
  13. (2000). Brain tissue responses to ischemia.
  14. (1999). Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures.
  15. (2005). Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
  16. (2005). Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. doi
  17. (2007). Cardiovascular risk, hypertension, and NSAIDs. Curr Rheumatol Rep
  18. (2007). Cardiovascular thromboembolic adverse effects associated with cyclooxygenase-2 selective inhibitors and nonselective antiinflammatory drugs. Anesth Analg
  19. (2005). CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J Cereb Blood Flow Metab doi
  20. (1998). Cellular regulation of prostaglandin H synthase catalysis.
  21. (2006). Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res doi
  22. (2007). Chronic inhibition of cyclooxygenase-2 induces dendritic hypertrophy and limited functional improvement following motor cortex stroke. Neuroscience
  23. (2000). Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
  24. (2005). Coupling between cyclooxygenases and terminal prostanoid synthases. Biochem Biophys Res Commun
  25. (2007). COX-2 oxidative metabolite of endocannabinoid 2-AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity. doi
  26. (2007). COX-2: friend or foe? Curr Pharm Des
  27. (2006). Coxibs and cardiovascular side-effects: from light to shadow. Curr Pharm Des
  28. (1997). Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons.
  29. (2003). Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteasomal inhibition.
  30. (1998). Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents.
  31. (1997). Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage.
  32. (1996). Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia. doi
  33. (2002). Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology. Neurobiol Aging
  34. (2001). Cyclooxygenase enzymes: catalysis and inhibition. Curr Opin Struct Biol
  35. (2005). Cyclooxygenase inhibition and cardiovascular risk. Circulation doi
  36. (2002). Cyclooxygenase inhibition as a strategy to ameliorate brain injury.
  37. (2004). Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases.
  38. (2004). Cyclooxygenase-2 activity contributes to neuronal expression of cyclin D1 after anoxia/ischemia in vitro and in vivo. Brain Res Mol Brain Res
  39. (2005). Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res
  40. Cyclooxygenase-2 mediates the development of cortical spreading depression-induced tolerance to transient focal cerebral ischemia in rats. Neuroscience 2006; 140(2):723-730. PLA2 PGH2 Cyclooxygenase activity PGE2 Free radicals Peroxidase activity doi
  41. (2002). Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury. Brain Res Mol Brain Res
  42. (2006). Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and the risk of ischemic stroke: a nested case-control study. Stroke
  43. (2000). Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem
  44. (2003). Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res
  45. (2000). Delayed neuronal death in hippocampal CA1 pyramidal neurons after forebrain ischemia in hyperglycemic gerbils: amelioration by indomethacin. Brain Res
  46. (1997). Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid. Neuroscience
  47. (2001). Differential modulation of prostaglandin H synthase-2 by nitric oxide-related species in intact cells. Biochemistry
  48. (2007). Drug insight: cyclo-oxygenase-2 inhibitors--a critical appraisal. Nat Clin Pract Rheumatol
  49. (1989). Effect of cyclooxygenase and lipoxygenase inhibitors on delayed neuronal death in the gerbil hippocampus. Stroke
  50. (1993). Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats. Brain Res
  51. (1989). Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats. Stroke
  52. (1992). Effect of indomethacin on delayed neuronal death of hippocampal CA1 sector in gerbil under different levels of controlled cranial temperatures. Nippon Ika Daigaku Zasshi
  53. (1991). Effect of indomethacin on edema following single and repetitive cerebral ischemia in the gerbil. Stroke
  54. (1988). Effect of mannitol, nimodipine, and indomethacin singly or in combination on cerebral ischemia in rats. Stroke
  55. (1998). Effect of selective inhibition of cyclooxygenase 2 on temporary focal cerebral ischemia in rats.
  56. (2007). Effects of cyclooxygenase (COX) inhibition on memory impairment and hippocampal damage in the early period of cerebral hypoperfusion in rats.
  57. (2007). Effects of EP1 receptor on cerebral blood flow in the middle cerebral artery occlusion model of stroke in mice.
  58. (2000). Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett doi
  59. (2003). EP2 and EP4 prostanoid receptor signaling. Life Sci
  60. (2007). Epidemiology of stroke in Europe: geographic and environmental differences.
  61. (1980). Evidence for a peroxide-initiated free radical mechanism of prostaglandin biosynthesis.
  62. (2007). Excitotoxic mechanisms in stroke: An update of concepts and treatment strategies. Neurochem Int
  63. (2005). Expression of inducible nitric oxide synthase and cyclooxygenase-2 mRNA in brain damage induced by lipopolysaccharide and intermittent hypoxia-ischemia in neonatal rats.
  64. (2004). Failing the public health--rofecoxib, Merck, and the FDA. doi
  65. (2008). FINAL edited form as:
  66. (1997). G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis.
  67. (2004). High-dose aspirin is neuroprotective in a rat focal ischemia model. Brain Res
  68. (2003). High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats.
  69. (2007). Hoppe A et al. Stroke epidemiology, prevention, and management strategies at a regional level: Latin America and the Caribbean. Lancet Neurol
  70. (2005). Ibuprofen protects ischemia-induced neuronal injury via up-regulating interleukin-1 receptor antagonist expression. Neuroscience
  71. (2003). Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. doi
  72. (1999). In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines.
  73. (1999). Increased cyclin D1 in vulnerable neurons in the hippocampus after ischaemia and epilepsy: a modulator of in vivo programmed cell death?
  74. (2002). Increased severity of stroke in CB1 cannabinoid receptor knock-out mice.
  75. (1988). Indomethacin ameliorates ischemic neuronal damage in the gerbil hippocampal CA1 sector. Stroke
  76. (1998). Indomethacin inhibits delayed DNA fragmentation of hippocampal CA1 pyramidal neurons after transient forebrain ischemia in gerbils. Brain Res
  77. (1994). Indomethacin modulates ischemia-evoked release of glutamate and adenosine from the rat cerebral cortex. Brain Res
  78. (1996). Induction of cyclooxygenase-2 following anoxic stress in piglet cerebral arteries. Microcirculation doi
  79. (1999). Induction of cyclooxygenase-2 in the rat brain after a mild episode of focal ischemia without tissue inflammation or neural cell damage. Neurosci Lett
  80. (1999). Induction of cyclooxygenase-2 messenger RNA after transient and permanent middle cerebral artery occlusion in rats: comparison with c-fos messenger RNA by using in situ hybridization. doi
  81. (1995). Induction of cyclooxygenase-2 mRNA and protein following transient focal ischemia in the rat brain. Neurosci Lett doi
  82. (1995). Induction of prostanoid biosynthesis by bacterial lipopolysaccharide and isoproterenol in rat microglial cultures.
  83. (2007). Inflammation and ischaemic stroke. Curr Opin Neurol
  84. (2004). Inflammation in stroke: the good, the bad, and the unknown. Ernst Schering Res Found Workshop
  85. (1998). Inhibition of prostanoid synthesis protects against neuronal damage induced by focal ischemia in rat brain. Neurosci Lett
  86. (1998). Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia.
  87. (1994). International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev
  88. (2004). Intraparenchymal administration of interleukin-1beta induces cyclooxygenase-2-mediated expression of membrane- and cytosolic-associated prostaglandin E synthases in mouse brain.
  89. (2007). Ischemic preconditioning via epsilon protein kinase C activation requires cyclooxygenase-2 activation in vitro. Neuroscience doi
  90. (2002). Klittich WS. Long term cost-of-illness in stroke: an international review. Pharmacoeconomics
  91. (2007). Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat.
  92. (2004). Matrix metalloproteinases in neuroinflammation and cerebral ischemia. Ernst Schering Res Found Workshop
  93. (2002). Matrix metalloproteinases in neuroinflammation. Glia
  94. (1997). Maturational regulation and regional induction of cyclooxygenase-2 in rat brain: implications for Alzheimer's disease. Exp Neurol
  95. (2007). Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks. Curr Pharm Des
  96. (2005). Microglia-specific expression of microsomal prostaglandin E2 synthase-1 contributes to lipopolysaccharide-induced prostaglandin E2 production.
  97. (2006). Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury.
  98. (2001). Mild cerebral ischemia induces loss of cyclindependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death.
  99. (2006). Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr Pharm Des
  100. (2006). Modulatory role of cyclooxygenase-2 in cerebrovascular coupling. Neuroimage
  101. (2005). Multiple cyclin-dependent kinases signals are critical mediators of ischemia/hypoxic neuronal death in vitro and in vivo.
  102. (2003). Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol
  103. (2008). Neuroprotection and glutamate attenuation by acetylsalicylic acid in temporary but not in permanent cerebral ischemia. Exp Neurol
  104. (2007). Neuroprotection by early and delayed treatment of acute stroke with high dose Aspirin. Brain Res
  105. (2005). Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia. Ann Neurol
  106. (2006). Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra. Acta Neuropathol doi
  107. (2004). Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia.
  108. (2006). Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.
  109. (2004). Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci
  110. (2004). Opposing effects of cyclooxygenase-2 selective inhibitors on oxygen-glucose deprivation-induced neurotoxicity.
  111. (2002). Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids
  112. (2002). Oxidative stress and cyclooxygenase-2 induction mediate cyanide-induced apoptosis of cortical cells. Toxicol Appl Pharmacol
  113. (2000). Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates.
  114. (1987). Oxygen radicals from arachidonate metabolism in abnormal vascular responses. Am Rev Respir Dis
  115. (2001). Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke
  116. (1999). Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci
  117. (2006). Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets. Pathobiology
  118. (2006). PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons. doi
  119. (2007). Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats.
  120. (2003). Post-ischemic cyclooxygenase-2 expression is regulated by the extent of cerebral blood flow reduction in non-human primates. Neurosci Lett doi
  121. (2006). Prevention of rat cortical neurons from prostaglandin E2-induced apoptosis by glycogen synthase kinase-3 inhibitors. Neurosci Lett
  122. (2005). Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation.
  123. (2005). Prostaglandin D2 mediates neuronal protection via the DP1 receptor.
  124. (2007). Prostaglandin E receptors.
  125. (2005). Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis.
  126. (2006). Prostaglandin E synthase: a novel drug target for inflammation and cancer. Curr Pharm Des
  127. (2002). Prostaglandin E(2) induces caspase-dependent apoptosis in rat cortical cells. Neurosci Lett
  128. (2006). Prostaglandin E2 deteriorates N-methyl-D-aspartate receptor-mediated cytotoxicity possibly by activating EP2 receptors in cultured cortical neurons. Life Sci
  129. (2004). Prostaglandin E2 induced caspase-dependent apoptosis possibly through activation of EP2 receptors in cultured hippocampal neurons. Neurochem Int
  130. (2006). Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. Neurosci Res
  131. (1994). Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res
  132. (2004). Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther
  133. (2006). Prostaglandin EP1 receptor contributes to excitotoxicity and focal ischemic brain damage. Toxicol Sci
  134. (2005). Prostaglandin EP4 receptor agonist protects against acute neurotoxicity. Brain Res
  135. (2002). Prostaglandin receptors: advances in the study of EP3 receptor signaling.
  136. (2004). Prostaglandin synthases: recent developments and a novel hypothesis. Prostaglandins Leukot Essent Fatty Acids
  137. (1998). Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature
  138. (1998). Prostanoid receptor heterogeneity through alternative mRNA splicing. Life Sci
  139. (2001). Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol
  140. (1994). Protection by prostaglandins from glutamate toxicity in cortical neurons. Neurochem Int
  141. (1995). Protective effect of KBT-3022, a new cyclooxygenase inhibitor, in cerebral hypoxia and ischemia.
  142. (2004). Redox regulates COX-2 upregulation and cell death in the neuronal response to cadmium. Cell Signal
  143. (2000). Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2.
  144. (1998). Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie
  145. (2006). Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. doi
  146. (2002). Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J Pharmacol Exp Ther
  147. (2006). Role of cyclooxygenase-2 induction by transcription factor
  148. (1996). Role of oxidants in ischemic brain damage. Stroke
  149. (2004). Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia.
  150. (2007). Roles of prostaglandin synthesis in excitotoxic brain diseases. Neurochem Int
  151. (2006). Signal transduction pathways of inflammatory gene expressions and therapeutic implications. Curr Pharm Des
  152. (1997). Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci U S A doi
  153. (2000). Spreading depression-induced cyclooxygenase-2 expression in the cortex. Neurochem Res
  154. (2007). Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury.
  155. (2006). Stimulation of prostaglandin EP2 receptors prevents NMDA-induced excitotoxicity.
  156. (2003). Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol
  157. (2007). Stroke in China: epidemiology, prevention, and management strategies. Lancet Neurol
  158. (2006). Stroke incidence and prevalence in Europe: a review of available data.
  159. (1999). Stroke: how large a public health problem, and how can the neurologist help? Arch Neurol
  160. (2005). Structural and functional differences between cyclooxygenases: fatty acid oxygenases with a critical role in cell signaling.
  161. (2003). Suppression of hyperemia and DNA oxidation by indomethacin in cerebral ischemia.
  162. (2005). Synaptic and vascular associations of neurons containing cyclooxygenase-2 and nitric oxide synthase in rat somatosensory cortex. Cereb Cortex
  163. (2004). Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ishemia in rats. Neurosci Lett
  164. (1993). Temporary focal cerebral ischemia in spontaneously hypertensive rats: the effect of ibuprofen on infarct volume. J Pharmacol Exp Ther
  165. (2005). Tenoxicam exerts a neuroprotective action after cerebral ischemia in rats. Neurochem Res
  166. (2004). The Atlas of Heart Disease and Stroke.
  167. (2002). The cyclooxygenase reaction mechanism. Biochemistry
  168. (1999). The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene. J Cereb Blood Flow Metab
  169. (2004). The cyclooxygenases. Genome Biol
  170. (2007). The cycloxygenase 2 (COX-2) story: it's time to explain, not inflame. J Cardiovasc Pharmacol Ther
  171. (2001). The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat. Neurosci Lett
  172. (2002). The highly selective cyclooxygenase-2 inhibitor DFU is neuroprotective when given several hours after transient cerebral ischemia in gerbils. Brain Res
  173. (1973). The inhibition of the fatty acid oxygenase of sheep vesicular gland by antioxidants. Biochim Biophys Acta
  174. (1996). The kinetic factors that determine the affinity and selectivity for slow binding inhibition of human prostaglandin H synthase 1 and 2 by indomethacin and flurbiprofen.
  175. (2007). The large and growing burden of stroke. Curr Drug Targets
  176. (2004). Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. Brain Res

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.