Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 {1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E(2) concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.

环氧合酶-2（cyclooxygenase-2，COX2）的诱导型同工型是脑中由突触活动诱导的即刻早期基因。COX2活性是炎症反应的重要介导因子，但目前尚不明确COX2活性在脑内是否具有致病性。为探究COX2活性在脑缺血性损伤中的作用，本研究在大鼠全脑缺血模型中检测了COX2信使核糖核酸（mRNA）与蛋白质的表达水平，以及COX2抑制剂给药对神经元存活的影响。全脑缺血后，海马CA1区神经元发生死亡前，其COX2 mRNA与蛋白质的表达均出现上调。与溶剂对照组相比，在全脑缺血前或缺血后给予COX2选择性抑制剂SC58125{1-[(4-甲基磺酰基)苯基]-3-三氟甲基-5-[(4-氟)苯基]吡唑}的大鼠，其海马CA1区神经元存活率显著升高。此外，与溶剂处理组相比，药物处理组大鼠在全脑缺血24小时后的海马前列腺素E2（prostaglandin E2，PGE2）浓度显著降低。上述结果表明，COX2活性可促进全脑缺血后海马CA1区神经元的死亡。