COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest.
COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest.
复制标题
COX2 衍生的初级前列腺素和环戊烯酮前列腺素在窒息心脏骤停后增加。
DOI：
10.1016/j.brainres.2013.04.029
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发表时间：
2013
期刊：
影响因子：
2.9
通讯作者：
Hickey,RobertW
中科院分区：
文献类型：
--
作者：
Liu,Hao;Rose,MarieE;Miller,TriciaM;Li,Wenjin;Shinde,SunitaN;Pickrell,AliciaM;Poloyac,SamuelM;Graham,StevenH;Hickey,RobertW
背景：环戊烯酮前列腺素已被确认为在缺氧缺血环境中潜在的神经毒性药物。环氧合酶-2(COX-2)是负责产生前列腺素的上游酶，在缺氧缺血性脑损伤后表达上调。然而，环戊烯酮前列腺素在全脑缺血后的时间产生和浓度尚未被描述。方法采用窒息心脏骤停(ACA)然后复苏的方法复制大鼠全脑缺血模型。复苏后24~7天处死大鼠，取出脑组织。进行蛋白质印迹、免疫组织化学和质谱学分析。用环氧合酶-2(COX-2)抑制剂SC58125对一组大鼠进行预处理。结果ACA后24小时，大鼠海马区即可表达COX-2。多种前列腺素，包括环戊烯酮前列腺素，在ACA后24小时内在海马区增加。前列腺素和环戊烯酮前列腺素浓度在缺血后3天和7天恢复到基线水平。COX-2抑制剂SC58125可完全阻断脑缺血后前列腺素和环戊酮前列腺素的升高。结论脑缺血后前列腺素，包括环戊酮前列腺素升高，24小时达高峰，可被COX-2抑制剂SC58125减弱。这些数据证实了脑缺血后存在潜在的神经毒性环戊烯酮前列腺素，从而确定了神经保护治疗的靶点和治疗窗口。
BACKGROUND: Cyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia.MethodsGlobal brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24h and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125.ResultsCOX-2 is induced in hippocampus at 24h following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24h following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins.ConclusionsProstaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24h and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxic cyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.