Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain
Induction of cyclooxygenase-2 accounts for restraint stress-induced oxidative status in rat brain
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DOI：
10.1038/sj.npp.1300187
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发表时间：
2003-09-01
影响因子：
7.6
通讯作者：
Leza, JC
中科院分区：
文献类型：
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作者：
Madrigal, JLM;Moro, MA;Leza, JC
环氧合酶（考克斯）是花生四烯酸代谢为前列腺素类的限速酶。虽然它在脑神经元中组成型表达，但诱导型同种型（考克斯-2）在病理条件如癫痫发作、缺血或一些退行性疾病中也上调。为了评估应激后考克斯-2是否受到调节，我们使用了成年雄性Wistar大鼠，其中一些大鼠在6小时内被固定。在应激开始后2-6小时，脑皮质中PGE（2）浓度增加，同时考克斯-2蛋白增强。免疫组织化学研究表明，应激后考克斯-2表达于皮层和海马的神经元样细胞形态。给予PDTC（150 mg/kg）（一种转录因子NF-κ B的抑制剂）或MK-801（0.2 mg/kg）（一种N-甲基-D-天冬氨酸受体阻断剂）可防止应激诱导的考克斯-2活性和蛋白水平的增加，表明这些因素在应激诱导脑内考克斯-2的机制中具有意义。为了评估考克斯-2是否解释了应激后脑中观察到的氧化状态，在应激开始前1小时对一组动物腹膜内注射NS-398，一种特异性考克斯-2抑制剂。NS-398（5 mg/kg）可降低皮质中应激诱导的丙二醛积累，并防止应激诱导的谷胱甘肽氧化。最后，NS-398降低了Ca 2+非依赖性诱导型一氧化氮合酶（iNOS，NOS-2）的活性，并降低了应激诱导的皮质NO代谢产物水平的积累。NS-398的这些作用似乎是由于考克斯-2的特异性抑制，因为它对应激诱导的皮质酮释放、谷氨酸释放和NF-κ B活化没有影响。这些研究结果进行了讨论，作为可能的损害和/或适应性的作用，应激诱导的考克斯-2在大脑中。
Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolism of arachidonic acid into prostanoids. Although it is constitutively expressed in brain neurons, the inducible isoform (COX-2) is also upregulated in pathological conditions such as seizures, ischemia or some degenerative diseases. To assess whether COX-2 is regulated after stress, we have used adult male Wistar rats, some of which were immobilized during 6 h. An increase in PGE(2) concentration occurs in brain cortex after 2-6 h of the onset of stress as well as an enhancement of COX-2 protein. Immunohistochemical studies indicate that COX-2 is expressed in the cortex and hippocampus after stress in cells with morphology of neurons. Administration of PDTC (150 mg/kg), an inhibitor of the transcription factor NF-kappaB or MK-801 (0.2 mg/kg), an N-methyl-D-aspartate receptor blocker, prevents both stress-induced increase in COX-2 activity and protein levels, suggesting an implication of these factors in the mechanism by which stress induces COX-2 in brain. To assess if COX-2 accounts for the oxidative status seen in brain after stress, a group of animals were i.p. injected with NS-398, a specific COX-2 inhibitor 1 h prior to the onset of stress. NS-398 (5 mg/kg) decreases stress-induced malondialdehyde accumulation in cortex as well as prevents the stress-induced oxidation of glutathione. Finally, NS-398 reduced Ca2+-independent inducible nitric oxide synthase (iNOS, NOS-2) activity and lowered the stress-induced accumulation of NO metabolite levels in cortex. These effects of NS-398 seem to be due to the specific inhibition of COX-2, since it has no effect on stress-induced corticosterone release, glutamate release, and NF-kappaB activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.