The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats
The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats
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DOI：
10.1007/s00213-005-2195-5
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发表时间：
2005-07-01
影响因子：
3.4
通讯作者：
Leza, JC
中科院分区：
文献类型：
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作者：
García-Bueno, B;Madrigal, JLM;Leza, JC
基本原理：制动应激后，肿瘤坏死因子-α释放后，氧化/亚硝化介质在脑中蓄积（TNF α）和其他细胞因子、核因子κ B（NF κ B B）活化、一氧化氮合酶2（NOS-2）和环氧合酶2（考克斯-2）在脑内的表达。本研究旨在评估考克斯的某些抗炎产物是否可以改变应激后脑中观察到的氧化/亚硝化物质的积累，并研究实现这种效果的机制。年轻成年雄性Wistar大鼠在6小时内进行单次固定。结果：在应激动物中，抗炎15 d-PGJ（2）的脑水平随着考克斯-2表达的增加而增加。用NS-398抑制考克斯-2可防止应激诱导的15 d-PGJ（2）增加。注射超生理剂量的15 d-PGJ（2）（80 - 120 μ g/kg）可降低应激诱导的NOS-2活性增加以及应激诱导的NO代谢物增加。另一方面，15 d-PGJ（2）减少应激诱导的丙二醛（脂质过氧化反应的指标）在皮层中的积累，并防止主要抗氧化剂谷胱甘肽的氧化。15 d-PGJ（2）在应激中的抗氧化特性的机制包括NF κ B阻断（通过防止应激诱导的I κ B α降低）以及抑制应激动物中的TNF α释放。在测试剂量下，15 d-PGJ（2）减少应激过程中考克斯-2的表达和PGE（2）的释放，提示这种内源性化合物的另一种机制。结论：这些发现表明这种抗炎途径在脑应激反应中的作用，并为防止氧化/亚硝化物质的积累和随后的脑损伤提供了可能性。
Rationale: Immobilisation stress is followed by accumulation of oxidative/nitrosative mediators in brain after the release of tumour necrosis factor-alpha (TNF alpha) and other cytokines, nuclear factor kappa B ( NF kappa B) activation, nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) expression in the brain.Objectives: This study was conducted to assess if some of the anti-inflammatory products of COX can modify the accumulation of oxidative/nitrosative species seen in brain after stress and to study the mechanisms by which this effect is achieved.Methods: Young-adult male Wistar rats were subjected to a single session of immobilisation during 6 h. Results: In stressed animals, brain levels of the anti-inflammatory 15d-PGJ(2) increases concomitantly with COX-2 expression. Inhibition of COX-2 with NS-398 prevents stress-induced 15d-PGJ(2) increase. Injection of supraphysiological doses of 15d-PGJ(2) (80 - 120 mu g/kg) decreases stress-induced increase in NOS-2 activity as well as the stress-induced increase in NO metabolites. On the other hand, 15d-PGJ(2) decreases stress-induced malondialdehyde ( an indicator of lipid peroxidation) accumulation in cortex and prevents oxidation of the main anti-oxidant glutathione. The mechanisms involved in the anti-oxidative properties of 15d-PGJ(2) in stress involve NF kappa B blockade ( by preventing stress-induced I kappa B alpha decrease) as well as inhibition of TNF alpha release in stressed animals. At the doses tested, 15d-PGJ(2) decreases COX-2 expression and PGE(2) release during stress, suggesting an alternative mechanism for this endogenous compound.Conclusions: These findings demonstrate a role for this anti-inflammatory pathway in the brain response to stress and open the possibility for preventing accumulation of oxidative/nitrosative species and subsequent brain damage.