García-Bueno Borja, Madrigal José L M, Pérez-Nievas Beatriz G, Leza Juan Carlos
Department of Pharmacology, Faculty of Medicine and Pharmacology and Toxicology Institute, Consejo Superior de Investigaciones Centificas-UCM, Complutense University, 28040 Madrid, Spain.
Endocrinology. 2008 Apr;149(4):1969-78. doi: 10.1210/en.2007-0482. Epub 2007 Dec 13.
Stress exposure leads to oxidative/nitrosative and neuroinflammatory changes that have been shown to be regulated by antiinflammatory pathways in the brain. In particular, acute restraint stress is followed by cyclooxygenase (COX)-2 up-regulation and subsequent proinflammatory prostaglandin (PG) E2 release in rat brain cortex. Concomitantly, the synthesis of the antiinflammatory prostaglandin 15d-PGJ(2) and the activation of its nuclear target the peroxisome proliferator-activated receptor (PPAR)-gamma are also produced. This study aimed to determine the possible role of the main stress mediators: catecholamines, glucocorticoids, and excitatory amino acids (glutamate) in the above-mentioned stress-related effects. By using specific pharmacological tools, our results show that the main mediators of the stress response are implicated in the regulation of prostaglandin synthesis and PPARgamma activation in rat brain cortex described after acute restraint stress exposure. Pharmacological inhibition (predominantly through beta-adrenergic receptor) of the stress-released catecholamines in the central nervous system regulates 15d-PGJ(2) and PGE(2) synthesis, by reducing COX-2 overexpression, and reduces PPARgamma activation. Stress-produced glucocorticoids carry out their effects on prostaglandin synthesis through their interaction with mineralocorticoid and glucocorticoid receptors to a very similar degree. However, in the case of PPARgamma regulation, only the actions through the glucocorticoid receptor seem to be relevant. Finally, the selective blockade of the N-methyl-d-aspartate type of glutamate receptor after stress also negatively regulates 15d-PGJ(2) and PGE(2) production by COX-2 down-regulation and decrease in PPARgamma transcriptional activity and expression. In conclusion, we show here that the main stress mediators, catecholamines, GCs, and glutamate, concomitantly regulate the activation of proinflammatory and antiinflammatory pathways in a possible coregulatory mechanism of the inflammatory process induced in rat brain cortex by acute restraint stress exposure.
应激暴露会导致氧化/亚硝化和神经炎症变化，这些变化已被证明受大脑中抗炎途径的调节。特别是，急性束缚应激后，大鼠大脑皮层中环氧合酶（COX）-2上调，随后促炎前列腺素（PG）E2释放。与此同时，抗炎前列腺素15d-PGJ(2)的合成及其核靶点过氧化物酶体增殖物激活受体（PPAR）-γ的激活也会发生。本研究旨在确定主要应激介质：儿茶酚胺、糖皮质激素和兴奋性氨基酸（谷氨酸）在上述应激相关效应中的可能作用。通过使用特定的药理学工具，我们的结果表明，应激反应的主要介质参与了急性束缚应激暴露后大鼠大脑皮层中前列腺素合成和PPARγ激活的调节。中枢神经系统中应激释放的儿茶酚胺的药理学抑制（主要通过β-肾上腺素能受体）通过减少COX-2的过度表达来调节15d-PGJ(2)和PGE(2)的合成，并降低PPARγ的激活。应激产生的糖皮质激素通过与盐皮质激素和糖皮质激素受体相互作用，对前列腺素合成产生非常相似程度的影响。然而，在PPARγ调节方面，似乎只有通过糖皮质激素受体的作用才是相关的。最后，应激后选择性阻断N-甲基-D-天冬氨酸型谷氨酸受体也通过下调COX-2和降低PPARγ转录活性及表达来负向调节15d-PGJ(2)和PGE(2)的产生。总之，我们在此表明，主要应激介质儿茶酚胺、糖皮质激素和谷氨酸在急性束缚应激暴露诱导的大鼠大脑皮层炎症过程的可能共同调节机制中，同时调节促炎和抗炎途径的激活。
