Stress Mediators Regulate Brain Prostaglandin Synthesis and Peroxisome Proliferator-Activated Receptor-γ Activation after Stress in Rats

Abstract

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-PGJ2 and the activation of its nuclear target the peroxisome proliferator-activated receptor (PPAR)-γ 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 PPARγ activation in rat brain cortex described after acute restraint stress exposure. Pharmacological inhibition (predominantly through β-adrenergic receptor) of the stress-released catecholamines in the central nervous system regulates 15d-PGJ2 and PGE2 synthesis, by reducing COX-2 overexpression, and reduces PPARγ 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 PPARγ 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-PGJ2 and PGE2 production by COX-2 down-regulation and decrease in PPARγ 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.