Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats

Background: A growing body of evidence has demonstrated that peroxisome proliferator-activated receptor gamma (PPAR gamma) play a role in brain inflammatory conditions because various PPAR gamma ligands inhibit proinflammatory mediators, such as cytokines (tumor necrosis factor alpha [TNF alpha]) and inducible nitric oxide synthase (NOS-2). As has been previously shown, immobilization stress and stress-related neuropsychologic conditions are followed by accumulation of oxidative/nitrosative mediators in brain after the release of cytokines, nuclear factor kappa B activation, and NOS-2 and cyclooxygenase 2 (COX-2) expression in the brain. Methods. To assess whether PPAR gamma activation can modify the accumulation of oxidative/nitrosative species seen in brain after stress, and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized during 6 hours) were injected (IP) with the high-affinity ligand rosiglitazone (RS) at the onset of stress. Results. Stress increased PPAR gamma expression in cortical neurons and glia as assessed by Western blot and immunohistochemistry. In stressed animals, RS (1-3 mg/kg,) decreased stress-induced increases in NOS-2 activity. On the other band, the PPAR gamma ligand decreased stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevented oxidation of the main antioxidant glutathione. The mechanisms involved in the antioxidative properties of RS in stress involve nuclear factor kappa B blockade (by preventing stress-induced I kappa B alpha decrease) and inhibition of TNF alpha release in stressed animals. At the doses tested, RS did not decrease COX-2 expression and prostaglandin E2 release during stress. Finally, RS also decreased chronic (repeated immobilization for 21 days) stress-induced accumulation of oxidative/nitrosative mediators. Conclusions. Taken together, these findings suggest a role for this antiinflammatory pathway in the brain response to stress and the possibility of pharmacologic modulation for preventing accumulation of oxidative/nitrosative species and subsequent brain damage in stress-related neuropsychologic conditions.