Effects of chronic systemic treatment with peroxisome proliferator-activated receptor α activators on neuroinflammation induced by intracerebral injection of lipopolysaccharide in adult mice.

We examined whether chronic systemic treatment with agonists for peroxisome proliferator-activated receptor α (PPARα) influences neuroinflammation induced by lipopolysaccharide (LPS) injection into the somatosensory cortex in adult mice. Mice were pretreated with Wy-14643 or fenofibrate, both at 30 mg/kg, for 7 days. These treatment protocols increased the amount of PPARα mRNA and active form of PPARα protein in the brain. LPS injection reduced the PPARα mRNA level in the brain. On the contrary, TNFα, IL-1β, IL-6, iNOS, COX-2, ICAM-1, VCAM-1, and PECAM-1 were elevated at 6h after LPS. Wy-14643 and fenofibrate inhibited the elevations of TNFα, IL-1β, IL-6, COX-2, ICAM-1, and VCAM-1. Wy-14643, but not fenofibrate, also attenuated the iNOS elevation. At 3 days after LPS, Wy-14643 and fenofibrate showed similar inhibitions in these molecules. LPS injection also elevated IL-6 protein levels in the brain and serum at 6h, which was inhibited by fenofibrate. Histological analyses showed that Wy-14643 and fenofibrate profoundly attenuated microglia/macrophage activation, neutrophil recruitment, and neuronal injury at 3 days after LPS. These findings suggest that activation of PPARα attenuates neuroinflammation in the adult mouse brain, implicating that PPARα may be a potential therapeutic target for CNS diseases in which neuroinflammation plays a substantial role.