The nuclear receptor peroxisome proliferator-activated receptor (PPAR)-a plays a prominent role in several physiological processes including the inflammatory response, and its activation mediates a reduced production of pro-inflammatory factors. Using PPAR-a knockout (KO) mice, we report here a detailed investigation on the role of PPAR-a in brain damage-associated inflammatory and antioxidant processes after a subacute model of Parkinson's disease (PD). 1-methyl-4-phenylpyridinium, the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Immunohistochemistry and Western blotting analysis were performed to detect the expression of neuronal and inducible nitric oxide synthase, cyclooxygenase-2, matrix metalloproteinase 2 and 9 activity, nitrotyrosine formation, phosphorylation of p38MAPK, NF-kB activation, expression of apoptotic proteins, comparing mice lacking PPAR-a KO with wild-type. Brain oxidative stress was dramatically enhanced in KO mice, as documented by an increased content in malondialdehyde, decreased levels of glutathione, and marked increase of oxidative products. These data indicate that PPAR-a plays an important role in integrating and regulating central inflammation, antioxidant mechanisms in the process of MPTP-induced toxicity, and suggest that the use of PPAR-a agonists may be of interest for the prevention of PD.