||Thiazolidinedione (TZD) agonists of peroxisome proliferators-activated receptor gamma (PPAR-γ) display neuroprotective effects in experimental PD models, however mechanisms of neuroprotection are unclear. CNS PPAR-γ are expressed in neurons and microglia, and both cell types can be potential targets for neuroprotection. Moreover, receptor-dependent as well as -independent mechanisms have been proposed. We investigated the mechanism of rosiglitazone-mediated neuroprotection in the progressive MPTP/probenecid (MPTPp) mouse model of PD. C57BL/6J mice received MPTP (25 mg/kg) plus probenecid (100 mg/kg) twice/week for 5 weeks. Rosiglitazone (10 mg/kg) was given daily until sacrifice, starting on the 4th week of MPTPp treatment, when a partial neurodegeneration and microgliosis in the SNc were observed. PPAR-γ, that are constitutively expressed in TH-positive neurons and CD11b-positive microglia were assessed by immunofluorescence in each experimental group. MPTPp treatment induced an overexpression of PPAR-γ in both dopaminergic neurons and microglia (139.9% and 121.7% of controls respectively). The administration of rosiglitazone to MPTPp-treated mice counteracted this increase in microglia only, where PPAR-γ overexpression was reverted to control levels (90% of control). Thereafter, we assessed the effect of rosiglitazone on microglia activation through the evaluation of CD11b immunoreactivity, and production of the proinflammatory cytokine TNF-α. Chronic MPTPp progressively increased CD11b expression, conferring to microglia a morphology classified as highly activated state, based on Kreutzberg classification (1996). Moreover, TNF-α levels were increased in microglia (457.38% of control) by chronic neurotoxin treatment. Co-administration of rosiglitazone with MPTPp increased CD11b expression as compared with vehicle, although to a lesser extent than MPTPp alone. Moreover, rosiglitazone reverted the MPTP-induced increase of TNF-α expression to control levels. Nigrostriatal degeneration was assessed in the striatum and SNc. Chronic MPTPp treatment caused a severe decline of striatal dopamine/DOPAC content, and a partial degeneration of TH-positive neurons in the SNc (30% of control). Administration of rosiglitazone to MPTPp-treated mice from the fourth treatment-week arrested the degenerative process in both areas. Results suggest that PPAR-γ expressed in microglia, are a main target in rosiglitazone-mediated neuroprotection in PD, that may occur by reduction of the inflammatory cyitokine TNF-α production by these cells.