Matrix metalloproteinases (MMPs) are involved in neuroinflammatory-based brain pathologies. However, their involvement in Parkinson's disease, characterized by degeneration of dopaminergic (DA) nigro-striatal neurons, is unknown. We investigated, in the striatum and substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP)-injected mice (C57/Bl6), changes in mRNA expression, protein level and cell localization of metalloproteinase-9 (MMP-9), a protease highly expressed in brain and up-regulated in several neuropathologies. In control and MPTP-treated mice, MMP-9 is mainly expressed by neurons. However, early (1-24 h) after MPTP injection, in SN and striatum the number of MMP-9+ microglia, astrocytes and oligodendrocytes increase, consequently to toxin-induced inflammation, along with MMP-9 mRNA and protein levels. Neuroinflammation, oligodendrogliosis and MMP-9 glial expression decline within 2 weeks, although total protein levels remain higher than control. Quantitative immunohistochemical studies on MMP-9 knock-out mice show a decrease in both glia activation and loss of DA neurons and fibers, respect to wild type. We hypothesize that MMP-9 plays a role in MPTP-induced neuroinflammation, emphasizing nigro-striatal neuron degeneration. Observed oligodendrogliosis may be an important, although neglected, aspect in the pathogenesis of Parkinsonism, suggesting a late role of MMP-9 in axon regeneration of survived neurons. Grants: MIUR; Fund. Seneca; CIBERNED