Aim: 

Matrix metalloproteinases (MMPs) play a role in several brain pathologies associated with neuroinflammatory events. However, their involvement in the molecular pathways leading to the progression of a parkinsonian phenotype, characterized by nigro-striatal neuron degeneration and a microglia-mediated inflammatory reaction in the substantia nigra (SN) and striatum, is still unknown.

Methods: 

We investigated changes in mRNA expression, protein level and cellular localization of metalloproteinase-9 (MMP-9), a member of MMPs expressed in brain and up-regulated in several pathological conditions, in the striatum and SN of 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP)-injected mice. C57/Bl6 mice were acutely injected with MPTP (80 mg/kg b.w.) and killed after 1, 24, 48 and 72 h, 1 and 2 wk.

Results: 

MMP-9 mRNA level increase significantly, compared to control (saline-injected mice), in both SN and striatum early after (24-48h) last MPTP injection, successively returning to control level, or lower. Similarly, protein levels of both pro- and active MMP-9 increase significantly 1 h (striatum) and 24 h (SN) after MPTP injection, remaining higher than control. Co-immunolabeling on brain cryosections of MMP-9 and different cell specific markers (NeuN: neurons; GFAP: astrocytes; F4/80: activated microglia; BMP: oligodendrocytes) shows that, in both control and MPTP-injected mice, MMP-9 is mainly localized in cell bodies and axons of nigro-striatal neurons. Only a minor component of astrocytes and activated microglia (control and MPTP-injected mice) and oligodendrocytes (MPTP-injected mice) shows puncta of MMP-9 immunopositivity.

Conclusion: 

We, therefore, hypothesize that MMP-9 secreted primarily, although not exclusively, by reactive/dying neurons, may play a role in the early response to MPTP administration, which consists in the retraction/degeneration of dopaminergic neuron axons in the striatum and inflammatory glia activation, and at later stages in the axonal regeneration of survived neurons.