Matrix Metalloproteinase-9 Is Elevated in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism in Mice

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading components of the extracellular matrix. Recent evidence has implicated MMPs in the pathogenesis of neurodegenerative diseases as Alzheimer's disease and amyotrophic lateral sclerosis. In this study, we investigated the involvement of MMP-9 (gelatinase B) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease using zymography, immunohistochemistry, and Western blot analysis. The activity of MMP-9 was upregulated at 3 h after MPTP injection in the striatum and after 24 h in the substantia nigra. Although MMP-9 expression decreased in the striatum by 72 h, it remained elevated in the substantia nigra compared to controls up to 7 d after MPTP administration. Immunohistochemistry showed that neurons and microglia are the source of MMP-9 expression after MPTP administration to mice. Treatment with a hydroxamate-based MMP inhibitor, Ro 28-2653 significantly reduced dopamine depletion and loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. MMP-9 expression as measured via zymography in the substantia nigra was reduced by the MMP inhibitor. These results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

“…Altered gelatinase expression in the SN of post-mortem brains of PD patients was first reported by Lorenzl et al (2002), according to whom no alteration in MMP-9 protein and activity levels were observed compared to age-matched controls. Later on, the same authors reported an increase in MMP-9 mRNA, protein, and activity levels in the SN and striatum of pools of MPTP-treated mice (Lorenzl et al 2004), although these data were not detailed in terms of postinjection times, and lacked a proper quantitative/qualitative evaluation of the type/s of cells in which MMP-9 expression was modulated. According to our data, MMP-9 indeed turns out to be highly expressed and modulated in mouse SNpc and striatum from the very first stages of MPTPinduced neuroinflammation, and throughout the 2 weeks period of observation.…”

“…Gelatin zymography is a poorly sensitive and quite variable technique, and the signal we obtained from both SN and striatum was too low to be properly quantified (see also Lorenzl et al 2004 on pools of entire midbrain extracts). In situ zymography, instead, showed that in both brain areas, MPTP treatment elicited an increase in cellular and extracellular fluorescent signal when compared to control (Fig.…”

α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1

“…A number of papers have reported on the role of MMPs in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD), and multiple sclerosis (3)(4)(5). Of these, Parkinson's disease is the second most common neurodegenerative disease and affects ∼1% of the population aged over 65 y (6).…”

“…Several MMPs have been reported to be upregulated postmortem in the substantia nigra of the PD brain (7). Furthermore, it has been reported that MMP-9 is upregulated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice and that its inhibition suppressed the death of dopaminergic neurons (4). In addition, MMP-3 was found to contribute to dopaminergic neuronal cell death by inducing intracellular apoptotic signaling pathways (8).…”

Urokinase-Type Plasminogen Activator Induces BV-2 Microglial Cell Migration Through Activation of Matrix Metalloproteinase-9

“…Recently, uPA-plasmin system has been implicated as a potent activator of matrix metalloproteinase-9 (MMP-9, gelatinase B), a zinc-dependent endopeptidase which contributes to cell invasiveness by the degradation of ECM components [22,34]. Increased activity of this enzyme has been implicated in their beneficial actions, such as axonal growth, myelin formation, and regeneration [12,39], as well as deleterious actions, such as BBB dysfunction, inflammation, neurotoxicity and other CNS disorders including ischemia, AD, Parkinson's disease and MS [8,27,42,43].…”