Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.
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.
Lorenzl
Stefan
S
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA.
Calingasan
Noel
N
Yang
Lichuan
L
Albers
David S
DS
Shugama
Shuei
S
Gregorio
Jason
J
Krell
H W
HW
Chirichigno
Jason
J
Joh
Tong
T
Beal
M Flint
MF
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000503:physiopathology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000201:enzymology* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014446:Tyrosine 3-Monooxygenase; D020780:Matrix Metalloproteinase 9; D004298:Dopamine