Inhibition of matrix metalloproteinases ameliorates blood-brain barrier disruption and neuropathological lesions caused by avirulent Semliki Forest virus infection.
Semliki Forest virus (SFV) infection of mice is a useful model of viral neuropathogenesis in animals and avirulent strains such as SFV-A7 induce immune-mediated demyelination and death of neurones by necrosis and apoptosis. Matrix metalloproteinases (MMPs) have been implicated in various diseases including arthritis and cancer in many species. In this report, we show that MMP-2 and MMP-9 expression is induced in the brains of mice infected i.n. with SFV-A7. Treatment of mice with the pan MMP inhibitor GM6001 ameliorated the development of SFV-induced neuropathological lesions via an effect on the integrity of the blood-brain barrier. Low levels of neuronal necrosis and demyelination in GM6001-treated mice correlated with localisation of fibrinogen staining to thin-walled blood vessels and less intense staining of the perivascular neuropil.
Keogh
Brian
B
Immune Regulation Research Group, Biochemistry Department, Trinity College, Dublin 2, Ireland.
Sheahan
Brian J
BJ
Atkins
Gregory J
GJ
Mills
Kingston H G
KH
D018354:Alphavirus Infections / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology*; D015153:Blotting, Western; D002493:Central Nervous System Diseases / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005340:Fibrinogen / Q000276:immunology; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D012672:Semliki forest virus / Q000276:immunology*
D004151:Dipeptides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D005340:Fibrinogen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9