Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blood-brain barrier (BBB) disruption occurs during human immunodeficiency virus encephalopathy, but the mechanisms involved are not understood. We studied how acute and ongoing exposure to human immunodeficiency virus 1 envelope gp120 alters BBB structure and permeability. Intravenous Evans blue, given before stereotaxic gp120 injection into the caudate putamen of rats, was rapidly extravasated. Gelatinolytic activity, studied by in situ zymography, was increased after gp120 administration and was localized within cerebral vessel walls. The gp120 increased the expression of matrix metalloproteinases (MMPs) 2 and 9. Laminin and claudin-5, key BBB components and targets of both MMPs, were greatly reduced upon gp120 administration. The gp120 increased lipid peroxidation in the vascular endothelium and in neurons. Prior administration of rSV40 vectors carrying the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase protected from gp120-induced BBB damage. N-methyl-D-aspartate receptor activation upregulated pro-MMP-9 and increased MMP-9 gelatinase activity, and memantine, an N-methyl-D-aspartate receptor blocker, mitigated gp120-induced BBB abnormalities. Using intra-caudate putamen SV(gp120) to test the effects of chronic exposure to expressed gp120, we determined that oxidant stress and increased BBB permeability occurred as in acute exposure. These data indicate that both direct administration and cellular expression of gp120 lead to disruption of the BBB by increasing MMPs and reducing vascular tight junction proteins via mechanisms involving reactive oxygen species generation and oxidant injury.
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PMID:HIV-1 gp120-induced injury to the blood-brain barrier: role of metalloproteinases 2 and 9 and relationship to oxidative stress. 2061 38

Matrix metalloproteinases (MMPs) are implicated in diverse processes, such as neuroinflammation, leakiness of the blood-brain barrier (BBB) and direct cellular damage in neurodegenerative and other CNS diseases. Tissue destruction by MMPs is regulated by their endogenous tissue inhibitors (TIMPs). TIMPs prevent excessive MMP-related degradation of extracellular matrix components. In a rat model of human immunodeficiency virus (HIV)-related encephalopathy, we described MMP-2 and MMP-9 upregulation by HIV-1 envelope gp120, probably via gp120-induced reactive oxygen species. Antioxidant gene delivery blunted gp120-induced MMP production. We also studied the effect of gp120 on TIMP-1 and TIMP-2 production. TIMP-1 and TIMP-2 levels increased 6 h after gp120 injection into rat caudate-putamen (CP). TIMP-1 and TIMP-2 colocalized mainly with neurons (92 and 95%, respectively). By 24 h, expression of these protease inhibitors diverged, as TIMP-1 levels remained high but TIMP-2 subsided. Gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase or glutathione peroxidase into the CP before injecting gp120 there reduced levels of gp120-induced TIMP-1 and TIMP-2, recapitulating the effect of antioxidant enzymes on gp120-induced MMP-2 and MMP-9. A significant correlation was observed between MMP/TIMP upregulation and BBB leakiness. Thus, HIV-1 gp120 upregulated TIMP-1 and TIMP-2 in the CP. Prior antioxidant enzyme treatment mitigated production of these TIMPs, probably by reducing MMP expression.
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PMID:HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy. 2209 73