HIV-1 gp120-induced injury to the blood-brain barrier: role of metalloproteinases 2 and 9 and relationship to oxidative stress.
HIV-1 gp120-induced injury to the blood-brain barrier: role of metalloproteinases 2 and 9 and relationship to oxidative stress.
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DOI：
10.1097/nen.0b013e3181e8c96f
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发表时间：
2010-08
影响因子：
3.2
通讯作者：
Strayer DS
中科院分区：
文献类型：
--
作者：
Louboutin JP;Agrawal L;Reyes BA;Van Bockstaele EJ;Strayer DS
Blood-brain barrier (BBB) disruption occurs during HIV encephalopathy but the mechanisms involved are not understood. We studied how acute and ongoing exposure to HIV-1 envelope gp120 alters BBB structure and permeability. Intravenous Evans Blue, given before stereotaxic gp120 injection into the caudate-putamen (CP) of rats, was extravasated rapidly. Gelatinolytic activity, studied by in situ zymography, was increased after gp120 administration and was localized within cerebral vessel walls. gp120 increased 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. 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 (NMDAR) activation upregulated pro-MMP-9 and increases MMP-9 gelatinase activity and memantine, an NMDAR blocker, mitigated gp120-induced BBB abnormalities. Using intra-CP 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.
