期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 34, 期 4, 页码 646-653出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2013.240
关键词
blood brain barrier; human immunodeficiency virus-1; matrix metalloproteinase; peroxisome proliferator-activated receptor; Tat protein; neurotoxicity
资金
- National Institutes of Health [MH063022, MH098891, MH072567, DA027569, CA133257]
- American Heart Association [AHA09POST2060217]
- National Nature Science Foundation of China [81160152, 81371333]
- Guangxi Nature Science Foundation [2013GXNSFCA019013]
- National Center for Research Resources [P20 RR15592]
The strategies to protect against the disrupted blood brain barrier (BBB) in HIV-1 infection are not well developed. Therefore, we investigated the potential of peroxisome proliferator-activated receptor (PPAR) agonists to prevent enhanced BBB permeability induced by HIV-1-specific protein Tat. Exposure to Tat via the internal carotid artery (ICA) disrupted permeability across the BBB; however, this effect was attenuated in mice treated with fenofibrate (PPAR alpha; agonist) or rosiglitazone (PPAR gamma agonist). In contrast, exposure to GW9662 (PPAR gamma antagonist) exacerbated Tat-induced disruption of the BBB integrity. Increased BBB permeability was associated with decreased tight junction (TJ) protein expression and activation of ERK1/2 and Akt in brain microvessels; these effects were attenuated by cotreatment with fenofibrate but not with rosiglitazone. Importantly, both PPAR agonists also protected against Tat-induced astrogliosis and neuronal loss. Because disruption of TJ integrity has been linked to matrix metalloproteinase (MMP) activity, we also evaluated Tat-induced effects in MMP-9-deficient mice. Tat-induced cerebrovascular toxicity, astrogliosis, and neuronal loss were less pronounced in MMP-9-deficient mice as compared with wild-type controls and were further attenuated by PPAR agonists. These results indicate that enhancing PPAR activity combined with targeting MMPs may provide effective therapeutic strategies in brain infection by HIV-1.
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