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Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection¹

Farshid Noorbakhsh^*,, Nathalie Vergnolle, Justin C. McArthur, Claudia Silva^*, Mohammed Vodjgani, Patricia Andrade-Gordon^¶, Morley D. Hollenberg and Christopher Power^2,*

Departments of^* Clinical Neurosciences and Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada; Department of Neurology, Johns Hopkins University, Baltimore, MD 21218; Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran; and ^¶ Johnson & Johnson Pharmaceutical Research and Development, Spring House, PA 19477

Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF- and IL-1 were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF- protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF- were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

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