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Activation of the Adenosine A₁ Receptor Inhibits HIV-1 Tat-Induced Apoptosis by Reducing Nuclear Factor-B Activation and Inducible Nitric-Oxide Synthase

Departments of Pharmacology (S.J., D.M., K.A.J., V.R.), Medicine (A.M.), and Surgery (D.M., L.P.R.), Southern Illinois University School of Medicine, Springfield, Illinois; Department of Pharmacology, Georgetown University Medical Center, Washington, DC (S.C.P.); and Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York (L.F.S., S.B.M.)

Human immunodeficiency virus dementia (HIV-D) is a nonfocal central nervous system manifestation characterized by cognitive, behavioral, and motor abnormalities. The pathophysiology of neuronal damage in HIV-D includes a direct toxic effect of viral proteins on neuronal cells and an indirect effect caused by the release of inflammatory mediators and neurotoxins by activated macrophages/microglia and astrocytes, culminating into neuronal apoptosis. Previous studies have documented that the nucleoside adenosine mediates neuroprotection by activating adenosine A₁ receptor subtype (A₁AR) linked to suppression of neuronal excitability. In this study, we show that A₁AR activation protects against HIV-1 Tat-induced toxicity in primary cultures of rat cerebellar granule neurons and in rat pheochromocytoma (PC12) cell. In PC12 cells, HIV-1 Tat increased [Ca²⁺]_i levels, release of nitric oxide (NO), and expression of inducible nitric-oxide synthase (iNOS) and A₁AR. Activation of A₁AR suppressed Tat-mediated increases in [Ca²⁺]_i and NO. Furthermore, A₁AR agonists inhibited iNOS expression in a nuclear factor-B (NF-B)-dependent manner. It is noteworthy that activation of the A₁AR or inhibition of NOS protected against Tat-induced apoptosis in PC12 cells and cerebellar granule cells. Moreover, activation of the A₁AR-inhibited Tat-induced increases in the levels of proapoptotic proteins Bax and caspase-3. Taken together, our results demonstrate that the A₁AR protects against HIV-1 toxicity by inhibiting NF-B, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.

Address correspondence to: Dr. Vickram Ramkumar, Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9629. E-mail: vramkumar{at}siumed.edu