TY - JOUR T1 - Activation of the Adenosine A<sub>1</sub> Receptor Inhibits HIV-1 Tat-Induced Apoptosis by Reducing Nuclear Factor-κB Activation and Inducible Nitric-Oxide Synthase JF - Molecular Pharmacology JO - Mol Pharmacol SP - 856 LP - 867 DO - 10.1124/mol.106.031427 VL - 72 IS - 4 AU - Sandeep C. Pingle AU - Sarvesh Jajoo AU - Debashree Mukherjea AU - Lynn F. Sniderhan AU - Krishna A. Jhaveri AU - Adriana Marcuzzi AU - Leonard P. Rybak AU - Sanjay B. Maggirwar AU - Vickram Ramkumar Y1 - 2007/10/01 UR - http://molpharm.aspetjournals.org/content/72/4/856.abstract N2 - 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-κB (NF-κB)-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-κB, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis. The American Society for Pharmacology and Experimental Therapeutics ER -