Received for publication October 5, 2006.
Revised June 26, 2007.
Accepted for publication June 26, 2007.

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

Abstract

HIV dementia (HIV-D) is a non-focal 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 due to 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 intracellular Ca²⁺ ([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. Further, A₁AR agonists inhibited iNOS expression in an NF-B dependent manner. Importantly, 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.

Key words: Adenosine, Purinergic, Nitric oxide, Nitric oxide synthases, Gi family, IP3/DAG, NFkappaB, Ca imaging, Receptor binding studies, Regulation of gene expression