Activation of the Adenosine A₁Receptor Inhibits HIV-1 Tat-Induced Apoptosis by Reducing Nuclear Factor-κB Activation and Inducible Nitric-Oxide Synthase

Abstract

Human immunodeficiency virus dementia (HIV-D) is a nonfocalcentral 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 A 1 receptor subtype (A 1 AR) linked to suppression of neuronal excitability. In this study, we show that A 1 AR 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 [Ca 2ϩ ] i levels, release of nitric oxide (NO), and expression of inducible nitric-oxide synthase (iNOS) and A 1 AR. Activation of A 1 AR suppressed Tat-mediated increases in [Ca 2ϩ ] i and NO. Furthermore, A 1 AR agonists inhibited iNOS expression in a nuclear factor-B (NF-B)-dependent manner. It is noteworthy that activation of the A 1 AR or inhibition of NOS protected against Tat-induced apoptosis in PC12 cells and cerebellar granule cells. Moreover, activation of the A 1 AR-inhibited Tat-induced increases in the levels of proapoptotic proteins Bax and caspase-3. Taken together, our results demonstrate that the A 1 AR protects against HIV-1 toxicity by inhibiting NF-B, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.

Adenosine A1Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea

“…Previous studies have indicated that round window application of R-PIA reduced cisplatin-induced hearing loss and hair cell damage (Whitworth et al, 2004). In this study, we showed a similar effect of R-PIA when administered by the trans-tympanic route.…”

“…Additional studies have also shown that the chemotherapeutic agent cisplatin induces the expression of the cochlear A 1 AR, which likely represents a compensatory mechanism by the cochlea to counter the toxic effects of increased ROS generation by cisplatin (Ford et al, 1997b). Activation of A 1 AR was also shown to confer protection of OHCs against cisplatin-induced damage and death and hearing loss (Whitworth et al, 2004;Gunewardene et al, 2013). However, it has been suggested that A 1 ARs are not localized to OHCs, but rather are found on IHCs, Deiter's cells, and spiral ganglion (SG) neurons (Vlajkovic et al, 2009).…”

“…However, it is also possible that protection of the OHCs is mediated indirectly by reductions in cisplatin-induced damage to other regions of the cochlea, such as IHCs, stria vascularis (SVA), SG, or spiral ligament (SL). In addition, a previous study has shown direct inhibition by AR drugs of TRPV1 channels (Puntambekar et al, 2004), which are also expressed on OHCs (Mukherjea et al, 2008). Inhibition of these channels confers protection against cisplatin-induced hearing loss (Mukherjea et al, 2008).…”

“…Phosphorylation could also be mediated by PKC-␦ (Jain et al, 1999) or PKC-(Aziz et al, 2010). A number of studies have implicated ERK1/2 and p38 in cisplatin-mediated damage to the auditory hair cells (Wu et al, 2005;Previati et al, 2007;So et al, 2007;So et al, 2008;Abi-Hachem et al, 2010;Tabuchi et al, 2011). We therefore, hypothesized that cisplatin increases Ser 727 p-STAT1 via the MAPK pathway.…”

“…Adenosine regulates a variety of pathophysiological processes involving neuronal damage or death (Ribeiro et al, 2002) and inflammation (Cronstein, 1994). In recent studies, the activation of ARs on immune cells suppressed the production of proinflammatory mediators, including TNF-␣ (Bouma et al, 1994;Haskó et al, 1996;Sajjadi et al, 1996).…”