Activation of the adenosine A1 receptor inhibits HIV-1 tat-induced apoptosis by reducing nuclear factor-kappaB activation and inducible nitric-oxide synthase.
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 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(2+)](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(2+)](i) and NO. Furthermore, A(1)AR agonists inhibited iNOS expression in a nuclear factor-kappaB (NF-kappaB)-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-kappaB, thereby reducing the expression of iNOS and NO radicals and neuronal apoptosis.
Pingle
Sandeep C
SC
Department of Pharmacology, Southern Illinois University School of Medicine, PO Box 19629, Springfield, IL 62794-9629, USA.
Jajoo
Sarvesh
S
Mukherjea
Debashree
D
Sniderhan
Lynn F
LF
Jhaveri
Krishna A
KA
Marcuzzi
Adriana
A
Rybak
Leonard P
LP
Maggirwar
Sanjay B
SB
Ramkumar
Vickram
V
D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D058907:Adenosine A1 Receptor Agonists; D015696:Gene Products, tat; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II