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Molecular Pharmacology

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Research ArticleArticle

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

Sandeep C. Pingle, Sarvesh Jajoo, Debashree Mukherjea, Lynn F. Sniderhan, Krishna A. Jhaveri, Adriana Marcuzzi, Leonard P. Rybak, Sanjay B. Maggirwar and Vickram Ramkumar
Molecular Pharmacology October 2007, 72 (4) 856-867; DOI: https://doi.org/10.1124/mol.106.031427
Sandeep C. Pingle
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Sarvesh Jajoo
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Debashree Mukherjea
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Lynn F. Sniderhan
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Krishna A. Jhaveri
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Adriana Marcuzzi
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Leonard P. Rybak
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Sanjay B. Maggirwar
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Vickram Ramkumar
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Abstract

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.

Footnotes

  • This work was supported from the Southern Illinois University School of Medicine Excellence in Academic Medicine Award (to V.R.) and National Institutes of Health grants DC02396 (to L.P.R.), NS054578 (to S.B.M.), and T32-AI49105 (to L.F.S.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.031427.

  • ABBREVIATIONS: HIV-D, human immunodeficiency virus-dementia; A1AR, adenosine A1 receptor; iNOS, inducible nitric-oxide synthase; NF-κB, nuclear factor κB; PC12 cells, pheochromocytoma 12 cells; CGN, cerebellar granule neuron; R-PIA, R-phenylisopropyladenosine; DPCPX, 8-cyclopentyl-1,3-di[2′,3′-3H] propylxanthine; AR, adenosine receptor; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; bp, base pair; EMSA, electrophoretic mobility shift assay; GAPDH, glyceraldehyde phosphate dehydrogenase; AP-1, activator protein-1; FITC, fluorescein isothiocyanate; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; AM, acetoxymethyl ester; l-NAME, NG-nitro-l-arginine methyl ester; SNAP, S-nitroso-N-acetylpenicillamine; C-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; OCT-1, octamer transcription factor-1; DAF-2 DA, 4,5-diaminofluorescein diacetate; CHAPS, 3-[(3-cholamidopropyl) dimethylammonio]-1 propanesulfonate; ZM241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a] [1,3,5] triazin-5-ylamino]ethyl) phenol; MRS1220, N-(9-chloro-2-(2-furanyl)[1,2,4]-triazolol[1,5-c]quinazolin-5-benzeneacetamide; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; CGS21680, 4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl] benzenepropanoic acid.

    • Received October 4, 2006.
    • Accepted June 26, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (4)
Molecular Pharmacology
Vol. 72, Issue 4
1 Oct 2007
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Research ArticleArticle

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

Sandeep C. Pingle, Sarvesh Jajoo, Debashree Mukherjea, Lynn F. Sniderhan, Krishna A. Jhaveri, Adriana Marcuzzi, Leonard P. Rybak, Sanjay B. Maggirwar and Vickram Ramkumar
Molecular Pharmacology October 1, 2007, 72 (4) 856-867; DOI: https://doi.org/10.1124/mol.106.031427

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Research ArticleArticle

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

Sandeep C. Pingle, Sarvesh Jajoo, Debashree Mukherjea, Lynn F. Sniderhan, Krishna A. Jhaveri, Adriana Marcuzzi, Leonard P. Rybak, Sanjay B. Maggirwar and Vickram Ramkumar
Molecular Pharmacology October 1, 2007, 72 (4) 856-867; DOI: https://doi.org/10.1124/mol.106.031427
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