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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

Ian Popoff, Humberto Jijon, Brett Monia, Michele Tavernini, Michael Ma, Rob McKay and Karen Madsen
Journal of Pharmacology and Experimental Therapeutics December 2002, 303 (3) 1145-1154; DOI: https://doi.org/10.1124/jpet.102.039768
Ian Popoff
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Humberto Jijon
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Brett Monia
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Michele Tavernini
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Michael Ma
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Rob McKay
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Karen Madsen
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Abstract

poly(ADP-ribose) polymerase-2 (PARP-2) is a newly described member of the PARP family of nuclear enzymes. Previous studies have shown pharmacological inhibition of PARP activity to have a beneficial role in attenuating inflammation. We developed a chemically modified 2′-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 110251) inhibitor of PARP-2 and tested it for efficacy in the interleukin (IL)-10-deficient mouse. In tissue culture, ISIS 110251 reduced PARP-2 mRNA expression in a concentration- and sequence-specific manner. In 129 Sv/Ev mice, ISIS 110251 reduced PARP-2 mRNA in liver by 80%. This reduction was dependent upon treatment duration and was independent of the method of delivery. In interleukin-10-deficient mice with established colitis, treatment with ISIS 110251 normalized colonic epithelial barrier and transport function, reduced proinflammatory cytokine secretion and inducible nitric-oxide synthase activity, and attenuated inflammation. Our data demonstrate that selective inhibition of PARP-2 activity results in a marked improvement of colonic inflammatory disease in a mouse model of chronic colitis and a normalization of colonic function.

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Journal of Pharmacology and Experimental Therapeutics: 303 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 3
1 Dec 2002
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

Ian Popoff, Humberto Jijon, Brett Monia, Michele Tavernini, Michael Ma, Rob McKay and Karen Madsen
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1145-1154; DOI: https://doi.org/10.1124/jpet.102.039768

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Antisense Oligonucleotides to poly(ADP-ribose) Polymerase-2 Ameliorate Colitis in Interleukin-10-Deficient Mice

Ian Popoff, Humberto Jijon, Brett Monia, Michele Tavernini, Michael Ma, Rob McKay and Karen Madsen
Journal of Pharmacology and Experimental Therapeutics December 1, 2002, 303 (3) 1145-1154; DOI: https://doi.org/10.1124/jpet.102.039768
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