Abstract
Poly(ADP-ribose) polymerase (PARP) activity has been implicated in the pathogenesis of several central nervous system (CNS) disorders. For example, the presence of extensive poly(ADP)ribosylation in CNS tissues from animals with experimental allergic encephalomyelitis (EAE) indicates that PARP activity may be involved in this inflammatory disease process. Using PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl], a selective PARP inhibitor, we studied the mechanisms through which PARP activity may contribute to the onset of acute EAE. PLSJL mice immunized with myelin antigens were treated with PJ34, and the effects on the progression of EAE and several other parameters relevant to the disease process were assessed. PJ34 exerted therapeutic effects at the onset of EAE that were associated with reduced CNS inflammation and the maintenance of neurovascular integrity. Expression of genes encoding the intercellular adhesion molecule-1 (ICAM-1) and the inflammatory mediators interferon-γ, tumor necrosis factor-α, and inducible nitric-oxide synthase were decreased in CNS tissues from drug-treated animals. Administration of PJ34 biased the class of myelin basic protein (MBP)-specific antibodies elicited from IgG2a to IgG1 and IgG2b and modulated antigen-specific T-cell reactivity. Therefore, the mode of action of PJ34 at the onset of EAE is likely mediated by a shift in the MBP-specific immune response from a proinflammatory Th1 toward an anti-inflammatory Th2 phenotype.
Footnotes
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This work was supported by a grant from the National Institutes of Health (R43NS42389) to C.S. and, in part, by a grant from the National Multiple Sclerosis Society (RG 2896A8/5) to D.C.H.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.103.063214.
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ABBREVIATIONS: EAE, experimental allergic encephalomyelitis; CNS, central nervous system; PARP, poly(ADP-ribose) polymerase; PJ34, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl; BBB, blood-brain barrier; MBP, myelin basic protein; CFA, complete Freund's adjuvant; PBS, phosphate-buffered saline; RT-PCR, reverse transcription-polymerase chain reaction; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; iNOS, inducible nitric-oxide synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; APC, antigen-presenting cells; ELISA, enzyme-linked immunosorbent assay.
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↵1 Current address: Department of Biochemical Pharmacology, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, UK, EC1M 6BQ.
- Received November 19, 2003.
- Accepted May 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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