J Pharmacol Exp Ther. 2004 May 24
Scott GS, Kean RB, Mikheeva T, Fabis MJ, Mabley JG, Szabo C, Hooper DC.
Queen Mary's School of Medicine and Dentistry.
Poly(ADP-ribose) polymerase (PARP) activity has been implicated in the pathogenesis of several 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, 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 adhesion molecule ICAM-1, and the inflammatory mediators IFN-gamma, TNF-alpha and iNOS 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 pro-inflammatory Th1 towards an anti-inflammatory Th2 phenotype.