The Therapeutic Effects of PJ34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl], a Selective Inhibitor of Poly(ADP-Ribose) Polymerase, in Experimental Allergic Encephalomyelitis Are Associated with Immunomodulation

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-␥, tumor necrosis factor-␣, 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.

Quantitative proteomics and dynamic imaging reveal that G3BP-mediated stress granule assembly is poly(ADP-ribose)-dependent following exposure to MNNG-induced DNA alkylation

“…Multiple PARPs inhibitors [3AB (Durkacz et al, 1980), PJ-34 (Scott et al, 2004) and AG14361 (Veuger et al, 2003)] were tested and gave similar results (data not shown). In addition, HeLa cells exposed to H 2 O 2 (1 mM) had delayed G3BP-mediated SG formation upon PARP inhibition with ABT-888 (supplementary material Fig.…”

Use of a Poly(ADP-Ribose) Polymerase Inhibitor to Suppress Inflammation and Neuronal Death After Cerebral Ischemia-Reperfusion

“…20,[23][24][25][26] PJ34 is one of the most potent inhibitors of PARP-1 developed, 36 and prior studies show that it readily crosses the blood-brain barrier. [37][38][39] Although characterized as a PARP-1 inhibitor, it is likely that this agent also acts on other PARP family members. PJ34 does not have any known effects at other sites, but such effects cannot be excluded.…”

A Key Role for Poly(ADP-Ribose) Polymerase-1 Activity during Human Dendritic Cell Maturation

“…Specifically, the enzyme positively regulates activation of macrophages (8,9,35), microglia (7,36), granulocytes (37), lymphocytes (6,13,14), as well as TNF-␣-challenged endothelial cells (38). Also, parp-1 null mice are resistant to endotoxic shock (39), and PARP-1 inhibitors provide protection in models of pleuritis (40), arthritis (41), asthma (42), colitis (43,44), allergic encephalomyelitis (6,15,45), and other autoimmune disorders (46). In this context, the present findings point to the negative regulation of DCs by PARP-1 inhibitors as a key mechanism through which this class of drugs suppresses the inflammatory response.…”

“…In particular, numerous reports demonstrate that PARP-1 and PAR formation positively regulate transcription in several types of immune cells (4 -7), as well as macrophage activation (8,9), granulocyte migration (10,11), and T cell proliferation (6,12,13). Also, PARP-1 inhibition increases Ab class-switching (14), and alters Ab production during the autoimmune response in the CNS (15). Additional reports underscore the active role of poly ADP-ribosylation in immune activation of microglia and astrocytes (5,7,16).…”