Br J Pharmacol 2002 Nov 6;137(6):761-770
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. Department of Cellular and Molecular Physiology, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.
1 In the presence of genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1) leads to NAD(+) and ATP depletion, participating in the pathogenesis of several disorders including inflammation.
Accordingly, chemical inhibitors of PARP-1 are efficacious anti-inflammatories, albeit the underlying molecular mechanisms are still under debate.
2 This study investigated the effect of the PARP-1 inhibitors 6(5H)-phenanthridinone and benzamide as well as that of benzoic acid, an inactive analogue of benzamide, on development of experimental allergic encephalomyelitis (EAE) in rats.
Both 6(5H)-phenanthridinone and benzamide attenuated development of EAE, reducing clinical score, neuroimmune infiltration and expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin-1beta and -2, cyclooxygenase-2, tumour necrosis factor-alpha and interferon-gamma in the spinal cord of myelin-immunized rats.
Importantly, no evidence of NAD(+) and ATP depletion as well as poly(ADP-ribose) formation was detected in the spinal cord.
3 By contrast, a robust formation of poly(ADP-ribose) occurred in B- and T-cell areas in lymph nodes of myelin-immunized rats and was suppressed by the treatment with 6(5H)-phenanthridinone and benzamide.
In cultures of activated rat lymphocytes, 6(5H)-phenanthridinone and benzamide reduced the DNA-binding activity of NF-kappaB and AP-1 and transcription of pro-inflammatory cytokines such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha.
4 Notably, benzoic acid did not reproduce the in vivo and in vitro effects of its parent compound.
5 These findings indicate that PARP-1 promotes transcriptional activation in lymphocytes and inhibitors of its enzymatic activity are useful for the treatment of autoimmune disorders of the central nervous system.