Inhibitors of poly(ADP‐ribose) polymerase‐1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats

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. 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‐1β and ‐2, cyclooxygenase‐2, tumour necrosis factor‐α and interferon‐γ 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. 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‐κB and AP‐1 and transcription of pro‐inflammatory cytokines such as interleukin‐2, interferon‐γ and tumour necrosis factor‐α. Notably, benzoic acid did not reproduce the in vivo and in vitro effects of its parent compound. 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.British Journal of Pharmacology (2002) 137 , 761–770. doi: 10.1038/sj.bjp.0704934