JPET # 76711 1 Inhibitors of poly ( ADP - ribose ) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma

Poly(ADP-ribose) polymerase, (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with stroke and neurotrauma. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity) and apoptosis (measured by TUNEL coloration). Infiltration of spinal cord tissue with neutrophils was associated with a marked increase in immunoreactivity for PAR, index of PARP activation, in the spinal cord tissue. These inflammatory events were associated with the activation of nuclear factor-κB (NF-κB) at 4h after spinal cord damage. Treatment of the mice with the PARP inhibitors, 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) PAR formation, (3) neutrophil infiltration and (4) apoptosis. Treatment with these PARP inhibitors also reduced DNA binding of NF-κB and of IκB-α degradation. In a separate set of experiments we have also demonstrated that PARP inhibitors significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events associated with spinal cord trauma. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on September 27, 2004 as DOI: 10.1124/jpet.104.076711 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from