The potent inhibitor of poly(ADP‐ribose) polymerase‐1, 5‐aminoisoquinolinone, promotes autophagy and reduces neural tissue damage and locomotor impairment after spinal cord injury in mice (663.4)

Abstract

Evidence indicate that Poly (ADP‐ribose) Polymerase (PARP) plays an important role in cerebral ischemia/reperfusion, stroke and neurotrauma. Overactivation of PARP consumes NAD+ and ATP culminating in cell dysfunction and necrosis. PARP has also been shown to associate with and regulate the function of several transcription factors. PARP is involved in the up‐regulation of numerous pro‐inflammatory genes that play a pathogenetic role in the later stage of neurotrauma. The aim of this study was to investigate the effects of a potent PARP‐1 inhibitor, 5‐aminoisoquinolinone (5‐AIQ), on secondary inflammatory damage associated with an experimental model of spinal cord injury (SCI). SCI was induced in mice through a spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four‐level T5 to T8 laminectomy, and 5‐AIQ (3 mg/kg, intraperitoneally, 1 and 6 hours after SCI) was injected into mice and once daily thereafter for 10 days. Our results demonstrated that the administration of 5‐AIQ significantly decreased the phosphorylation of the p70S6K protein and led to higher expression levels of LC3 and Beclin 1 in the injured spinal cord. In addition, neuronal loss and cell death in the injured spinal cord were significantly reduced in the 5‐AIQ‐treated mice compared to the vehicle‐treated mice. Furthermore, the 5‐AIQ‐treated mice showed significantly higher locomotor function in Basso Mouse Scale scores than did the vehicle‐treated mice. These results indicate that 5‐AIQ promoted autophagy, and reduced neural tissue damage and locomotor impairment after SCI.