Role of ABT888, a Novel Poly(ADP-Ribose) Polymerase (PARP) Inhibitor in Countering Autophagy and Apoptotic Processes Associated to Spinal Cord Injury.

Accidents are the cause of some 50 deaths per 100,000 population each year; some 3% of these are from traumatic spinal cord injury (SCI), a damage that causes temporary or permanent motor deficits, often leading to permanent neurological alterations. The activation of poly(ADP-ribose) polymerase (PARP) as DNA damage response, together with autophagy and apoptosis processes contributes to the secondary injury processes seen after SCI. Thus, in the present study, a mouse compression model of SCI was used to determine whether the treatment with ABT888, as PARP-1/2 inhibitor, could restore the neuronal damage induced by SCI. Mice were orally administered with ABT888 (at a dose of 25 mg/kg) 1 h and 6 h after SCI induction. Histological analysis, myeloperoxidase (MPO) activity, and Basso Mouse scale (BMS) were performed. The expression of autophagy-related proteins and apoptosis-inducing factors was quantified in the cytosolic fraction from spinal cord tissue collected after 24 h after SCI. TUNEL assay was performed in SCI-tissues 24 h after damage. ABT888 treatment significantly reduced histological damage and neutrophilic infiltration, improving motor skills. PARP-1/2 inhibition by ABT888 slowed cell death, decreasing autophagy-activation proteins. These results showed that ABT888, inhibiting PARP-1/2 activity, through a reduction in the apoptosis-autophagy machinery, plays a protective role after SCI, suggesting a new insight into the potential application of ABT888 as novel candidate in SCI therapies.