Targeting the PARP1-p53 Axis Could Mitigate Necrotic-Apoptotic Signaling and Secondary Neurodegeneration After Spinal Cord Injury.

Overactivation of poly(ADP-ribose) polymerase 1 (PARP1) contributes to secondary injury after spinal cord injury (SCI) by promoting energy depletion and necrotic cell death. Although PARP1 inhibitors have shown neuroprotective effects, their functional benefits remain modest, and the underlying reasons are poorly understood. This study was conducted in two phases using a rat contusion SCI model. Phase I evaluated a biphasic intraperitoneal dosing regimen of the PARP1 inhibitor 3-aminobenzamide (3-AB), based on the temporal profile of PARP1 activation, through behavioral and histological assessments. As only insignificant improvement was observed, phase II employed a reverse translational approach to investigate the molecular basis of this limited efficacy. Western blot analysis was performed following intraparenchymal administration of 3-AB alone or combined with the p53 inhibitor pifithrin-µ (PFT-µ) to examine proteins associated with necrotic and apoptotic signaling. Phase I showed only modest, statistically insignificant improvements in locomotor recovery and tissue preservation with 3-AB treatment. Phase II demonstrated that PARP1 inhibition alone was associated with increased p53-mediated apoptotic signaling, whereas combined PARP1 and p53 inhibition more effectively reduced such apoptotic signaling by perturbing apoptosis-inducing factor translocation, cytochrome c release, and caspase-dependent apoptotic activation. These findings indicate that dual inhibition suppresses injury-associated cell death pathways more effectively than PARP1 inhibition alone. These findings suggest that interactions between PARP1 and p53 signaling may limit the therapeutic efficacy of PARP1-inhibition monotherapy after SCI and support further investigation of combined PARP1 and p53 inhibition as a potential therapeutic strategy.