NAD supplementation and PARP inhibition following spinal cord injury in mice: Hurdles and considerations for therapeutic use

Abstract

Study design Narrative review and data-based perspectiveObjectives Compare the current literature on poly(ADP-ribose) (PAR) polymerase (PARP) inhibition and NAD+ supplementation in spinal cord injury (SCI) and determine the effectiveness of both treatment paradigms in improving pathophysiological outcomes induced by SCI in mice.Methods Using a spinal cord contusion mouse model, a severe SCI was induced at the L1 spinal level in female C57Bl/6 J mice. 25 mg/kg PARP inhibitor (Veliparib), 750 mg/kg NR, or vehicle was administered intraperitoneally starting at 1 h post-injury (n = 13-18 mice per group), followed by daily treatments up to 8 days post-injury, and every other day thereafter until sacrifice (28 days post-injury). Functional recovery (by Basso Mouse Scale, BMS) and tissue-level effects were evaluated.Results Functional recovery, lesion size (demyelinated (MBP), astrocyte (GFAP), and inflammatory (IBA1) area), and DNA damage load (gamma H2AX and PAR) did not improve with either Veliparib or NR treatment compared to vehicle-treated animals. Moreover, NR treatment decreased survival and increased astrogliosis in SCI mice compared to the vehicle control group.Conclusions Within the experimental paradigm, neither PARP inhibition nor NAD+ supplementation improved major pathophysiological outcomes associated with an SCI. The results are reviewed in the context of previous reports using PARP inhibition or NAD+ supplementation strategies in SCI. At present, caution is recommended when considering these clinical modalities in treating SCI, and priorities to identify the best therapeutic paradigms are presented.