Nicotinamide mononucleotide elevates NAD+ to protect spinal cord tissue from injury and reduces inflammatory response to promote motor recovery

Spinal Cord Injury (SCI) induces localized tissue damage that extends to neighboring cells and tissues within hours, days, or even weeks, exacerbating the severity of the injury. During the progressive aggravation of the injury, intracellular Nicotinamide adenine dinucleotide (NAD+) levels rapidly decline. NAD + is a crucial coenzyme involved in various physiological processes, particularly energy metabolism, and plays a vital role in tissue repair. Depletion of NAD+ adversely affects and amplifies tissue damage. Exogenous supplementation of NAD+ precursors and other means can increase NAD+ levels. Nicotinamide mononucleotide (NMN), a direct precursor of NAD+, has demonstrated safety and efficacy in enhancing NAD+ content and protecting tissues in preclinical and clinical studies. However, there is still limited evidence regarding the neuroprotective effects of NMN in spinal cord injury. In this study, we propose the hypothesis that NMN can elevate NAD+ levels, safeguard spinal cord tissues, attenuate post-injury inflammatory responses, and promote motor recovery. Our findings revealed that intraperitoneal injection of NMN (500 mg/kg) immediately after moderate contusion-type spinal cord injury and daily for 7 consecutive days significantly raised NAD+ levels in mouse spinal cord tissues. Histological evaluation using paraffin hematoxylin-eosin staining of spinal cord vacuole area and immunofluorescence staining of neuron count and fluorescence intensity demonstrated that NMN administration reduced the vacuole area in spinal cord tissues and increased the number of neurons, thereby safeguarding the spinal cord tissues. Improved motor function was indicated by BMS score, gait coordination analysis, grip strength assessment, and baton transfer endurance assessment. Transcriptome sequencing, qRT-PCR, protein microarray, and ELISA results collectively suggest that NMN may exert neuroprotective effects by reducing inflammatory responses. Furthermore, Western Blot analysis indicated that this effect may be mediated via the NF-κB pathway. In conclusion, these findings suggest that NMN, an NAD⁺ precursor, increases NAD⁺ levels in injured spinal cord tissue. NMN alleviates tissue injury and exerts neuroprotective effects, potentially suppressing neuroinflammation in an NF-κB pathway-dependent manner, thereby promoting locomotor recovery after SCI.