Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery

ABSTRACT Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days and weeks following injury leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD + ), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD + -dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD + depletion propagates tissue damage. Augmenting NAD + by exogenous application of NAD + , its synthesizing enzymes or its cellular precursors mitigates tissue damage. Among the NAD + precursors, nicotinamide riboside (NR) appears to be particularly well-suited for clinical translation. It safely and effectively augments cellular NAD + synthesis in a variety of species, including rats and humans, and in a variety of preclinical models, elicits tissue protection. Evidence of NR’s efficacy in the context of SCI repair, however, is currently lacking. These studies tested the hypothesis that administration of NR can effectively enhance NAD + in the injured spinal cord and that augmenting spinal cord NAD + protects spinal cord tissue from injury and leads to improvements in locomotor recovery. The results show that intraperitoneal administration of NR (500 mg/kg), administered four days prior to and two weeks following a mid-thoracic contusion-SCI injury, doubles spinal cord NAD + levels in Long-Evans rats. NR administration preserves spinal cord tissue after injury including neurons and axons, as determined by gray and white matter sparing, and enhances motor function, as assessed by the BBB subscore and missteps on the horizontal ladderwalk. Collectively, the findings demonstrate that administration of the NAD + precursor, NR, to elevate NAD + within the injured spinal cord mitigates the tissue damage and functional decline that occurs following SCI. HIGHLIGHTS Nicotinamide Riboside augments spinal cord nicotinamide adenine dinucleotide (NAD + ). Elevating NAD + protects spinal cord tissue from spinal cord injury (SCI). Elevating NAD + enhances motor recovery following SCI.