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. Nicotinamide riboside (NR) is considered to be one of the most promising NAD⁺ precursors for clinical application due to its ability to safely and effectively boost cellular NAD⁺ synthesis in rats and humans. Moreover, various preclinical studies have demonstrated that NR can provide tissue protection. Despite these promising findings, little is known about the potential benefits of NR in the context of SCI. In the current study, we tested whether NR administration could effectively increase NAD⁺ levels in the injured spinal cord and whether this augmentation of NAD⁺ would promote spinal cord tissue protection and ultimately lead to improvements in locomotor function. Our findings indicate that administering NR (500 mg/kg) intraperitoneally from four days before to two weeks after a mid-thoracic contusion-SCI injury, effectively doubles NAD⁺ levels in the spinal cord of Long-Evans rats. Moreover, NR administration plays a protective role in preserving spinal cord tissue post-injury, particularly in neurons and axons, as evident from the observed gray and white matter sparing. Additionally, it enhances motor function, as evaluated through the BBB subscore and missteps on the horizontal ladderwalk. Collectively, these findings demonstrate that administering NR, a precursor of NAD⁺, increases NAD⁺ within the injured spinal cord and effectively mitigates the tissue damage and functional decline that occurs following SCI.

Keywords: Nicotinamide adenine dinucleotide; Nicotinamide riboside; Spinal cord injury.