Combination Therapy with Nicotinamide Riboside, Pterostilbene, and Ibudilast Protects Motor Neurons and Prolongs Survival in ALS: Preclinical Findings

Synopsis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by oxidative stress, inflammation, and the progressive death of motor neurons. This study tested a triple therapy combining nicotinamide riboside (NR)—a vitamin B3–derived NAD+ booster, pterostilbene (PT)—a natural antioxidant, and ibudilast—an anti-inflammatory drug that targets specific enzymes and immune factors. In two mouse models of ALS (SOD1G93A and FUSR521C), this combination improved motor function, delayed disease progression, and extended survival more effectively than any treatment alone. The therapy significantly reduced microgliosis and astrogliosis (signs of neuroinflammation) and lowered inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β in spinal fluid. NR and PT reduced harmful reactive oxygen (H₂O₂) and nitric oxide (NO) production in neurons and glial cells, while ibudilast specifically suppressed TNF-α and oxidative stress from microglia. Mechanistically, the treatment prevented the formation of toxic radicals (OH and –OONO) that destroy motor neurons. These results suggest that the NR + PT + ibudilast combination provides synergistic neuroprotection by reducing oxidative and nitrosative stress, offering a promising new multi-target therapy for ALS.

Journal

Neurotherapeutics