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Abstract

Oxidative stress and neuroinflammation are major contributors to the pathophysiology of ALS. Nicotinamide riboside (a NAD⁺ precursor) and pterostilbene (a natural antioxidant) were efficacious in a human pilot study of ALS patients and in ALS SOD1^G93A transgenic mice. Ibudilast targets different phosphodiesterases and the macrophage migration inhibitory factor, reduces neuroinflammation, and in early-phase studies improved survival and slowed progression in ALS patients. Using two ALS murine models (SOD1^G93A, FUS^R521C) the effects of nicotinamide riboside, pterostilbene, and ibudilast on disease onset, progression and survival were studied. In both models ibudilast enhanced the effects of nicotinamide riboside and pterostilbene on survival and neuromotor functions. The triple combination reduced microgliosis and astrogliosis, and the levels of different proinflammatory cytokines in the CSF. TNFα, IFNγ and IL1β increased H₂O₂ and NO generation by motor neurons, astrocytes, microglia and endothelial cells isolated from ALS mice. Nicotinamide riboside and pterostilbene decreased H₂O₂ and NO generation in all these cells. Ibudilast specifically decreased TNFα levels and H₂O₂ generation by microglia and endothelial cells. Unexpectedly, pathophysiological concentrations of H₂O₂ or NO caused minimal motor neuron cytotoxicity. H₂O₂-induced cytotoxicity was increased by NO via a trace metal-dependent formation of potent oxidants (i.e. OH and ^-OONO radicals). In conclusion, our results show that the combination of nicotinamide riboside, pterostilbene and ibudilast improve neuromotor functions and survival in ALS murine models. Studies on the underlying mechanisms show that motor neuron protection involves the decrease of oxidative and nitrosative stress, the combination of which is highly damaging to motor neurons.

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