N-acetyl-l-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model

Abstract

BackgroundWhether l-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known. Resultsl-NAT delays disease onset and mortality in mSOD1G93A ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation. Conclusionl-NAT offers protection in a mouse model of ALS. SignificanceData suggest the potential of l-NAT as a novel therapeutic strategy for ALS and provide insight into its action mechanisms.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, while inflammation has been implicated in its pathogenesis. Both inhibitors of cytochrome c release and antagonists of the neurokinin 1 receptor (NK-1R) have been reported to provide neuroprotection in ALS and/or other neurodegenerative diseases by us and other researchers. However, whether N-acetyl-l-tryptophan (l-NAT), an inhibitor of cytochrome c release and an antagonist of NK-1R, provides neuroprotection in ALS remains unknown. Here we demonstrate that the administration of l-NAT delayed disease onset, extended survival, and ameliorated deteriorations in motor performance in mSOD1G93A ALS transgenic mice. Our data showed that l-NAT reached the spinal cord, skeletal muscle, and brain. In addition, we demonstrate that l-NAT reduced the release of cytochrome c/smac/AIF, increased Bcl-xL levels, and inhibited the activation of caspase-3. l-NAT also ameliorated motor neuron loss and gross atrophy, and suppressed inflammation, as shown by decreased GFAP and Iba1 levels. Furthermore, we found gradually reduced NK-1R levels in the spinal cords of mSOD1G93A mice, while l-NAT treatment restored NK-1R levels. We propose the use of l-NAT as a potential therapeutic invention against ALS.