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

Background: Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NM-1R, provides protection in ALS is not known. Results: L-NAT delays disease onset and mortality in mSOD1(G93A) ALE mice by inhibiting mitochondrial cell death pathways, inflammation, and NM-1R downregulation. Conclusion: L-NAT offers protection in a mouse model of ALS. Significance: Data 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 NM-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 mSOD1(G93A) 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 Bc1-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 NM-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NM-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALE. (C) 2015 Elsevier Inc. All rights reserved.