N‐acetyl‐ l ‐tryptophan, but not N‐acetyl‐ d ‐tryptophan, rescues neuronal cell death in models of amyotrophic lateral sclerosis

作者：Ana C. Sirianni, Jiying Jiang, Jiang Zeng, Lilly L. J. Mao, Shuanhu Zhou, Peter E. Sugarbaker, Xinmu Zhang, Wei Li, Robert M. Friedlander, Xin Wang · 发表于：Journal of Neurochemistry · 年份：2015 · DOI：10.1111/jnc.13190 · 被引用次数：51 · 研究领域：Amyotrophic Lateral Sclerosis Research、Cholinesterase and Neurodegenerative Diseases、Alzheimer's disease research and treatments

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss. Evidence suggests that mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, glutamate excitotoxicity, and proteasomal dysfunction are all responsible for ALS pathogenesis. N-acetyl-tryptophan has been identified as an inhibitor of mitochondrial cytochrome c release and therefore is a potential neuroprotective agent. By quantifying cell death, we demonstrate that N-acetyl-l-tryptophan (L-NAT) and N-acetyl-DL-tryptophan are neuroprotective in NSC-34 motor neuron-like cells and/or primary motor neurons, while their isomer N-acetyl-d-tryptophan has no protective effect. These findings are consistent with energy minimization and molecular modeling analysis, confirming that L-NAT generates the most stable complex with the neurokinin-1 receptor (NK-1R). L-NAT inhibits the secretion of Substance P and IL-1β (Enzyme-Linked Immunosorbent Assay and/or dot blots) and mitochondrial dysfunction by effectively inhibiting the release of cytochrome c/Smac/AIF from mitochondria into the cytoplasm and activation of apoptotic pathways, including the activation of caspase-1, -9, and -3, as well as proteasomal dysfunction through restoring chymotrypsin-like, trypsin-like, and caspase-like proteasome activity. These data provide insight into the molecular mechanisms by which L-NAT offers neuroprotection in models of ALS and suggest its potential as a novel therapeutic ...