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

Abstract

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 strategy for ALS. We demonstrate that L-NAT (N-acetyl-l-tryptophan), but not D-NAT, rescues NSC-34 cells and primary motor neurons from cell death. L-NAT inhibits the secretion of Substance P and IL-1β, and caspase-1 activation, the release of cytochrome c/Smac/AIF, and the activation of caspase -9, and -3, as well as proteasomal dysfunction. The data suggest the potential of L-NAT as a novel therapeutic strategy for amyotrophic lateral sclerosis (ALS). AIF, apoptosis-inducing factor.

• Authors: Ana C Sirianni, Jiying Jiang, Jiang Zeng, Lilly L Mao, Shuanhu Zhou, Peter Sugarbaker, Xinmu Zhang, Wei Li, Robert M Friedlander, Xin Wang
• Journal: Journal of neurochemistry (J Neurochem) Vol. 134 Issue 5 Pg. 956-68 (Sep 2015) ISSN: 1471-4159 [Electronic] England
• PMID: 26031348 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 International Society for Neurochemistry.

Chemical References

• Interleukin-1beta
• Neurokinin-1 Receptor Antagonists
• Neuroprotective Agents
• Receptors, Neurokinin-1
• Substance P
• N-acetyltryptophan
• Tryptophan
• Cytochromes c
• Caspases
• Proteasome Endopeptidase Complex

Topics

• Amyotrophic Lateral Sclerosis (pathology)
• Animals
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line
• Cytochromes c (metabolism)
• Drug Evaluation, Preclinical
• Hybrid Cells
• Interleukin-1beta (metabolism)
• Mice
• Mitochondria (drug effects)
• Motor Neurons (drug effects, pathology)
• Neurokinin-1 Receptor Antagonists (pharmacology)
• Neuroprotective Agents (pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Receptors, Neurokinin-1
• Stereoisomerism
• Substance P (metabolism)
• Tryptophan (analogs & derivatives, pharmacology)