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

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 pathogenes...

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Published in:Journal of neurochemistry 2015-09, Vol.134 (5), p.956-968
Main Authors: Sirianni, Ana C., Jiang, Jiying, Zeng, Jiang, Mao, Lilly L., Zhou, Shuanhu, Sugarbaker, Peter, Zhang, Xinmu, Li, Wei, Friedlander, Robert M., Wang, Xin
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - pathology
Animals
Apoptosis
Apoptosis - drug effects
Caspases - metabolism
Cell Line
Cytochrome
Cytochromes c - metabolism
Drug Evaluation, Preclinical
Hybrid Cells
Interleukin-1beta - secretion
Mice
Mitochondria - drug effects
mitochondrial death pathway
Motor Neurons - drug effects
Motor Neurons - pathology
Neurochemistry
Neurokinin-1 Receptor Antagonists - pharmacology
neuroprotection
Neuroprotective Agents - pharmacology
N‐acetyl‐l‐tryptophan
Proteasome Endopeptidase Complex - metabolism
Receptors, Neurokinin-1
Stereoisomerism
structure‐bioactivity relationship
substance P
Substance P - secretion
Tryptophan - analogs & derivatives
Tryptophan - pharmacology
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Summary: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. 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.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.13190