title: 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.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Sirianni
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Anatomy, Weifang Medical University, Weifang, Shandong, China.
authors.forename: Jiying
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute of Analytical Chemistry for Life Science, School of Public Health, Nantong University, Nantong, Jiangsu, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Aimcan Pharma Research & Technologies, Guelph, Canada.
authors.forename: Lilly L
authors.initials: LL
authors.lastname: Mao
authors.affiliation: Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shuanhu
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sugarbaker
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xinmu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Friedlander
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006822:Hybrid Cells; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018040:Receptors, Neurokinin-1; D013237:Stereoisomerism; D013373:Substance P / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D064729:Neurokinin-1 Receptor Antagonists; D018696:Neuroprotective Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; C006392:N-acetyltryptophan; D014364:Tryptophan; D045304:Cytochromes c; D020169:Caspases; D046988:Proteasome Endopeptidase Complex
keywords: N-acetyl-l-tryptophan; amyotrophic lateral sclerosis; mitochondrial death pathway; neuroprotection; structure-bioactivity relationship; substance P