title: N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.
abstract: BACKGROUND
  Whether L-NAT, a cytochrome c release inhibitor and an antagonist of NK-1R, provides protection in ALS is not known.
  
  
  RESULTS
  L-NAT delays disease onset and mortality in mSOD1(G93A) ALS mice by inhibiting mitochondrial cell death pathways, inflammation, and NK-1R downregulation.
  
  
  CONCLUSIONS
  L-NAT offers protection in a mouse model of ALS.
  
  
  CONCLUSIONS
  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 NK-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 Bcl-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 NK-1R levels in the spinal cords of mSOD1(G93A) mice, while L-NAT treatment restored NK-1R levels. We propose the use of L-NAT as a potential therapeutic invention against ALS.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Fotinos
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qiaofeng
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, P.R. China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Brigham and Women`s Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Baranov
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yanyang
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bharati
authors.initials: B
authors.lastname: Sinha
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Brigham and Women`s Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xwang@rics.bwh.harvard.edu.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D018040:Receptors, Neurokinin-1; C006392:N-acetyltryptophan; D014364:Tryptophan; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Amyotrophic lateral sclerosis; Inflammation; Mitochondrial death pathway; N-acetyl-l-tryptophan; Neurokinin 1 receptor; Neuroprotection; mSOD1(G93A) mice