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N-acetyl-L-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model.
Li, Wei; Fotinos, Anastasios; Wu, Qiaofeng; Chen, Yanchun; Zhu, Yongjin; Baranov, Sergei; Tu, Yanyang; Zhou, Edward W; Sinha, Bharati; Kristal, Bruce S; Wang, Xin.
Afiliação
  • Li W; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Fotinos A; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Wu Q; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Chen Y; 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.
  • Zhu Y; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Baranov S; 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.
  • Tu Y; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Zhou EW; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Sinha B; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kristal BS; 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.
  • Wang X; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xwang@rics.bwh.harvard.edu.
Neurobiol Dis ; 80: 93-103, 2015 Aug.
Article em En | MEDLINE | ID: mdl-25986728
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. CONCLUSION: L-NAT offers protection in a mouse model of ALS. SIGNIFICANCE: 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triptofano / Esclerose Lateral Amiotrófica Limite: Animals Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Triptofano / Esclerose Lateral Amiotrófica Limite: Animals Idioma: En Revista: Neurobiol Dis Assunto da revista: NEUROLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos