N-acetyl-l-tryptophan delays disease onset and extends survival in an amyotrophic lateral sclerosis transgenic mouse model

Neurobiology of Disease

Yongjin Zhu¹  Edward W. Zhou²  Qiaofeng Wu³  Bruce S. Kristal³  Yanchun Chen³  Anastasios Fotinos³  Xin Wang³  Wei Li³  Yanyang Tu³  Sergei Baranov³  Bharati Sinha³ 

[1] Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, P.R. China;Department of Surgery, Brigham and Women`s Hospital, Harvard Medical School, Boston, MA 02115, USA;Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA;

关键词: N-acetyl-l-tryptophan;    Amyotrophic lateral sclerosis;    mSOD1G93A mice;    Neuroprotection;    Mitochondrial death pathway;    Inflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 mSOD1G93A 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 mSOD1G93A 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 mSOD1G93A mice, while l-NAT treatment restored NK-1R levels. We propose the use of l-NAT as a potential therapeutic invention against ALS.

【 授权许可】

Unknown