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