Downregulating the canonical Wnt/ß-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes by decreasing oxidative stress.
Neurochem Res
; 37(7): 1409-19, 2012 Jul.
Article
en En
| MEDLINE
| ID: mdl-22374471
ABSTRACT
Although a growing body of evidence supports the importance of the Wnt/ß-catenin signaling pathway and oxidative stress in the pathogenesis of autism, it is unclear whether a relationship exists between the Wnt/ß-catenin pathway and oxidative homeostasis. The present study examines the effects of sulindac, a small molecule inhibitor of the Wnt/ß-catenin signaling pathway, on the oxidative status of rats that are prenatally exposed to valproic acid (VPA), which is used in an animal model of autism. Our data show that sulindac treatment downregulated the canonical Wnt/ß-catenin signaling pathway by enhancing the expression of Glycogen Synthase Kinase 3ß and attenuating the expression of ß-catenin in comparison to levels in VPA-treated rats. Concomitantly, a marker of lipid peroxidation, 4-hydroxynonenal, was reduced as well. Sulindac treatment ameliorated the pain threshold, repetitive/stereotypic activity, learning and memory abilities and behavioral abnormalities of rats in our autism model. Our working model suggests that the upregulation of the Wnt/ß-catenin signaling pathway induced by VPA administration during early pregnancy produces an imbalance of oxidative homeostasis that facilitates susceptibility to autism. This information may be instrumental in designing appropriate therapeutic regimens with small molecule inhibitors of the Wnt/ß-catenin pathway for the treatment of autism-like behavioral phenotypes.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Trastorno Autístico
/
Transducción de Señal
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Regulación hacia Abajo
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Estrés Oxidativo
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Beta Catenina
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Vía de Señalización Wnt
Límite:
Animals
Idioma:
En
Revista:
Neurochem Res
Año:
2012
Tipo del documento:
Article
País de afiliación:
China