Downregulating the Canonical Wnt/β-catenin Signaling Pathway Attenuates the Susceptibility to Autism-like Phenotypes by Decreasing Oxidative Stress

Abstract

Although a growing body of evidence supports the importance of the Wnt/β-catenin signaling pathway and oxidative stress in the pathogenesis of autism, it is unclear whether a relationship exists between the Wnt/β-catenin pathway and oxidative homeostasis. The present study examines the effects of sulindac, a small molecule inhibitor of the Wnt/β-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/β-catenin signaling pathway by enhancing the expression of Glycogen Synthase Kinase 3β and attenuating the expression of β-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/β-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/β-catenin pathway for the treatment of autism-like behavioral phenotypes.

Salidroside Protection Against Oxidative Stress Injury Through the Wnt/β-Catenin Signaling Pathway in Rats with Parkinson’s Disease

“…A study observed decreased SOD and GSH-Px activity, as well as increased MDA content of the substantia nigra in PD rats, which was similar to our findings [32]. The activation of the Wnt/β-catenin signaling pathway results in imbalanced oxidative homeostasis as evidenced by the relationship between inhibited OS and over-activated Wnt/β-catenin signaling pathway in another study [33, 34]. In terms of the qRT-PCR and western blot assays, the results showed that in comparison with the sham or the control groups, mRNA and protein expression of GSK-3β increased, while GSK-3β-Ser9 protein expression and β-catenin and cyclinD1 mRNA and protein expression decreased in the other groups.…”

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…In VPA exposure rats, the levels of WNT1 and WNT2 in the prefrontal cortex and hippocampus are up-regulated (Kalkman, 2012). Down-regulation of the Wnt signaling pathway attenuates the susceptibility to autism-like phenotypes in VPA-exposed mice (Zhang et al, 2012) (Zhang et al, 2015). Consistent with these reports, our study showed that Wnt signaling was over-activated in VPA-exposed rats, and inhibition of Wnt signaling by sulindac relieved ASD-like behaviors.…”

“…The level of p-ERK was unchanged (n = 6, not significant versus control group). Recent research showed that canonical Wnt signaling is activated in VPA-exposed ASD rats (Zhang et al, 2012). Our study further validated this finding.…”

“…In BTBR T+tfJ and Neuroligin (NL)-3 knock-down autism model mice, the Wnt and β-catenin proteins are decreased in the frontal cortex (Cao et al, 2012). Downregulating the canonical Wnt/β-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes in Molecular and Cellular Neuroscience 75 (2016) [27][28][29][30][31][32][33][34][35] valproic acid (VPA)-treated mice (Zhang et al, 2012). Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors in mice (Sowers et al, 2014).…”

The Role of Thiamine in Autism

“…The dysregulation of the Wnt pathway may contribute to the pathogenesis of neurodevelopmental disorders such as autism. Sundilac, an inhibitor of the Wnt/β-catenin pathway, decreased activated GSK3β levels and ameliorated repetitive/stereotypic activity as well as the learning, memory, and behavioral abnormalities of rat autism models [159]. Exposure to pyrithiamine, an anti-thiamine compound, also increases β-amyloid protein accumulation and GSK3 activity in the brain [160].…”