Sulindac attenuates valproic acid-induced oxidative stress levels in primary cultured cortical neurons and ameliorates repetitive/stereotypic-like movement disorders in Wistar rats prenatally exposed to valproic acid

Abstract

Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodevelopental disorders, such as autism. In the present study, the possible neuroprotective properties of sulindac, a non-steroidal anti-inflammatory drug (NSAID), were investigated in vitro using cultured cortical neurons with valproic acid (VPA)-induced neurotoxicity, as well as in vivo through the behavioral analysis of rats prenatally exposed to VPA as a model of autism. VPA induced 4-hydroxynonenal (4-HNE) expression, reactive oxygen species (ROS) generation and decreased cell viability in primary cultured cortical neurons established from timed-pregnant (embryonic day 18) Wistar rat pups. However, co-incubation of the neurons with VPA and sulindac reduced oxidative stress and increased cell viability. The rats were administered an intraperitoneal injection with one of the following: VPA, sulindac, VPA and sulindac, or physiological saline, and their offspring were subjected to the open field test. During the test trials, repetitive/stereotypic-like movements for each rat were recorded and analyzed. The results revealed that treatment with both sulindac and VPA reduced the VPA-induced repetitive/stereotypic-like activity and the sulindac and VPA-treated animals responded better in the open field test compared to the VPA-treated animals. The results from the present study demonstrate that the antioxidant properties of sulindac may prove to be beneficial in the treatment of autism, suggesting that the upregulation of the Wnt/β-catenin signaling pathway disrupts oxidative homeostasis and facilitates susceptibility to autism.

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.…”

N-acetylcysteine ameliorates repetitive/stereotypic behavior due to its antioxidant properties without activation of the canonical Wnt pathway in a valproic acid-induced rat model of autism

“…However, treatment with NAC did not appear to affect the nuclear and cytoplasmic β-catenin levels, or the phosphorylation of β-catenin and GSK-3β, thus suggesting that the Wnt pathway may not be involved in NAC-mediated amelioration of autism-like behavior in VPA-treated rats. These results are in accordance with our previous in vitro study, which demonstrated that NAC reduced oxidative stress in primary neuronal cultures following pre-treatment with VPA without affecting the activity of the Wnt pathway (45). These findings suggested that the unaltered activity of the canonical Wnt pathway may be an indirect consequence, of reduced oxidative stress in VPA-exposed offspring followed by NAC administration.…”

“…Wnt and its associated signaling proteins have been identified as targets for GSH (44), whereas NAC has been demonstrated to inhibit the activation of the canonical Wnt pathway in the retinas of diabetic rats (43). Furthermore, previous studies have reported a critical role for the Wnt pathway in the pathogenesis of autism (23,28,45). In a previous study by the present authors, VPA was revealed to inhibit the phosphorylation, and thus the inactivation, of β-catenin, which is a key effector during canonical Wnt signaling, possibly through the upregulation of WNT1 and WNT2 expression, thereby activating the canonical Wnt pathway (46).…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…In terms of exploratory behaviour, rearings decreased at 400-600 mg/kg (i.p. or s.c.; Table 1), except in one study where it increased [52]. No changed parameters were seen to cause this [52].…”

“…or s.c.; Table 1), except in one study where it increased [52]. No changed parameters were seen to cause this [52]. Locomotion gave mixed results across the doses, with some having increased locomotion (hyperlocomotion), others having decreased locomotion (hypolocomotion; Table 1).…”