ABSTRACT
Introduction: Autism spectrum disorder (ASD) is a disabling psychiatric disease characterized by impairments in communication and social skills. The pathophysiology of autism is complex and not fully known. Considering the incidence of sleep disorders in individuals with ASD and the important role of orexin in sleep, it is possible to hypothesize that an alteration of the orexinergic system could be implicated in the pathogenesis of autism symptoms. The present study was conducted to investigate the effect of suvorexant [dual orexin receptor antagonists (DORAs)] on autism-like behavior in prenatally valproic acid (VPA)-exposed rats]. Methods: Wistar female rats were administered VPA [600 mg/kg, intraperitoneally (i.p.)] or normal saline (10 ml/kg, i.p.; vehicle control) on gestational day 12.5. Thirty-two male offspring were divided into four groups: Control, VPA, Suvorexant+VPA, and VPA+Risperidone. The pups were given suvorexant [20 ml/kg, by mouth/orally (p.o.)] or risperidone (1 ml/kg, p.o.) daily from postnatal day (PND) (40-54). The offspring were tested for repetitive behaviors and cognitive ability with a Y-maze task on PND 55, and social interaction was assessed by play behavior in the open field on PND 56. And anxiety with using the three-chamber social assay on PND 56. Results: In the Y-maze apparatus, spontaneous alteration significantly decreased in the prenatal VPA-treated rats compared to control rats showing autistic-like behavior, and 2-week suvorexant increased the alternation, indicating the beneficial effect of suvorexant. Prenatal treatment with VPA, impaired play behavior (sniffing, grooming, and darting), and increased anxiety-related behavior. Suvorexant treatment attenuated the problems in male offspring's social behavior. Conclusion: Our results showed that suvorexant improved ASD-associated behaviors in the VPA-treated rats, and the orexinergic system may be associated with the pathogenesis of autism symptoms.
ABSTRACT
Background: Autism is a complicated neurodevelopmental disorder characterized by several behavioral impairments. The pathology of autism is complex and not fully known. Several recent studies have shown alterations in the activities of antioxidant enzymes in autism. Vitamin C is a potent antioxidant that is present in high concentrations in the brain and acts as a neuromodulator. Prefrontal abnormality has been hypothesized to underlie autistic symptoms. The present study investigated the protective effect of prenatally Vitamin C on autistic-like behaviors, oxidative stress status, and histopathological change of prefrontal in valproic acid (VPA) rat model of autism. Method: The model of autism was induced by subcutaneous administration of Valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. Vitamin C was administered 600 mg/L in drinking water from the 5th day of gestaion (GD5) up to postnatal day 23 (PND23). Thirty-two rat offspring were divided into four groups: Control, Vitamin C, VPA, and Vitamin C + VPA. The offspring were tested for repetitive behaviors and cognitive ability with a Y-maze task and social interaction with a play behavior task on 31st of Postnatal days. Glutathione (GSH), superoxide dismutase (SOD) activity, and the histological change in the prefrontal lobe were assessed at the end of the study. The number of neurons from the left prefrontal lobe was counted in duplicate from slides stained with hematoxylin-eosin. Results: In the Y-maze apparatus, spontaneous alteration significantly decreased in the prenatal VPA treated rats compared to control rats showing autistic-like behavior; pre and postnatal Vitamin C treatment increased the alternation indicated benefit effect of Vitamin C. Prenatal VPA treatment impaired play behavior such as sniffing, grooming and darting. Vitamin C treatment attenuated the problems in male offspring social behavior. Histological examination showed an increase in the number of cells in the prefrontal cortex of valproic acid offspring rats compared to other groups. Moreover, prenatal VPA decreased antioxidant enzyme activities in the cortex (PFC) attenuated by Vitamin C administration. Conclusion: The present study showed that valproic acid induced oxidative stress and neural changes in the prefrontal lobe when administered prenatally which in turn may cause the development of some autistic-like behaviors, and vitamin C may reduce this symptom with its antioxidant effects.