Effects of Dietary n-3/n-6 PUFA Ratios on Animal Behaviors and Inflammation in a Prenatal Valproic Acid Exposure-Induced Rat Model of Autism

Background: In clinic, valproic acid (VPA) has been widely used in the treatments of epilepsy and is currently under clinical trials for the treatments of multiple diseases. However, gravidas receiving VPA treatment during their early stage of pregnancy were reported to be associated with elevated incidences of autism in their child. In this study, the potential influences of n-3/n-6 polyunsaturated fatty acids (PUFAs) as supplements were investigated in VPA-induced autistic rat model. Materials and Methods: A rat model of autism spectrum disorder (ASD) was established by VPA exposure at the E12.5 day of gestation. Neonatal male Wistar rats (n = 24) were divided into VPA group, A group and B group, while normal neonatal male Wistar rats served as controls. At P21 days, animals in the control and VPA groups were fed with standard chow, while rats in the A group were fed with n-3 PUFA free chow, and those in the B group with n-3/n-6 PUFA (1:5) chow. The duration of the diet was from P21 days to 3 months. All rats were subjected to the examinations of repetitive stereotyped behaviors and changes in social interaction at the end of supplement. The neuroinflammation in the brain and serum was also evaluated. Hematoxylin-eosin (HE) staining and Nissl staining were used to observe the neuronal injury in hippocampus. Results: In the B group, the repetitive stereotyped behaviors reduced, the social communication was improved, the neuronal loss and proinflammatory cytokines in the hippocampus reduced, and the extracellular STAT3 activation was inhibited in the hippocampus, as compared to the B group. Conclusion: Supplements with n-3/n-6 PUFA (1:5) rescues repetitive stereotyped behaviors and social deficits in neonatal rats exposed to VPA, likely due to the improved inflammatory responses through the alteration of STAT3 signaling. This study provides evidence for the use of n-3/n-6 PUF in the treatment of autism in humans.