Neuroinflammatory Response to Postnatal Administration of Valproic Acid in Wistar Rats as a Mechanism for the Development of Autism Spectrum Disorders: The Role of Neutrophils

Abstract

Highlights What are the main findings? Postnatal administration of VPA induces an autism-like phenotype in rats. Autism-like behavior is associated with increased activity of neutrophil elastase, α1-proteinase inhibitor, and the complement system, indicating systemic inflammation. What are the implications of the main findings? Increased activity of neutrophil elastase in the cerebellum indirectly indicates neutrophil infiltration into the central nervous system. Neutrophils are suggested to be involved in the neuroinflammatory mechanism of autism spectrum disorders. Abstract Background/Objectives: According to current concepts, neuroinflammation is one of the putative causes of autism spectrum disorders (ASD) development. However, the role of neutrophils in neuroinflammation remains insufficiently studied. The study was aimed to determine the role of neutrophils in the neuroinflammatory mechanism of ASD development based on a comparative analysis of physiological and behavioral disturbances and the inflammatory response to early postnatal administration of valproic acid (VPA) to Wistar rats. Methods: The study was performed on 38 rat pups of both sexes, half of which were injected intraperitoneally with an aqueous solution of VPA at a dose of 150 mg/kg from 6 to 12 postnatal days (PND); control rats received water. Standard physiological and behavioral tests were used: weight monitoring, pain sensitivity (Hot Plate test) on 25 PND, and social behavior (sib/non-sib test) on 55 PND. Neutrophil elastase (NE) and alpha1-proteinase inhibitor (α1-PI) activity in serum and cerebellum homogenate was measured spectrophotometrically. Complement system (CS) activity was analyzed by the death rate of Tetrahymena pyriformis ciliates in the presence of rat serum. Results: Early postnatal administration of VPA to Wistar rats induces physiological and behavioral changes characteristic of ASD, confirming the validity of the experimental model used. These changes are accompanied by increased activity of inflammatory factors (CS, α1-PI, NE) in the rat serum, indicating the development of inflammation. VPA treatment increased NE activity in the cerebellum, which may indicate neutrophil infiltration of the brain and neuroinflammation development. Conclusions: The data obtained indicate the role of neutrophils in neuroinflammatory mechanisms of ASD development.