Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease characterized by cognitive and sensorimotor impairment. Numerous research findings have consistently shown that alteration of Smo-Shh (smoothened-sonic hedgehog) signaling during the developmental process plays a significant role in ASD and triggers neuronal changes by promoting neuroinflammation and apoptotic markers. Purmorphamine (PUR), a small purine-derived agonist of the Smo-Shh pathway, shows resistance to hippocampal neuronal cell oxidation and decreases neuronal cell death. The goal of this study was to investigate the neuroprotective potential of PUR in brain intoxication induced by intracerebroventricular-propionic acid (ICV-PPA) in rats, with a focus on its effect on Smo-Shh regulation in the brain of rats. In addition, we analyze the impact of PUR on myelin basic protein (MBP) and apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic) in rat brain homogenates. Chronic ICV-PPA infusion was administered consecutively for 11 days to induce autism in rats. In order to investigate behavioral alterations, rats were tested for spatial learning in the Morris Water Maze (MWM), locomotive alterations using actophotometer, and beam crossing task, while Forced Swimming Test (FST) for depressive behavior. PUR treatment with 5 mg/kg and 10 mg/kg (i.p.) was administered from day 12 to 44. Besides cellular, molecular and neuroinflammatory analyses, neurotransmitter levels and oxidative markers have also been studied in brain homogenates. The results of this study have shown that PUR increases the level of Smo-Shh and restores the neurochemical levels, and potentially prevents morphological changes, including demyelination.