Several studies have documented the role of hyper-activation of extracellular signal-regulated kinases (ERK) in Autism pathogenesis. Alpha-mangostin (AMG) is a phytoconstituents with anti-oxidants, anti-inflammatory, and ERK inhibition properties in many diseases. Our research aims to investigate the neuroprotective effect of AMG in the rat model of intracerebroventricular-propionic acid (ICV-PPA) induced autism with a confirmation of its effect on the ERK signaling. Autism was induced in Wistar rats (total 36 rats; 18 male/18 female) by multiple doses of PPA through ICV injection for 11 days. Actophotometer and beam walking tasks were used to evaluate animals’ motor abilities, and the Morris water maze task was utilized to confirm the cognition and memory in animals. Long term administration of AMG100 mg/kg and AMG200 mg/kg continued from day 12 to day 44 of the experiment. Before that, animals were sacrificed, brains isolated, morphological, gross pathological studies were performed, and neurochemical analysis was performed in the brain homogenates. Cellular and molecular markers, including ERK, myelin basic protein, apoptotic markers including caspase-3, Bax, Bcl-2, neuroinflammatory markers, neurotransmitters, and oxidative stress markers, have been tested throughout the brain. Thus, AMG reduces the overactivation of the ERK signaling and also restored autism-like behavioral and neurochemical alterations.

Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chromosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized primarily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has recently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addition, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder.

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