Autism is the category used within the newest edition of the diagnostic and statistical manual of neurodevelopmental disorders. Autism is a spectrum of disorder where a variety of behavioural patterns observed in autistic patients, such as stereotypes and repetitive behavior, hyperexcitability, depression-like symptoms, and memory and cognitive dysfunctions. Neuropathological hallmarks that associated with autism are mitochondrial dysfunction, oxidative stress, neuroinflammation, Neuro-excitation, abnormal synapse formation, overexpression of glial cells in specific brain regions like cerebellum, cerebral cortex, amygdala, and hippocampus. ICV injection of propionic acid (PPA) (4 μl/0.26 M) mimics autistic-like behavioral and biochemical alterations in rats. Literature findings reveal that there is a link between autism neuronal mitochondrial coenzyme-Q10 (CoQ10) and ETC-complexes dysfunctions are the keys pathogenic events for autism. Therefore, in the current study, we explore the neuroprotective interventions of Solanesol (SNL) 40 and 60 mg/kg alone and in combination with standard drugs Aripiprazole (ARP) 5 mg/kg, Citalopram (CTP) 10 mg/kg, Memantine (MEM) 5 mg/kg and Donepezil (DNP) 3 mg/kg to overcome behavioral and biochemical alterations in PPA induced experimental model of Autism. Chronic treatment with SNL 60 mg/kg in combination with standard drug shows a marked improvement in locomotion, muscle coordination, long-term memory and the decrease in depressive behavior. While, chronic treatment of SNL alone and in combination with standard drug aripiprazole, citalopram, donepezil, and memantine shows the Neuroprotective potential by enhancing the cognitive deficits, biochemical alterations along with reducing the level of inflammatory mediators and oxidative stress.

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 AMG 100 mg/kg and AMG 200mg/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 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.

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