Remediate Effect of Ryanodine Receptor Antagonist in Valproic-Acid Induced Autism

Hariom Kumar ¹ , Vishal Diwan ² and Bhupesh Sharma ^{1, 3*}

¹Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, India.

²UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Australia.

³CNS Pharmacology, Conscience Research, India.

Corresponding Author E-mail: bhupeshsharmaresearch@gmail.com

Abstract: Autism spectrum disorder (ASD) mainly diagnosed with social behavioral problems, lack of communication, social interaction, and repetitive behavior along with cognitive dysfunction. Ryanodine receptors are involved in various neurological and behavioral impairments in different conditions. The role of Ryanodine receptors has not been explored in experimental ASD. The present study explicates the role of ryanodine receptor antagonist; ruthenium red (RR) in prenatal valproic acid (Pre-VPA) administered experimental ASD phenotypes. Three chamber social behavior, Y-Maze were utilized to assess social interaction, spontaneous alteration, respectively. Hippocampus and Prefrontal cortex (PFC) were utilized for various biochemical assessments, whereas cerebellum was used for assessments of blood brain barrier (BBB) permeability. Pre-VPA rats showed reduction in spontaneous alteration, social interaction. Pre-VPA administration were decreased PFC levels of IL-10, and GSH along with hippocampus cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF).  Also, the animals have shown increase in PFC levels of IL-6, TNF-α, TBARS, Evans blue leakage and water content. Daily administration of R Red considerably diminished Pre-VPA administered reduction in spontaneous alteration, social interaction, CREB, BDNF and increase in inflammation, oxidative stress, BBB permeability. Conclusively, Pre-VPA has induced autistic phenotype, which were attenuated by ryanodine receptor antagonist.  Ryanodine receptor antagonists may further test for their pharmacological effects in ASD phenotypes.

Keywords: Blood Brain Barrier; CREB; IL-6, BDNF; Ryanodine; Social Interaction

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