Valproic Acid and Propionic Acid Modulated Mechanical Pathways for ASD

What is it about?

Abstract: Autism spectrum disorder (ASD) is a composite disorder of brain development with uncertain etiology and pathophysiology. Genetic factors are important in ASD causation, although environmental factors are also involved in ASD pathophysiology. Environmental factors might affect the genetic processes of brain development through the modulation of molecular pathways that might be involved with ASD. Valproic acid and propionic acid are the major environmental factors that serve as medicine and food preservative. VPA is used as an anti-epileptic medicine, but it has adverse effects on pregnant women and alters the developmental patterns of the embryo. It is a multi- targeting agent and affects 5-HT, GABA, etc. PPA is a secondary metabolite of gut microbiota that is commonly used as a food preservative. PPA plays a significant role in ASD causation by altering the several developmental molecular pathways like PTEN/Akt, mTOR/Gskβ, Cytokines activated pathways, etc., at the prenatal and neonatal stage. Moreover, ASD complexity might be increased by other important factors like vitamin A deficiency. Vitamin A is important for cortical brain development and neuronal cell differentiation. Additionally, several important genes such as RELN, Lhx2, CREB, IL-6, NMDA, BDNF, etc., are also altered in ASD and involved in brain development, central nervous system, and enteric nervous system. These genes affect neuronal differentiation, hyperactivity, oxidative stress, oxytocin, and GABA imbalance lead to improper behavior in autistic individuals. These genes are also studied in VPA and PPA ASD-like animal models. In this review, we explored the mechanical pathways that might be altered with VPA and PPA exposures at the embryonic developmental stage or neonatal developmental stage.

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Why is it important?

VPA and PPA are potential risk factors for the occurrence of ASD. VPA is a common drug for the treatment of epilepsy, whereas PPA is a secondary metabolite of gut microbiota and commercially used for food reservation. Both VPA and PPA potentially alter the early neurodevelopment in the prenatal and postnatal stages. Both VPA and PPA are chemicals commonly used in the development of ASD animal models. These animal models might help to explore the pathophysiology and etiology of ASD in animal models because they mimic ASD like-symptoms as humans. These chemicals cause the ASD like-symptoms with a different mechanism of action. VPA acts as a multi-targeting agent and leads to epigenetic changes, gene alterations through growth factors, protein modification, etc. In contrast, PPA induces hyperactivation of the maternal immune system and alters various pathways like IL-6, TNF-α, and IFN-γ activated pathways, PTEN/Akt pathway, etc. PPA directly affects the proliferation of glial cells and early neural cell development, causing ASD at the prenatal or postnatal stage. PPA also induces CREB and regulates epigenetic changes in the neuronal cell in the developmental stage. Vitamin A is also involved in eyes and forebrain development in the embryonic stage. Vitamin A deficiency might increases the severity of ASD by affecting histone acetylation, GFAP alteration, oxytocin reduction, etc. These environmental factors are the most prominent risk factors for ASD. These important pathways might help in developing a new treatment for ASD by targeting particular proteins like mTOR, PTEN, Akt, CREB, etc. Some modifiers (RELN, Lhx2, SHH, LIF, etc.) are also involved in ASD causation and might be able to regulate brain development at the prenatal stage.

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