Mechanisms of Valproic acid-Induced Autism: Canonical Wnt-β- Catenin Pathway

Abstract

Valproic acid (VPA) is anti-epileptic and mood stabilizer drug that induces autism spectrum disease (ASD). However, VPA has several side effects; hepatic steatosis, hepatotoxicity, hemorrhagic pancreatitis, encephalopathy, bone marrow suppression and metabolic disorders such as obesity. VPA proved to be unavoidable and could not be excluded in epileptic pregnant women. Non-controlled epileptic attacks during pregnancy produce high risk of injury to both mother and fetus. However, VPA crosses the placenta and accumulate in the fetal circulation with higher concentration than that in the maternal blood, causing toxicity and teratogenicity. Gestational VPA treatment for a life-threatening epilepsy caused numerous defects in children, including neural tube defects, intellectual impairments and cognitive-behavioral impairments. 8.9% of children exposed to VPA in utero develop autistic features. VPA exposure in the first trimester of gestation represented the highest risk for the child to develop autism, showed classical signs of autism, and developmental and behavioral delays. The full mechanisms of VPA are not fully elicited. This review discusses canonical Wnt/β-Catenin pathways as possible mechanism involved in autism induction upon VPA use.

Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder

“…Previous studies suggest several signaling processes as mechanisms of action of VPA, including Wnt/β-catenin, PI3K/Akt, and MAPK/ERK pathways [ 69 , 349 , 406 ]. However, it is still unclear how many of these processes are dysregulated as a direct result of a VPA mechanism of action.…”

“…β-catenin is regulated by the phosphorylation of glycogen synthase kinase-3β (GSK-3β), which leads to its degradation and the stabilization of cytoplasmic β-catenin [ 349 , 409 ]. Some studies suggest that VPA stimulates the canonical Wnt signaling pathway through the modulation of HDAC and GSK-3β [ 406 , 409 ]. VPA is proposed to activate Wnt-dependent gene expression through its HDACi activity [ 349 , 410 - 412 ].…”

“…This signaling protein is known to be an important regulator of neural circuit formation [ 408 , 424 ], indicating that these pathways play a role in neural proliferation, migration, and differentiation during embryonic brain development. It is possible that Wnt/β-catenin signaling is dysregulated in ASD [ 406 , 425 ].…”

Cardioprotective Effects of α-Asarone Against Hexavalent Chromium-Induced Oxidative Damage in Mice

“…Future research should focus on elucidating the precise biological mechanisms by which heavy metals influence cardiovascular health and developing effective strategies to mitigate these risks. 11 , 12 Such studies will be critical in shaping our approach to reducing the burden of CVD, particularly in populations most vulnerable to heavy metal exposure. 13 , 14 …”