Emerging mechanisms of valproic acid-induced neurotoxic events in autism and its implications for pharmacological treatment

Prenatal exposure to VPA induced ASD was possibly related to the abnormal of transcription level and signaling pathway, synaptic dysfunction, decreased neurogenesis, neuroinflammation, oxidative stress as well as altered brain-gut axis. Based on these mechanisms, melatonin, resveratol, minocycline and astaxanthin can be used to relieve symptoms of ASD. [Display omitted] •The prenatal exposure to VPA is significantly associated with congenital malformations andneurocognitive disability in children.•The aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminishedneurogenesis, oxidative stress are involved in the pathological process of ASD.•Unravelling the precise neuronal toxic mechanisms of VPA is helpful for repurposingpharmacological approaches in the future for ASD therapy. Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious disease has been available. Valproic acid (VPA) is a broad-spectrum, antiepileptic drug, and it is also a potent teratogen. Epidemiological studies have shown that children exposed to VPA are at higher risk for ASD during the first trimester of their gestational development. Several animal and human studies have demonstrated important behavioral impairments and morphological changes in the brain following VPA treatment. However, the mechanism of VPA exposure-induced ASD remains unclear. Several factors are involved in the pathological phase of ASD, including aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminished neurogenesis, oxidative stress, etc. In this review, we aim to outline the current knowledge of the critical pathophysiological mechanisms underlying VPA exposure-induced ASD. This review will give insight toward understanding the complex nature of VPA-induced neuronal toxicity and exploring a new path toward the development of novel pharmacological treatment against ASD.