The Neurotoxic Mechanisms of Valproic Acid and Their Association With Neurodevelopmental Disorders: A Narrative Review.

UNLABELLED: Valproic acid (VPA), which is an anticonvulsant and mood stabilizer, has been applied in treating several neurological and psychiatric conditions. However, severe neurotoxic side effects may result from its use, especially when taken at certain developmental stages of a child's brain. Consequently, the present narrative review aimed not only to summarize what is presently known about the neurotoxicity of VPA and the related neuropsychiatric disorders, but also to focus on potential interventions. Most of VPA's neurotoxic effects are due to its ability to increase reactive oxygen species (ROS) production, cause mitochondrial dysfunction, and alter epigenetics. It also facilitates neuronal damage by distorting the excitatory and inhibitory neurotransmission, increasing the excitotoxicity, oxidative stress, and mitochondrial dysfunction. These neurotoxic mechanisms are strongly associated with multiple neurodevelopmental disorders (NDDs). For example, prenatal VPA use is one of the common risk factors in autism spectrum disorder (ASD) that is correlated with complex social and communication deficits. VPA, which is used to treat epilepsy, may paradoxically increase seizure propensity by affecting neuronal excitability and synaptic input. Understanding these pathways can help reduce VPA's neurotoxicity without diminishing its efficacy in sensitized children.

HIGHLIGHTS: VPA induces epigenetic dysregulation through HDAC.VPA impairs mitochondria, increasing ROS and ATP depletion.The impaired balance of GABA/glutamate induces the change in neural circuitry.

PLAIN LANGUAGE SUMMARY: Valproic acid (VPA) is a commonly used medicine to treat epilepsy, bipolar disorder and migraine. For many people, it is effective and life-changing. Nonetheless, it has been found that when consumed during pregnancy or in the early life of the brain, VPA can predispose children to some developmental disorders such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder, intellectual disability (ADHD), and developmental delays. In this review, we examined how VPA can affect the developing brain. Studies suggest that VPA may interfere with how brain cells grow, connect, and communicate. It is capable of raising the levels of harmful molecules such as reactive oxygen species (ROS) that damage cells and lower the energy production in the brain. VPA can also change how genes are regulated, affecting important processes involved in brain development. In addition, it may disrupt the balance of chemical messengers that allow brain cells to send signals to one another. Together, these effects can alter brain structure and function during critical stages of development. Understanding these mechanisms is important for both doctors and families. It assists in understanding why prenatal exposure to VPA is risky and why its prescription must be the responsibility of care, particularly in women of childbearing age. This information also aids in designing safer treatment plans and protection therapies that can reduce the damage but retain the advantage of the drug. Finally, the most vulnerable children can be safeguarded by enhancing awareness and clinical advice, whereas children requiring effective treatment are not left unattended.