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

Current Neuropharmacology 260 Send Orders for Reprints to Current Neuropharmacology, 2024, 22, 260-289 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Three Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder Impact Factor: 5.3 BENTHAM SCIENCE David Zarate-Lopez1,2, Ana Laura Torres-Chávez1,2, Alma Yadira Gálvez-Contreras3,* and Oscar Gonzalez-Perez1,* 1 Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040, México; 2Physiological Science Ph.D. Program, School of Medicine, University of Colima, Colima 28040, Mexico; 3Department of Neuroscience, Centro Universitario de Ciencias de la Salud, University of Guadalajara, Guadalajara 44340, México ARTICLE HISTORY Received: August 04, 2023 Revised: August 30, 2023 Accepted: August 30, 2023 DOI: 10.2174/1570159X22666231003121513 Abstract: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with increased prevalence and incidence in recent decades. Its etiology remains largely unclear, but it seems to involve a strong genetic component and environmental factors that, in turn, induce epigenetic changes during embryonic and postnatal brain development. In recent decades, clinical studies have shown that inutero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug, is an environmental factor associated with an increased risk of ASD. Subsequently, prenatal VPA exposure in rodents has been established as a reliable translational model to study the pathophysiology of ASD, which has helped demonstrate neurobiological changes in rodents, non-human primates, and brain organoids from human pluripotent stem cells. This evidence supports the notion that prenatal VPA exposure is a valid and current model to replicate an idiopathic ASD-like disorder in experimental animals. This review summarizes and describes the current features reported with this animal model of autism and the main neurobiological findings and correlates that help elucidate the pathophysiology of ASD. Finally, we discuss the general framework of the VPA model in comparison to other environmental and genetic ASD models. Keywords: Autism spectrum disorder, valproic acid, HDAC inhibition, neurodevelopment, prenatal exposure, pathophysiology. 1. INTRODUCTION Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that affects communication, social interaction, and behavior [1]. In the past few decades, the incidence and prevalence of ASD have been increasing, making it a major public health concern worldwide [2, 3]. Despite extensive research, the etiology of ASD remains largely unknown, but it is widely accepted that genetic and environmental factors play a significant role in its pathogenesis [4, 5]. One such environmental factor that has been linked to ASD is in-utero exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug [6], also used for the treatment of bipolar disorder, migraine, neuropathic pain, and headaches [7, 8]. Studies have shown that children exposed to VPA during pregnancy are more likely to develop ASD [9]. This association has been established through clinical studies where prenatal VPA exposure in rodents has been developed as a reliable translational model to study the *Address correspondence to these authors at the Laboratory of Neuroscience, School of Psychology, University of Colima, Colima 28040, México; E-mail: ; and Department of Neuroscience, Centro Universitario de Ciencias de la Salud, University of Guadalajara, Guadalajara 44340, México; E-mail: 1875-6190/24 $65.00+.00 pathophysiology of ASD [10]. However, the procedures used to replicate behavioral phenotypes have consistently differed in dosages, concentrations, the gestational development period of exposure to VPA, and the molecular and biological mechanisms proposed to explain the physiopathology associated with ASD. Several experimental models have been conducted on different species, including rodents, zebrafish, and non-human primates. Furthermore, recent advances have been made by using organoids from human induced pluripotent stem cells, which report gene expression patterns affected by VPA exposure and allow for correlation with the biological mechanisms proposed by animal studies [11-13]. Thus, increasing evidence suggests that VPA impacts the growth, migration, and differentiation of neurons and certain types of glia, as well as the development of functional synapses. This study aims to review the potential mechanisms by which prenatal exposure to VPA can result in changes to brain development in contrast to findings from other animal models and postmortem evidence from individuals diagnosed with ASD. 2. VALPROATE (VPA) Valproic acid, also known as 2-propyl pentanoic acid, is a branched and short-chain fatty acid chemically produced © 2024 Bentham Science Publishers Three Decades of Valproate: A Current Model for Studying ASD by different synthetic pathways [14], one of them as a product derivate from valeric acid [8] (Fig. 1). After oral administration, VPA is absorbed from the gut and metabolized in the liver by three routes, mainly glucuronidation, β oxidation in the mitochondria, and, in less proportion, by cytochrome P450-mediated oxidation [15, 16]. VPA has a high protein bound mainly to albumin and low clearance [15]. Fig. (1). Molecular structure of Valproate (VPA). (A) Valproic acid can be chemically synthesized from valeric acid, a natural substance from Valeriana officinalis. (B) Valproic acid by addition of sodium hydroxide to obtain sodium valproate. Both are the most common forms of valproate in the clinical. (A higher resolution/colour version of this figure is available in the electronic copy of the article). VPA was first introduced in the clinical as a broadspectrum antiepileptic drug [17], which is currently used for the treatment of multiple seizure disorders [18], bipolar disorder as a mood stabilizer [19], migraine [20, 21], and schizophrenia [22]. VPA is also used for the treatment of pediatric diseases such as epilepsy, conduct disorder and for symptoms of irritability, aggression, and impulsivity [8]. VPA can cross through the placenta and accumulate in the fetal circulation with a higher concentration than maternal blood [23, 24], conferring a major risk to the fetus by exposure to VPA. On the other hand, VPA metabolites, such as 4-ene VPA, cannot cross through the placenta, and fewer concentrations are observed in comparison to VPA [24, 25]. 3. STUDIES RELATED TO FETAL VPA SYNDROME AND ASD Gestational exposure to VPA has been extensively associated with an increased risk of major congenital malformations, delayed cognitive development, and ASD [26-31]. Currently, its clinical recommendation for pregnant women is controversial [6, 32, 33]. Fetal valproate syndrome (FVS) was first reported in 1993 to describe a group of major congenital malformations associated with exposure to VPA during the first trimester Current (...truncated)