**Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model**

Carmem Gottfried, Victorio Bambini-Junior, Diego Baronio, Geancarlo Zanatta, Roberta Bristot Silvestrin, Tamara Vaccaro and Rudimar Riesgo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54824

**1. Introduction**

Autism spectrum disorders (ASD) have attracted public attention by its high prevalence, elevated social cost and large impact on the family [1]. Since the first descriptions of au‐ tism made by Hans Asperger in 1938 [2] and by Leo Kanner in 1943 [3, 4], much discus‐ sion has focused in the search for the triggering points of autism and identifying risk factors has become a high priority of scientists. Nevertheless, even after almost seventy years since the first reports, the etiology of autism remains unknown and its molecular basis is not well understood. Environmental factors (such as virus, bacteria, drugs, etc.) known to increase the risk of autism have critical periods of action during embryogene‐ sis. Congenital syndromes are found in high rates in patients with autism including so‐ matic changes originated early in the first trimester [5].

The link between rubella and autism came from epidemic rubella in which the incidence of autism diagnosis in prenatally exposed offspring was more than 10-fold higher than normal. The study describes 243 children exposed to congenital rubella, where 25% presented mental retardation, 15% had reactive behavior and 7% was included in the autism spectrum [6].

Valproic acid (VPA) has traditionally been prescribed for epilepsy, but is increasingly used for psychiatric condition, such as bipolar disease by its modulation on GABA neurotransmission [7]. Furthermore, it has been also shown to be associated with an increased prevalence of autism. In fact, prospective and retrospective studies demonstrate that exposure to VPA during pregnancy is associated with approximately three-fold increase in the rate of major anomalies

© 2013 Gottfried et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and a possible set of dysmorphic features with decreased intrauterine growth [8, 9], charac‐ teristics of Fetal Valprotate Syndrome (FVS) described in item 3. Histone deacetylase (HDAC) inhibition by VPA and changes in gene expression may explain part of the teratogenicity of this drug. *In utero* exposure of rodents to VPA has been proposed to induce a phenotype with behavioral characteristics reminiscent of those observed in ASD and provides a robust animal model for social cognitive impairment understanding and a potential screen for the develop‐ ment of novel therapeutics for this condition [10]. Other possible explanations include either the effect of VPA through the increase of fetal oxidative stress, affecting mainly the brain in comparison to other fetal organs, or its inhibitory action on the folic acid mechanism [11]. In agreement, it is possible to duplicate a number of anatomic and behavioral features charac‐ teristic of human cases by exposing rat embryos to a teratogenic agents at the time of neural tube closure [12].

Valproic Acid 2-Propylvaleric acid, 2-Propylpentanoic acid or Di-n-dipropylacetic acid

Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model

http://dx.doi.org/10.5772/54824

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**<sup>A</sup> <sup>B</sup>**

**Figure 1.** The molecular structure of VPA and derivatives showed in ball and stick view. A. Valproic acid. B. Valproate semisodium, C. Sodium valproate. In A is possible to compare both chemical and ball and stick structures (used also to

The therapeutic concentration of sodium valproate (the sodium salt of VPA) during chronic oral treatment ranges from 40-100 mg/mL (280–700 mmol/L) in plasma and from 6–27 mg/g (42–190 mmol/g) in brain [18]. From this point, to simplify the reading throughout the text, the

The VPA is marketed under brand names including: Convulex (Pfizer-UK and Byk Madaus-South Africa), Depakene (Abbott Laboratories-USA, Brazil and Canada), Depakine (Sanofi Aventis-France and Sanofi Synthelabo-Romania), Deprakine (Sanofi Aventis-Finland), Encorate (Sun Pharmaceuticals-India), Epilim (Sanofi Synthelabo-Australia), Valcote (Abbot

The VPA effects of clinical importance include GABAergic activity increase, excitatory neurotransmission decrease, and modification of monoamines [19]. The biochemical and

VPA abbreviation will be used when referring to valproic acid and derivatives.

Sodium Valproate Sodium 2-propylvalerate Valproate semisodium Sodium hydrogen bis(2-propylvalerate) Valproate Pivoxil Hydroxymethyl 2-propylvalerate pivalate

Valpromide 2-Propylvaleramide

**Table 1.** Chemical names of VPA and derivatives

illustrate derivatives).

Laboratories-Argentina).

**C**

biological effects of VPA are summarized in Table 2.

Thus, *in utero* exposure to VPA has been used as a reliable model to increase the understanding of behavioral effects evaluated by specific tests as sociability, social preference and stereotypic behavior, also observed in human patients [9, 13, 14]. The present chapter summarizes the current knowledge on the relationship between *in utero* exposure to VPA in humans and in autism-like animal model phenotypes, highlighting the importance of this model to the neurobiology of autism studies.
