**2. Valproic acid**

The compound VPA (Figure 1A) is a fatty acid synthesized in 1882 [15] as an analogue of valeric acid, found naturally in valerian (*Valeriana officinalis*), used at that time as an organic solvent. The chemical names to VPA and derivatives are shown in Table 1. Antiepileptic properties of VPA, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1962, when the French researcher Pierre Eymard in a serendipity discovery observed the anticonvulsant properties of VPA while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity [16]. He found that it prevented pentylene‐ tetrazol-induced convulsions in rodents. Since then, it has also been used for migraine and bipolar disorder. The U.S. Food and Drug Administration (FDA) approved VPA in 1978 for the treatment of seizure disorder and in 1986 approved its enteric-coated counterpart valproate semisodium (Figure 1B) also named divalproex sodium (USA), for the same indication. Valproate semisodium is a stable co-ordination compound comprised of sodium valproate (Figure 1C) and valproic acid in a 1:1 molar relationship in an enteric coated form. An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed. This compound dissociates to release valproate ions into the gastroin‐ testinal tract. Once in the blood, sodium valproate can be converted also in the acid form or conjugated as valproate semisodium [17]. The acid form is currently used to quantify plasma levels of all three.



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

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

The compound VPA (Figure 1A) is a fatty acid synthesized in 1882 [15] as an analogue of valeric acid, found naturally in valerian (*Valeriana officinalis*), used at that time as an organic solvent. The chemical names to VPA and derivatives are shown in Table 1. Antiepileptic properties of VPA, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1962, when the French researcher Pierre Eymard in a serendipity discovery observed the anticonvulsant properties of VPA while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity [16]. He found that it prevented pentylene‐ tetrazol-induced convulsions in rodents. Since then, it has also been used for migraine and bipolar disorder. The U.S. Food and Drug Administration (FDA) approved VPA in 1978 for the treatment of seizure disorder and in 1986 approved its enteric-coated counterpart valproate semisodium (Figure 1B) also named divalproex sodium (USA), for the same indication. Valproate semisodium is a stable co-ordination compound comprised of sodium valproate (Figure 1C) and valproic acid in a 1:1 molar relationship in an enteric coated form. An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed. This compound dissociates to release valproate ions into the gastroin‐ testinal tract. Once in the blood, sodium valproate can be converted also in the acid form or conjugated as valproate semisodium [17]. The acid form is currently used to quantify plasma

tube closure [12].

**2. Valproic acid**

levels of all three.

neurobiology of autism studies.

144 Recent Advances in Autism Spectrum Disorders - Volume I

**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 illustrate derivatives).

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

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 Laboratories-Argentina).

The VPA effects of clinical importance include GABAergic activity increase, excitatory neurotransmission decrease, and modification of monoamines [19]. The biochemical and biological effects of VPA are summarized in Table 2.


The classical autism was first reported to be one of the behavioral outcomes of VPA exposure [41] through several case reports [12, 39, 45]. The first epidemiological study with drugs as environmental risk factors of autism was described in 2000, with 57 offspring of women taking

> Poor social interaction 53 Poor communication skills 49 Short attention span 46 Insistence on routines 44

Hand flapping 25

**No of children VPA exposure in mg (weeks of gestation)**

1000 (0-5), 800 (5-40) 1200 (1-17), 1500 (17-26), 2000 (26-40)

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

147

1000 (0-40) 1000 (0-5), 800 (5-40) 1500 (0-40)

> 1000 (0-40) 1500 (0-40)

700 (0-40) 800 (0-40)

1000 (0-40) 1700 (0-40)

**Features % of children**

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

anticonvulsants (see ref [46], summarized in Tables 3 and 4).

**Table 3.** Autism features in children exposed *in utero* to anticonvulsants.

1 1

1 1 5

2 1

1 1

2 1

**Table 4.** Congenital malformations in children exposed *in utero* to VPA

Autistic features were present in 34 patients (60%).

Diastasis recti 1 1200 (0-40)

Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association (FACS) and five were referred to the Aberdeen Medical Genetics Service (AMGS). The number of patients exposed *in utero* to each anticonvulsant alone was 34 (60%) to VPA, 4 (7%) to carbamazepine, 4 (7%) to phenytoin, and 15 (26%) to more than one anticonvulsant. The number of patients with behavioral problems was 46 (81%), with hyperactivity or poor concentration was 22 (39%) and with attention deficit and hyperactivity disorder 4 (7%).

Neural tube defect

Genitourinary

Extremities

Eyes

Teeth

**Table 2.** Biochemical and biological effects of VPA
