Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague—Dawley Rats

Binkerd, Pamela E.; Rowland, Jon M.; Nau, Heinz; Hendrickx, Andrew G.

doi:10.1093/toxsci/11.1.485

Cited by 27 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sodium valproate (Sigma) was dissolved in saline at a concentration of 250 mg/ml. Administration of this dose to rats during embryogenesis has been shown to result in a maximum level of total VPA (900 mg/ml) in maternal plasma in less than 1 h, with a mean plasma elimination half-life of 2.3 h (Binkerd et al, 1988). Valproate-treated females and their offspring were healthy and number of animals per litter was normal compared to controls.…”

Section: Animalsmentioning

confidence: 97%

Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism

Schneider

Turczak

Przewłocki

2005

Neuropsychopharmacol

249

155

View full text Add to dashboard Cite

Environmental enrichment has been repeatedly shown to affect multiple aspects of brain function, and is known to improve cognitive, behavioral, and histopathological outcome after brain injuries. The purpose of the present experiments was to determine the effect of an enriched environment on behavioral aberrations observed in male rats exposed to valproic acid on day 12.5 of gestation (VPA rats), and proposed on the basis of etiological, anatomical, and behavioral data as an animal model of autism. Environmental enrichment reversed almost all behavioral alterations observed in the model. VPA rats after environmental enrichment (VPA-E) compared to VPA rats reared in standard conditions have higher sensitivity to pain and lower sensitivity to nonpainful stimuli; stronger acoustic prepulse inhibition; lower locomotor, repetitive/stereotypic-like activity, and enhanced exploratory activity; decreased anxiety; increased number of social behaviors; and shorter latency to social explorations. In comparison with control animals (Con), VPA-E rats exhibited increased number of pinnings in adolescence and social explorations in adulthood, and were less anxious in the elevated plus maze. Similar differences in social behavior and anxiety were observed between control rats exposed to environmental enrichment (Con-E) and control group reared in standard conditions. These results suggest that postnatal environmental manipulations can counteract the behavioral alterations in VPA rats. We propose environmental enrichment as an important tool for the treatment of autism spectrum disorders.

show abstract

Section: Animalsmentioning

confidence: 97%

Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism

Schneider

Turczak

Przewłocki

2005

Neuropsychopharmacol

249

155

View full text Add to dashboard Cite

show abstract

“…Sodium valproate (Sigma) was dissolved in saline at a concentration of 250 mg/ml. Administration of this dose to rats during embryogenesis has been shown to result in the maximum level of total VPA (900 mg/ml) in maternal plasma in less than 1 h, with a mean plasma elimination half-life of 2.3 h (Binkerd et al, 1988). Valproate-treated females and their offspring were healthy and a number of animals per litter were normal compared to controls.…”

Section: Animalsmentioning

confidence: 98%

“…Somatic effects of VPA are known to be similar to those of thalidomide (Binkerd et al, 1988), and its teratogenic effect is also observed in human beings (Lindhout et al, 1992;Ardinger et al, 1998) also causing, in addition to somatic dysfunction, CNS dysfunction described as fetal valproate syndrome, which has recently been connected with autism (Christianson et al, 1994;Williams and Hersh, 1997;Williams et al, 2001;Moore et al, 2000;Bescoby Chambers et al, 2001). In rats, the neural tube closes on day 11, and within the 12th day of gestation, production of the motor nuclei of trigeminal, abducens, and hypoglossal nerves is completed (Altman and Bayer, 1980).…”

Section: Introductionmentioning

confidence: 99%

Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism

Schneider

Przewłocki

2004

Neuropsychopharmacol

796

650

View full text Add to dashboard Cite

Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and nonverbal communication, and stereotyped, repetitive patterns of behaviors and interests. Recently, a new rodent model of autism was created by exposure of rat fetuses to valproic acid (VPA) on the 12.5th day of gestation (VPA rats). The model has striking anatomical, pathological, and etiological similarities to human data; however, it has not been characterized behaviorally. In order to determine if VPA rats present behavioral aberrations observed in autism, their behavior was extensively evaluated in a battery of tests. The results of the present experiments demonstrate that VPA rats exhibit: (1) lower sensitivity to pain and higher sensitivity to nonpainful stimuli, (2) diminished acoustic prepulse inhibition, (3) locomotor and repetitive/stereotypic-like hyperactivity combined with lower exploratory activity, and (4) decreased number of social behaviors and increased latency to social behaviors. In addition, VPA rats showed delayed maturation, lower body weight, delayed motor development, and attenuated integration of a coordinated series of reflexes, delayed nest-seeking response mediated by olfactory system, and normal negative geotaxis. Interestingly, all behavioral aberrations described in this paper appear before puberty, which could distinguish the VPA rat model of autism from other animal models of neurodevelopmental disorders, especially rodent models of schizophrenia. Our results bring further support to validity of the proposed VPA animal model of autism, suggesting similarities between the observed pattern of behavioral alterations in VPA rats and features of disturbed behavior in autistic patients.

show abstract

“…The anticonvulsant, valproic acid, on the other hand, is an effective teratogen in rodents, producing many of the same external defects seen after human exposure (Binkerd et al, 1988;Ehlers et al, 1992;Collins et al, 19921, and the malformations produced are similar to those observed in humans exposed to thalidomide. Behavioral studies after chronic prenatal dosing of rats with valproic acid have confirmed its brain-damaging effects iVorhees, 1987).…”

Section: New Data From a Group Of Cases Caused By Thalidomide Exposurementioning

confidence: 97%

Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei

et al. 1996

View full text Add to dashboard Cite

The underlying brain injury that leads to autism has been difficult to identify. The diagnostic criteria of the disease are not readily associated with any brain region or system, nor are they mimicked by vascular accidents, tumors, or degenerative neurological diseases occurring in adults. Fortuitously, a recent report of autism induced by thalidomide exposure provides evidence that the disease originates by an injury at the time of closure of the neural tube. The human data suggest that the initiating lesion includes the motor cranial nerve nuclei. To test this hypothesis, we first examined motor nuclei in the brainstem of a human autistic case. The autopsy brain exhibited near-complete absence of the facial nucleus and superior olive along with shortening of the brainstem between the trapezoid body and the inferior olive. A similar deficit has been reported in Hoxa-1 gene knockout mice in which pattern formation of the hindbrain is disrupted during neurulation. Alternatively, exposure to antimitotic agents just after neural tube closure could produce the observed pattern of deficits. Thus, the lesions observed in the autopsy case appear to match those predicted by the thalidomide cases in both time of origin and central nervous system (CNS) location. To produce similar brain lesions experimentally, we exposed rat embryos to valproic acid, a second teratogen newly linked to autism. Dams received 350 mg/kg of valproic acid (VPA) on day 11.5 (the day of neural tube closure), day 12, or day 12.5 gestation. Each treatment significantly reduced the number of motor neurons counted in matched sections of the earliest-forming motor nuclei (V, XII), and progressively later exposures affected the VIth and IIIrd cranial nerve nuclei. All treatments spared the facial nucleus, which forms still later. Counts from the mesencephalic nucleus of trigeminal, the dorsal motor nucleus of the vagus, and the locus ceruleus were not affected by exposure to VPA, even though these nuclei form during the period when exposure occurred. Despite its effects on the motor nuclei, valproic acid exposure did not alter the further development of the brain in any obvious way. Treated animals were robust and had no external malformations. The autopsy data and experimental data from rats confirm that CNS injuries occurring during or just after neural tube closure can lead to a selective loss of neurons derived from the basal plate of the rhombencephalon. The results add two new lines of evidence that place the initiating injury for autism around the time of neural tube closure.

show abstract

Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague—Dawley Rats

Cited by 27 publications

References 0 publications

Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism

Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism

Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism

Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei

Contact Info

Product

Resources

About