Abstract
Background: the influence of VPA on murine fertility, and on offspring is well documented: VPA decreases the fertility rate (by 25%) and the number of fÅ“tus. Furthermore, VPA causes behavioral alterations in rodents similar to the symptoms observed in autism.Objective: in this study we investigated the effects of exposure of non-pregnant adult rats to VPA in the offspring of these animals.Material and methods: non-pregnant adult rats were divided into 3 groups; (1) distilled water group, (2) VPA 200 mg / kg group and (3) VPA 400 mg/kg group. The products were administered orally daily for 30 days. At the end of treatments, all rats were put into monogamous mating with breeding males. The zootechnical characteristics (gestation period, litter size, mortality rate) were then noted. The young rats were then subjected to a battery of behavioral tests (reversal and anti-gravity reflexes, cliff avoidance, suspension, motor coordination and eye opening), carried out at different stages of life to assess sensorimotor development. Morphological abnormalities were also sought, as well as the mortality rate on the 28th day of life.Results: An increase in the mortality rate and a decrease in the mean lifespan were found in female rats exposed to VPA. Young rats from female rats exposed to VPA showed decreased success rates and performance in behavioral testing. Morphodevelopmental abnormalities such as adictalia or stump necrosis were found in the VPA groups. The offspring mortality rate of female rats exposed to VPA 200 mg/kg was 100%.Conclusion: VPA administered to non-pregnant adult rats causes developmental abnormalities, decreased success rates for performance testing, deformities and increased mortality in young rats from the treated rats by VPA. Â
Highlights
Valproic acid (2-propylvaleric acid, 2-propylpentanoic acid or n-dipropylacetic acid), derived from valeric acid, was first synthesized in 1882 by Burton (Chateauvieux et al, 2010)
Short-chain fatty acid, forming a clear liquid at room temperature, with a half-life of 9 to 16 hours. This molecule has been used as a “physiologically inert” solvent for organic compounds. It was in 1963, during a study focused on molecules with potential anti-convulsive activity, in which valproic acid (VPA) was used as a molecular carrier, that the pharmacological activity of VPA has been demonstrated: VPA prevented convulsions induced by pentylenetetrazol in rodents (Chateauvieux et al, 2010)
Female rats treated with valproic acid had a higher litter death rate than control animals, with 4.6 ± 1.14 (p
Summary
Valproic acid (2-propylvaleric acid, 2-propylpentanoic acid or n-dipropylacetic acid), derived from valeric acid (produced naturally by valerian, Valeriana officinalis), was first synthesized in 1882 by Burton (Chateauvieux et al, 2010). Prospective and retrospective studies demonstrate that VPA is a human teratogen It increases the risk of major abnormalities by about three times compared to other antiepileptics (Genton et al, 2006; Ornoy at al., 2009). Comparative studies show that while other antiepileptics increase the risk of malformation from 2.9 to 3.6%, the risk of the congenital malformation obtained with VPA is between 6.2 and 7.6% (Harden and Sethi, 2008) These disorders generally include spina bifida, and more rarely anencephaly, cardiac and craniofacial abnormalities, limb malformations and intrauterine growth delay (valproate syndrome) (Nanau and Neuman, 2013; Genton et al, 2006; Ibrahim, 2012). Children with valproate syndrome in general have developmental or communication trouble, such as autism spectrum disorder or decreased verbal intelligence (Ornoy, 2009)
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