Vitamin E decreases valproic acid induced neural tube defects in mice

doi:10.1016/S0304-3940(00)01457-9

Neuroscience Letters

Volume 292, Issue 3, 13 October 2000, Pages 179-182

https://doi.org/10.1016/S0304-3940(00)01457-9 Get rights and content

Abstract

The present study was undertaken to investigate the effect of vitamin E on valproic acid (VPA) induced teratogenesis. Pregnant Balb mice were divided into six groups of 10-11 animals each. The mice in group 1 served as control and were injected with saline subcutaneously on day 8 of gestation, whereas, animals in group 2 received a single injection of VPA (700 mg/kg (s.c.)). Groups 3 and 4 received an oral administration of vitamin E in the doses of 250 and 500 mg/kg, respectively, 1 h before VPA injection. Group 5 and 6 were given vitamin E only, in the same doses as group 3 and 4. On day 18 of gestation, the mice were killed by cervical dislocation. Embryotoxicity was assessed by counting the number of implants, live and dead fetuses, resorptions, crown rump length and fetal body weight. The fetuses were observed for malformations including neural tube defects (excencephaly), open eye lid and micrognathae. VPA administration resulted in a significant reduction of the average live fetuses/litter, fetal weight and crown rump length and a significant increase in malformations (excencephaly, open eye lid and micrognathae). Concomitant administration of vitamin E significantly attenuated VPA induced decrease in the fetal weight, crown rump length and malformations.

Section snippets

Acknowledgements

This work was financially supported by a grant from Research and Ethics Committee, Armed Forces Hospital, Riyadh, Saudi Arabia.

References (20)

K Ehlers et al.
Methionine reduces the valproic acid-induced spina bifida rate in mice without altering valproic acid kinetics
J. Nutr.
(1996)
M.A Elmazar et al.
Effect of supplementation with folinic acid, vitamin B₆ and vitamin B₁₂ on valproic acid induced teratogenesis in mice, Fundam
Appl. Toxicol.
(1992)
M.M Elmazar et al.
Ethanol potentiates valproic acid-induced neural tube defect (NTDS) in mice due to toxicokinetic interactions
Reprod. Toxicol.
(1995)
Z.J Hagay et al.
Prevention of diabetes associated embryopathy by over expression of the free radical scavenger copper, zinc superoxide dismutase in transgenic mouse embryos
Am. J. Obstet. Gynecol.
(1995)
M Ishibashi et al.
Oxygen induced embryopathy and the significance of glutathione dependent antioxidant system in the rat embryo during early organogenesis
Free Radic. Biol. Med.
(1997)
E Robert et al.
Maternal valproic acid and congenital neural tube defects
Lancet
(1982)
C Wegner et al.
Diurnal variation of folate concentration in mouse embryo and plasma. The protective effect of folinic acid on valproic acid-induced teratogenecity is time dependent
Reprod. Toxicol.
(1991)
K.N Buchi et al.
Protection against sodium valproate injury in isolated hepatocytes by alpha-tocopherol and N,N′-diphenyl-p-phenylenediamine
J. Clin. Pharmacol.
(1984)
L.V Dansky et al.
Mechanisms of teratogenesis: folic acid and antiepileptic therapy
Neurology
(1992)
P Durand et al.
Folic acid deficiency enhances oral contraceptive induced platelet hyperactivity
Arterioscler. Throm. Vasc. Biol.
(1997)

There are more references available in the full text version of this article.

Cited by (53)

Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum disorder
2019, Neuropharmacology
Citation Excerpt :
Accumulating evidence has suggested a role for oxidative stress and neuroinflammation in the embriotoxicity induced by VPA (Cipriani et al., 2018; Deckmann et al., 2018; Hegazy et al., 2015). It has been demonstrated that antioxidant pretreatment protects against VPA-induced teratogenesis in mice (Al Deeb et al., 2000; Zhang et al., 2010). Furthermore, VPA exposure resulted in increased expression of apoptotic markers that was attenuated by catalase supplementation (Tung and Winn, 2010).
Impairments in social interaction and verbal and non verbal communication are among the main features of Autism Spectrum Disorder (ASD). The causes of ASD are still unknown but the research efforts of the last decade have identified a number of factors (rare gene mutations, gene variations and adverse environmental events) that, interacting in complex ways, affect early brain development. The clinical evidence that prenatal exposure to the antiepileptic drug valproate (VPA) is associated with increased risk of neurodevelopmental delay, cognitive deficits and autism in children, has drawn the attention of scientists on VPA as a tool to unravel the environment contribution to ASD risk in children. In agreement with the clinical evidence, rodents prenatally exposed to VPA display behavioral anomalies resembling ASD symptoms. The mechanisms by which administration of VPA in pregnancy increases the risk of autism are still far to be clear as are still undetermined the specific targets of VPA in the developing brain both in humans and rodents. However, the robustness of the behavioral alterations, mainly in the social domain, and the neural/molecular changes revealed so far support the VPA model as a reliable instrument to investigate the neural underpinnings of social impairment.
Here we provide an update of preclinical studies on prenatal exposure to VPA in rodents with a focus on the social and communication deficits induced by VPA, discussing potential pitfalls and future directions in this research field and corroborating the potential of the VPA model to identify new pharmacological targets for ASD.
This article is part of the Special Issue entitled ‘The neuropharmacology of social behavior: from bench to bedside’.
Is post exposure prevention of teratogenic damage possible: Studies on diabetes, valproic acid, alcohol and anti folates in pregnancy: Animal studies with reflection to human
2018, Reproductive Toxicology
Citation Excerpt :
The reduction occurred without any reduction of VPA concentrations in maternal plasma or in the embryos. Al Deeb et al. [55] injected mice with 700 mg/kg of VPA on day 8 of pregnancy and in addition also treated orally mice with high doses of vitamin E one hour before VPA injection. They found that vitamin E significantly reduced the rate of NTD (exencephaly) and of other anomalies in the VPA treated mice.
We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol–induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.
Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats
2016, Food and Chemical Toxicology
Citation Excerpt :
VitE also counteracts testicular oxidative stress induced by exposure to prooxidants such as cadmium (El-Demerdash et al., 2004; Sen Gupta et al., 2004), alcohol (Maneesh et al., 2005), l-thyroxine (Sahoo et al., 2008), and pesticides (Astiz et al., 2013). Moreover, VitE has been shown to exhibit promising protective effects against VPA-induced teratogenicity in animal models and to alleviate the hepatotoxicity of VPA mainly through its anti-inflammatory and antioxidant actions (Al Deeb et al., 2000; Baran et al., 2006; Chen et al., 2014; Hsieh et al., 2014; Jurima-Romet et al., 1996). These observations strongly suggest that VitE may be an important protective agent for the maintenance of male fertility in conditions where it has been adversely affected by oxidative stress.
Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg⁻¹) was administered by gavage and VitE (50 mg kg⁻¹) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.
Prevention of valproic acid-induced neural tube defects by sildenafil citrate
2015, Reproductive Toxicology
This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10 mg/kg. One hour later, animals received a teratogenic dose of VPA (600 mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10 mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10 mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis.
The failure to detect drug-induced sensory loss in standard preclinical studies
2015, Journal of Pharmacological and Toxicological Methods
Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols.
Nrf2 and Nrf2-related proteins in development and developmental toxicity: Insights from studies in zebrafish (Danio rerio)
2015, Free Radical Biology and Medicine
Citation Excerpt :
The risk of embryotoxicity and teratogenicity following exposure to pro-oxidant chemicals depends on the balance between reactions generating oxidative stress and reactions that are protective or repair the damage [24, 25, 41-45]. Consistent with this, supplementation with small molecular anti-oxidants or stimulation of anti-oxidant enzymes protects embryos against the developmental toxicity of a variety of chemicals [46-55] and embryos with reduced antioxidant capacity are at increased risk for developmental toxicity and teratogenicity [24, 30, 44, 56-58]. Anti-oxidant defenses can be constitutive, protecting against and balancing redox potential under normal physiological conditions, and inducible defenses, which protect against toxicant-stimulated levels of oxidants or redox imbalance.
Oxidative stress is an important mechanism of chemical toxicity, contributing to developmental toxicity and teratogenesis as well as to cardiovascular and neurodegenerative diseases and diabetic embryopathy. Developing animals are especially sensitive to effects of chemicals that disrupt the balance of processes generating reactive species and oxidative stress, and those anti-oxidant defenses that protect against oxidative stress. The expression and inducibility of anti-oxidant defenses through activation of NFE2-related factor 2 (Nrf2) and related proteins is an essential process affecting the susceptibility to oxidants, but the complex interactions of Nrf2 in determining embryonic response to oxidants and oxidative stress are only beginning to be understood. The zebrafish (Danio rerio) is an established model in developmental biology and now also in developmental toxicology and redox signaling. Here we review the regulation of genes involved in protection against oxidative stress in developing vertebrates, with a focus on Nrf2 and related cap′n′collar (CNC)-basic-leucine zipper (bZIP) transcription factors. Vertebrate animals including zebrafish share Nfe2, Nrf1, Nrf2, and Nrf3 as well as a core set of genes that respond to oxidative stress, contributing to the value of zebrafish as a model system with which to investigate the mechanisms involved in regulation of redox signaling and the response to oxidative stress during embryolarval development. Moreover, studies in zebrafish have revealed nrf and keap1 gene duplications that provide an opportunity to dissect multiple functions of vertebrate NRF genes, including multiple sensing mechanisms involved in chemical-specific effects.

View all citing articles on Scopus

View full text

Vitamin E decreases valproic acid induced neural tube defects in mice

Abstract

Section snippets

Acknowledgements

J. Nutr.

Appl. Toxicol.

Reprod. Toxicol.

Am. J. Obstet. Gynecol.

Free Radic. Biol. Med.

Lancet

Reprod. Toxicol.

Protection against sodium valproate injury in isolated hepatocytes by alpha-tocopherol and N,N′-diphenyl-p-phenylenediamine

J. Clin. Pharmacol.

Mechanisms of teratogenesis: folic acid and antiepileptic therapy

Neurology

Folic acid deficiency enhances oral contraceptive induced platelet hyperactivity

Arterioscler. Throm. Vasc. Biol.