Antiepileptic drug therapy and reproductive consequences: Functional and morphologic effects

Kaneko, Sunao

doi:10.1016/0890-6238(91)90050-p

Cited by 37 publications

(10 citation statements)

References 113 publications

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“…2004). Although the teratogenic PB dose found in the present study was much higher than the reported human therapeutic dose (Kaneko 1991; Moore et al . 2000), the present findings would provide an animal‐experimental basis for assessing the increased risk of congenital heart disease in human offspring from mothers who use PB as monotherapy or in combination.…”

Section: Discussioncontrasting

confidence: 72%

Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats

Okuda

Nagao

2006

Congenital Anomalies

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The effects of prenatal exposure to phenobarbital (PB) on the cardiovascular system were examined in rat fetuses and pups. PB was administered at a dose of 80 or 120 mg/kg/day by gavage to Sprague Dawley (SD) rats on two consecutive gestational days (GD): 7-8, 8-9, 9-10, or 10-11. Fetuses were examined for cardiovascular malformations on GD 20. In addition, pups were examined for PB-induced cardiovascular malformations. Incidences of ventricular septal defect (VSD), overriding aorta, double outlet right ventricle and transposition of great arteries were significantly increased in the fetuses whose dams were administered PB at 120 mg/kg on GD 8-9, 9-10 or 10-11. GD 8-11 was the critical period for the cardiovascular malformations associated with administration of PB in rats. Various types of cardiovascular malformations were detected in pups from the PB-administered dam. Severe cardiovascular malformations induced by PB caused deaths on early postnatal days. However, slight malformations such as isolated VSD persisted until weaning, and did not affect postnatal viability.

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Section: Discussioncontrasting

confidence: 72%

Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats

Okuda

Nagao

2006

Congenital Anomalies

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“…Surviving pups treated with PHT had lower body weight during neonatal PHT treatment. It has been reported that PHT induces reduction of thyroid hormone thyroxin levels (Kaneko, 1991). Thyroid hormone is a major physiological regulator of mammalian brain development, cerebral cortex, and cerebellum (Jacobson, 1991 a ; Bernal and Nunez, 1995).…”

Section: Discussionmentioning

confidence: 99%

Developmental Neurotoxicity of Phenytoin on Granule Cells and Purkinje Cells in Mouse Cerebellum

Ohmori¹,

Ogura²,

Yasuda³

et al. 1999

Journal of Neurochemistry

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Phenytoin (PHT) is a primary antiepileptic drug. Cerebellar malformations in human neonates have been described following intrauterine exposure to PHT. The neonatal period of development in the cerebellum in mice corresponds to the last trimester in humans. To examine the neurotoxic effects of PHT in the developing cerebellum, we administered PHT orally to newborn mice once a day during postnatal days 2-4. We observed many apoptotic cells in the external granular layer (EGL) on postnatal day 5, labeled cells in the EGL still remaining 72 h after labeling with 5-bromo-2Ј-deoxyuridine, and EGL thicker than that in the control on postnatal day 14. These results showed that PHT induced cell death of external granule cells and inhibited migration of granule cells in cerebella. In specimens immunostained with antibody against inositol 1,4,5-trisphosphate receptor type 1, Purkinje cells in the treated group had poor and immature arbors, and partially showed an irregular arrangement. The motor performance of the treated mice in a rotating rod test was impaired, although there were no changes in muscular strength or in walking pattern at the period of maturity. These findings indicate that PHT induces neurotoxic damage to granule cells and Purkinje cells in the developing cerebellum and impairs selected aspects of motor coordination ability. Key Words: Phenytoin-Developmental neurotoxicity-Neonatal period-Mouse cerebellum-Apoptosis-Inositol 1,4,5-trisphosphate receptor type 1-Motor coordination.

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“…Key features of mEH comprise a broad substrate spectrum and almost ubiquitous expression in all body tissues, with particularly high expression in liver and kidney—consistent with a central role in detoxification (Guengerich 1982; Seidegard and DePierre 1983). mEH substrates comprise epoxides metabolically formed from environmental toxins such as benzene and polycyclic aromatic hydrocarbons (Gonzalez et al 1982; Jerina 1983; Oesch 1983; Wood et al 1983) and those from drugs such as phenytoin (Martz et al 1977) and carbamazepine (Kaneko 1991). In few cases mEH also contributes to the formation of genotoxic metabolites (Bauer et al 2003; Miyata et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Genetic enhancement of microsomal epoxide hydrolase improves metabolic detoxification but impairs cerebral blood flow regulation

Marowsky

Bockamp³

et al. 2016

Arch Toxicol

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Microsomal epoxide hydrolase (mEH) is a detoxifying enzyme for xenobiotic compounds. Enzymatic activity of mEH can be greatly increased by a point mutation, leading to an E404D amino acid exchange in its catalytic triad. Surprisingly, this variant is not found in any vertebrate species, despite the obvious advantage of accelerated detoxification. We hypothesized that this evolutionary avoidance is due to the fact that the mEH plays a dualistic role in detoxification and control of endogenous vascular signaling molecules. To test this, we generated mEH E404D mice and assessed them for detoxification capacity and vascular dynamics. In liver microsomes from these mice, turnover of the xenobiotic compound phenanthrene-9,10-oxide was four times faster compared to WT liver microsomes, confirming accelerated detoxification. mEH E404D animals also showed faster metabolization of a specific class of endogenous eicosanoids, arachidonic acid-derived epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs). Significantly higher DHETs/EETs ratios were found in mEH E404D liver, urine, plasma, brain and cerebral endothelial cells compared to WT controls, suggesting a broad impact of the mEH mutant on endogenous EETs metabolism. Because EETs are strong vasodilators in cerebral vasculature, hemodynamics were assessed in mEH E404D and WT cerebral cortex and hippocampus using cerebral blood volume (CBV)-based functional magnetic resonance imaging (fMRI). Basal CBV0 levels were similar between mEH E404D and control mice in both brain areas. But vascular reactivity and vasodilation in response to the vasodilatory drug acetazolamide were reduced in mEH E404D forebrain compared to WT controls by factor 3 and 2.6, respectively. These results demonstrate a critical role for mEH E404D in vasodynamics and suggest that deregulation of endogenous signaling pathways is the undesirable gain of function associated with the E404D variant.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1666-2) contains supplementary material, which is available to authorized users.

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Antiepileptic drug therapy and reproductive consequences: Functional and morphologic effects

Cited by 37 publications

References 113 publications

Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats

Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats

Developmental Neurotoxicity of Phenytoin on Granule Cells and Purkinje Cells in Mouse Cerebellum

Genetic enhancement of microsomal epoxide hydrolase improves metabolic detoxification but impairs cerebral blood flow regulation

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