This project will assess the contribution of genetic factors which mediate increased susceptibility to seizures during pregnancy. It has been known for many years that there is a marked reduction in the levels of vitamin B6 in the blood of pregnant women, and that in the pathologic pregnancies preenclampsia and eclampsia, this deficit is even greater. The significance of this observation is that vitamin B6 deficiency is known to be a predisposing factor for the development of seizures and eclampsia is characterized by generalized seizures which are life-threatening to mother and fetus alike. Vitamin B6 is required for synthesis and degradation of several neurotransmitters including norepinephrine dopamine, serotonin and Gamma-aminobutyric acid. During vitamin B6 deficiency there is, presumably, an alteration in the functioning of these neurotransmitter pathways, and it is this which results in predisposition to seizures. An enzyme which is induced in the livers of pregnant mice, Pi-aldehyde dehydrogenase (Pi-A1HD), is capable of metabolizing a form of vitamin B6, pyridoxal. It is likely that the development of seizures in pregnancy (eclampsia) is due partly to increased metabolism of vitamin B6 by Pi-A1DH. The experiments in this proposal are designed to test this hypothesis using genetically defined stocks of mice which differ in their susceptibility to pregnancy-induced seizures. Levels of neurotransmitters, Pi-A1DH activity and plasma vitamin B6 levels will be measured in mice which are prone to pregnancy-induced seizures and mice which do not develop pregnancy-induced seizures. Efforts will be made to identify specific neurochemical changes which correlate with seizure susceptibility in sensitive animals, but do not occur in resistant mice. The incidence of preeclampsia and eclampsia have remained constant in pregnancy, and approximately 4% are affected to some degree. Eclampsia remains a major cause of maternal and neonatal morbidity and mortality. Since the cause of the disease is unknown, treatment is symptomatic, and methods of prevention are unknown. These studies should reveal the nature of the neurochemical changes which precede eclampsia and if it is possible to establish cause-and-effect relationships it may allow for a rational approach to the prevention of eclampsia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD021709-03
Application #
3320748
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Type
Graduate Schools
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
van de Kamp, J L; Smolen, A (1995) Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B-6. Pharmacol Biochem Behav 51:753-8
Westrick, J A; Smolen, A (1994) Aminotransferase activities in mouse, Mus domesticus, erythrocytes separated according to age. Comp Biochem Physiol B Biochem Mol Biol 109:489-97
Smolen, A; Smolen, T N; Han, P C (1993) Alterations in regional brain GABA concentration and turnover during pregnancy. Pharmacol Biochem Behav 44:63-9
Rodriguez, L A; Fulker, D W; Cherny, S S (1993) A maximum-likelihood model-fitting approach to conducting a Hayman analysis of diallel tables with complete or missing data. Behav Genet 23:69-76
Smolen, T N; Smolen, A (1991) Purinergic modulation of ethanol-induced sleep time in long-sleep and short-sleep mice. Alcohol 8:123-30
Leibman, D; Furth-Walker, D; Smolen, A (1990) Vitamin B-6 metabolic enzymes in blood and placenta of pregnant mice. J Nutr 120:178-84
Furth-Walker, D; Leibman, D; Smolen, A (1990) Relationship between blood, liver and brain pyridoxal phosphate and pyridoxamine phosphate concentrations in mice. J Nutr 120:1338-43
Smolen, A; Smolen, T N (1989) Reproducibility of ethanol elimination rates in long-sleep and short-sleep mice. J Stud Alcohol 50:519-24
Furth-Walker, D; Leibman, D; Smolen, A (1989) Changes in pyridoxal phosphate and pyridoxamine phosphate in blood, liver and brain in the pregnant mouse. J Nutr 119:750-6
Smolen, A; Smolen, T N; van de Kamp, J L (1987) Sensitivity of inbred and selectively bred mice to ethanol. Alcohol 4:57-62

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