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.
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