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Pharmacology of neural tube defects
1Department of Biomedical and Health Sciences, Grand Valley State University, Allendale, Michigan, USA. cepip@iserv.net
Abstract:
The pharmacology of neural tube defects (NTDs) is a complex issue. Several theories regarding the etiology of NTDs emphasize the importance of interactions between genetic, environmental, and biochemical factors at a key point in time. One such factor is chronic drug therapy, a potential consequence of which is the formation of toxic drug metabolites, including free radicals (FRs), which have been implicated in the etiology of NTDs. Under normal physiological conditions, FRs are quickly destroyed by antioxidant defense systems. However, FR-mediated cellular damage can occur if these defense systems fail or are overburdened, such as in patients who are genetically deficient in FR scavenging enzyme activity (FRSEA) or who are receiving chronic drug therapy. Congenital defects, including NTDs, resulting from FR-induced damage have been reported in both experimental animals and humans. For example, the use of antiepileptic drugs (AEDs) during pregnancy that have the propensity to form FRs during their metabolism are associated with an increased risk of the development of congenital malformations, including NTDs. This article reviews the biochemistry of FRs, the factors regulating FR scavenging capacity, and the theories regarding the etiology of NTDs; presents a hypothesis of a unified mechanism for AED-induced NTDs and other congenital defects; and briefly discusses the roles of folate and selenium in the prevention of NTDs.
Insights
Chronic drug therapy, particularly antiepileptic drugs (AEDs), can increase the risk of neural tube defects (NTDs) by generating harmful free radicals (FRs). Antioxidant defenses may be overwhelmed, leading to congenital defects.
Area of Science:
- Pharmacology
- Biochemistry
- Developmental Biology
Background:
- Neural tube defects (NTDs) result from complex interactions between genetic, environmental, and biochemical factors.
- Chronic drug therapy can lead to the formation of toxic drug metabolites, including free radicals (FRs), implicated in NTD etiology.
- FR-mediated cellular damage occurs when antioxidant defense systems are compromised.
Purpose of the Study:
- To review the biochemistry of FRs and factors regulating antioxidant capacity.
- To explore theories on NTD etiology, focusing on FRs.
- To propose a unified mechanism for AED-induced NTDs and discuss preventive roles of folate and selenium.
Main Methods:
- Literature review of FR biochemistry and NTD etiology.
- Analysis of factors influencing FR scavenging enzyme activity (FRSEA).
- Hypothesis formulation for AED-induced NTDs.
Main Results:
- FRs generated during drug metabolism, especially from AEDs, are linked to increased NTD risk.
- Genetic deficiencies in FRSEA or chronic drug therapy can overwhelm antioxidant defenses.
- Congenital defects, including NTDs, have been associated with FR-induced damage in humans and animals.
Conclusions:
- A unified mechanism involving FRs may explain AED-induced NTDs and other congenital defects.
- Antioxidant status and drug metabolism pathways are critical in NTD development.
- Folate and selenium may play roles in preventing NTDs.