Abstract
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers’ serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.
Highlights
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects
Patients suffering from epilepsy usually require lifelong treatment with Antiepileptic drugs (AEDs)
LCM is a third-generation antiepileptic drug frequently used in epileptic patients, even during gestation
Summary
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. The use of mice as animal models has provided researchers the opportunity to gain insight into how specific treatments might affect neurodevelopmental and behavioural disorders[5] This approach is important for the teratogenic studies of a given drug for a chronic disease. Little is known about the teratogenic effects of LCM or its impact on neurodevelopment[7,8], and given that approximately 40% of pregnancies worldwide are unintended[9], we have assessed how treating pregnant mice with LCM (in equivalent doses to those used to treat epilepsy in humans) affects embryonic development, as well as the behaviour of the neonatal and young adult offspring. Our data indicate that LCM administration to pregnant mice may have teratogenic effects, and, it may have neurodevelopmental consequences inducing complex behaviours changes associated with schizophrenia spectrum disorders in the offspring of mice exposed to LCM when they reach adulthood
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