Lacosamide intake during pregnancy increases the incidence of foetal malformations and symptoms associated with schizophrenia in the offspring of mice (English)

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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. ; This work was supported by the Andalusian Regional Ministry of Economy, Science and Innovation (P11-cts-7634); the Andalusian Regional Ministry of Health (PI-0438-2010) and the Instituto de Salúd Carlos III (PS09/00050, CP08/00111, CPII14/00033) co-financed by European Development Regional Fund “A way to achieve Europe” ERDF to PYG; Fundación Ramón Areces, DGICYT BFU2011-27207, and the Junta de Andalucía CTS-2257 to AMC; Funding FEDER Project UNSE10–1E-429 to RFT and MVN; Francisco José de Caldas fellowship by COLCIENCIAS to V.V-L. ; Peer reviewed