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

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.

SUBMITTER: Lopez-Escobar B

PROVIDER: S-EPMC7203245 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

López-Escobar Beatriz B Fernández-Torres Rut R Vargas-López Viviana V Villar-Navarro Mercedes M Rybkina Tatyana T Rivas-Infante Eloy E Hernández-Viñas Ayleen A Álvarez Del Vayo Concepción C Caro-Vega José J Sánchez-Alcázar José A JA González-Meneses Antonio A Carrión M Ángel MÁ Ybot-González Patricia P

Scientific reports 20200506 1

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/histolog ...[more]

PMID: 32376856

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Project description:BackgroundDolutegravir (DTG) is a recommended first-line regimen for all people with Human Immunodeficiency Virus (HIV) infection. Initial findings from Botswana, a country with no folate fortification program, showed an elevated prevalence of neural tube defects (NTDs) with peri-conceptional exposure to DTG. Here we explore whether a low folate diet influences the risk of DTG-associated foetal anomalies in a mouse model.MethodsC57BL/6 mice fed a folate-deficient diet for 2 weeks, were mated and then randomly allocated to control (water), or 1xDTG (2.5 mg/kg), or 5xDTG (12.5 mg/kg) both administered orally with 50 mg/kg tenofovir disoproxil fumarate 33.3 mg/kg emtricitabine. Treatment was administered once daily from gestational day (GD) 0.5 to sacrifice (GD15.5). Foetuses were assessed for gross anomalies. Maternal and foetal folate levels were quantified.Findings313 litters (103 control, 106 1xDTG, 104 5xDTG) were assessed. Viability, placental weight, and foetal weight did not differ between groups. NTDs were only observed in the DTG groups (litter rate: 0% control; 1.0% 1xDTG; 1.3% 5xDTG). Tail, abdominal wall, limb, craniofacial, and bleeding defects all occurred at higher rates in the DTG groups versus control. Compared with our previous findings on DTG usage in folate-replete mouse pregnancies, folate deficiency was associated with higher rates of several defects, including NTDs, but in the DTG groups only. We observed a severe left-right asymmetry phenotype that was more frequent in DTG groups than controls.InterpretationMaternal folate deficiency may increase the risk for DTG-associated foetal defects. Periconceptional folic acid supplementation could be considered for women with HIV taking DTG during pregnancy, particularly in countries lacking folate fortification programs.FundingThis project has been funded by Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I and award #R01HD104553. LS is supported by a Tier 1 Canada Research Chair in Maternal-Child Health and HIV. HM is supported by a Junior Investigator award from the Ontario HIV Treatment Network.

Project description:BackgroundObservational and experimental evidence demonstrates that protein intake in infancy programs linear growth. To our knowledge, few studies have examined prenatal maternal protein intake.ObjectiveOur objective was to examine associations of maternal protein intake during pregnancy with offspring linear growth.DesignWe analyzed data from 1961 mother-child pairs in Project Viva. We assessed first- and second-trimester diet with the use of food-frequency questionnaires and analyzed protein intake as grams per kilogram prepregnancy weight per day. We used research measures of offspring length at birth and in infancy (∼6 mo), early childhood (∼3 y), and midchildhood (∼7 y), as well as clinical growth measures obtained from after birth through midchildhood. We calculated sex-specific birth length z scores for gestational age with the use of international reference data. We used mixed models with repeated length measures to predict individual length gain velocities for birth to <6 mo and 6 mo to 7 y of age, then used these velocities as outcomes in adjusted linear regression models with maternal protein intake as the main predictor.ResultsMean (range) second-trimester protein intake was 1.4 g · kg-1 · d-1 (0.3-3.1 g · kg-1 · d-1). After adjusting for maternal sociodemographics, gestational weight gain, maternal and paternal height, and (for postdelivery outcomes) child sex, gestational age, and breastfeeding duration, each 1-SD (0.36 g · kg-1 · d-1) increment in second-trimester protein intake corresponded to a -0.10 (95% CI: -0.18, -0.03) change in birth length z score, a -0.03 cm/mo (95% CI: -0.05, -0.01 cm/mo) change in slope of length growth from birth to <6mo, and a -0.09 cm/y (95% CI: -0.14, -0.05 cm/y) change in slope of length growth from 6 mo to midchildhood. Results were similar for first-trimester intake.ConclusionsIn a population with relatively high protein intake during pregnancy, higher protein intake was associated with shorter offspring birth length and slower linear growth into midchildhood. Results suggest that higher protein intake during pregnancy does not increase fetal and child growth and may even reduce early length growth. Project Viva was registered at clinicaltrials.gov as NCT02820402.

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Dataset Information

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

Publications

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

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