Teratogenic effects of lamotrigine on rat fetal brain: a morphometric study

Abstract

-A study of the teratogenic activity of an antiepileptic drug -lamotrigine -was carried out in the brain of fetuses of rats who had received the drug. The dosage levels studied corresponded to four times the median effective dose (ED50) in rats. The drug was administered during the organogenesis period. Rats were sacrificed one day prior to term and fetuses were macroscopically examined, weighted and cephalic segments sectioned (Wilson technique), for histological study by stereological analysis, using Merz's grid for drawing and point counts. Cortex, subcortex, ependyma and lateral ventricles were analyzed. The same methodology was applied to the control group; data were compared with by the non-parametric Mann-Whitney statistical analysis test. Results showed that fetuses of the experimental group had reduced body weight at birth, increased volume and diameter of the cerebral structure, increased density of the subcortical layer, and ventricle dilatation .Possible mechanisms of this teratogenicity were discussed.KEY WORDS: teratogenesis, lamotrigine. Efeitos teratogênicos da lamotrigina em cérebro de fetos de ratos: estudos morfométricoRESUMO -Foi realizado estudo da atividade teratogênica de uma droga antiepiléptica -lamotrigina -em cérebro de fetos de ratas que receberam a droga. Estudamos dose que corresponde a 4 vezes a dose efetiva mediana (ED50) em ratos. A droga foi administrada durante o período de organogênese, as ratas foram sacrificadas 1 dia antes do termo e os fetos foram examinados macroscópicamente, pesados e foram realizados cortes no segmento cefálico (técnica de Wilson) e feito preparo histológico para análise estereológica (utilizado grade de Merz para desenho e contagem dos pontos). Foram analisados: córtex, subcórtex, epêndima e ventrículos laterais. A mesma metodologia foi aplicada ao grupo controle e os dados foram submetidos a análise estatística por teste não paramétrico de Mann-Whitney. Os resultados mostraram nos fetos do grupo tratado: redução do peso ao nascimento, aumento do diâmetro e volume da estrutura cerebral, aumento da densidade da camada subcortical e dilatação ventricular. Possíveis mecanismos de teratogenicidade foram discutidos.PALAVRAS-CHAVES: teratogênese, lamotrigina.

Protective Potential of Cynodon Dactylon Extract on Lamotrigine Induced Brain Toxicity in Mice Fetuses.

“…Microscopic study in present work showed derangement of architecture and interruptions in the continuity of the cortical layers, oedematous appearance in subcortical and periventricular zone, dilatation of ventricles and disruption of ependymal lining along with destruction and clumping of choroid plexus have been observed in the brain of treated group I fetuses. A similar finding was reported by Marchi et al (2001), who revealed that the use of lamotrigine during the organogenesis period was associated with histological alterations. They analyzed cortex, subcortex, ependyma and lateral ventricles in their study on rat brain, after giving LTG on 9-11 day of pregnancy.…”

“…The mice brain was used for the present study whereas rat brain was used for the previous study. Marchi et al, (2001) mentioned that fetuses of the LTG treated group had reduced body weight at birth, increased volume and diameter of the cerebral structure 2153 (Marchi et al, 2001). Another study also reported no significant difference in mean brain weight and mean brain volume in control and experimental rat foetuses (Sah N et al, 2013).…”

Effect of Lamotrigine on fetal rat brain morphology

“…Marchi et al demonstrated low birth weight and altered brain structure, which included increased volume and diameter of the cerebral structure, increased density of the subcortical layer, and ventricle dilation in lamotrigine treated rat fetus [13]. In our study also, though not significantly different, offspring of lamotrigine treated rat demonstrated relatively lower mean body weight and body length, and greater mean brain weight and brain volume.…”

Lamotrigine to prevent depressive episodes in bipolar disorder

“…16 Terato genicity has been reported in animal studies 17 and, while human studies have been suggestive rather than conclusive, there may be a small increase in overall risk of malformations among newborns exposed to lamotrigine. This is most likely at doses of 400mg and over, which are uncommon in psychiatric populations.…”