Neurodevelopmental toxicity of escitalopram and venlafaxine in PC12 and chicken cerebellum granule neurons, and kinetic studies of escitalopram in chicken embryo.

Abstract

Depression during pregnancy can be a danger for both mother and fetus. Therefore, treatment is often considered necessary even though pregnant women are often excluded from clinical trials, and the knowledge of the potential risk of the drug for the fetus is often lacking. Therefore, an increased understanding of the effects of escitalopram and venlafaxine, the first treatment choice for pregnant women, on neurodevelopment is desired. In vitro viability studies were performed in PC12 cells and primary cultures of chicken cerebellum granule neurons with MTT assay after exposure to escitalopram and venlafaxine. In addition, western blot analysis, real-time PCR, and live cell imaging with IncuCyte were done for chicken granule neurons. High-content imaging for chicken cerebellum granule neurons stained for synaptogenesis was also done. The chicken embryo can be used for preclinical neurotoxicological studies. However, there is no available data on the distribution of escitalopram and its effect in the chicken fetus. Therefore, a kinetic analysis of the drug was performed. The studies in this thesis showed a decreased viability in both PC12 cells and chicken cerebellum granule neurons 72 hours after exposure to 100 µM escitalopram. However, no changes were found in the viability of chicken cerebellum granule neurons after exposure to venlafaxine. A significant reduction in neurite length was found in chicken cerebellum granule neurons for both escitalopram (100 µM) and venlafaxine (200 µM) 68 hours after exposure. The kinetic study of escitalopram injected onto CAM found that chickens can metabolize escitalopram into demethylescitalopram and that escitalopram reaches the brain in concentrations clinically relevant to human use. In conclusion, valuable information about the potential neurodevelopmental impact of antidepressants may be found in developing neuron cultures. Chicken embryo shows promise as an alternative in vivo model to testing pharmacokinetics and pharmacodynamic effects in the embryo.