Effects of antiseizure medications on placental cells: Focus on heterodimeric placental carriers
Graphical abstract
Introduction
Continuous supply of nutrients via the placenta is essential for optimal embryonic and fetal development. To acquire nutrients from maternal blood, placental trophoblasts rely on specialized carriers in their plasma membrane, mostly of the solute carrier (SLC) family (Lin et al., 2015; Palm and Thompson, 2017; Tetro et al., 2018). Some of these transport mechanisms additionally control the transplacental transfer of drugs taken by the pregnant mother, including antiseizure medications (ASMs) (Hasegawa et al., 2020; Ohman et al., 2005) or may be modulated by ASMs (Tetro et al., 2018). For instance, valproate affects the expression of transporters for carnitine (Lahjouji et al., 2004; Wu et al., 2004), folate (Fathe et al., 2014; Rubinchik-Stern et al., 2015), and thyroid hormones (Rubinchik-Stern et al., 2015) in placental brush-border membrane vesicles or in cultured cells and numerous transporters in rodent placentas in vivo (Jinno et al., 2020; Meir et al., 2016). We have additionally demonstrated that valproate modulates at the transcriptional level major carriers for folate and amino acids in term human placentas (Rubinchik-Stern et al., 2018) and in cultured placental tissue of gestational age 6–13 weeks (Tetro et al., 2019). Lamotrigine, carbamazepine and levetiracetam altered in the placental cell line BeWo the levels of carriers for folate, thyroid hormones, or both, including the L-type amino acid transporter LAT1/SLC7A5 (Rubinchik-Stern et al., 2015).
Given the emerging effects of ASMs on the growth and the structural and cognitive development of the fetus (Meador, 2020; Meador et al., 2013, 2020; Stephen et al., 2019; Tomson et al., 2018, 2011), in this work we extended our analysis to spotlight representative heterodimeric placental transporters. These transporters are comprised of a light chain (SLC7) and a heavy chain (SLC3). Among the heavy chains, rBAT (SLC3A1) is important for amino acid transport system b0,+, whereas 4F2hc/SLC3A2 interacts with transporters of several systems, including LAT1, LAT2 (SLC7A8) (system L) and the cystine/glutamate antiporter xCT (SLC7A11) (Gottesdiener et al., 1988). LAT-mediated transport of essential amino acids activates pro-growth pathways, whereas cystine helps protect against oxidative stress (McCracken and Edinger, 2013; Timmerman et al., 2013).
Section snippets
Reagents
Cell culture reagents were purchased from Biological Industries (Beit Haemek, Israel). The RNeasy mini-isolation kit was from Qiagen (Valencia, CA, U.S.A.). TaqMan reverse transcription reagents and fluorescent minor groove binder (MGB) probes were from Applied Biosystems (Foster City, CA, U.S.A.). Lacosamide was from UCB Pharma, Brussels, Belgium. All other reagents and drugs were purchased from Sigma-Aldrich (Rehovot, Israel).
Cell culture and treatments
The human placental trophoblastic choriocarcinoma BeWo cell line
Results
BeWo cells were sensitive to valproate, levetiracetam and carbamazepine, whereas the effects of lamotrigine and lacosamide were minimal. After a short incubation period (two days), valproate increased SLC7A8 (LAT2) and SLC7A11 (xCT) expression in a concentration-dependent manner, with 2.0-fold and 1.8-fold increases at 166 μg/mL valproate, respectively (p < 0.01) (Fig. 1A). Valproate effect on SLC7A8 expression was sustained at five days (Fig. 1B). Levetiracetam at its high therapeutic
Discussion
Fetal exposure to ASMs can produce structural malformations, cognitive deficits, and behavioral abnormalities, and has been associated with pregnancy complications (Stephen et al., 2019). Valproate is the most teratogenic ASM whereas the risk is lower with lamotrigine, levetiracetam, carbamazepine and oxcarbazepine (Kasradze et al., 2017; Meador et al., 2013; Stephen et al., 2019; Tomson et al., 2018). However, it has been suggested that even pregnancy-safer ASMs can harm the fetus at high
Funding
The study was supported by the Israel Science Foundation (ISF) Grant #2054/18. The sponsor was not involved in study design; collection, analysis and interpretation of data; writing of the report; and the decision to submit the article for publication.
Declaration of Competing Interest
Sara Eyal has received speaker honoraria from Megapharm, Israel. The other authors have no conflicts of interest.
Acknowledgments
We acknowledge the support of the Israel Science Foundation (Grant #506/13). Sara Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.
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