title: Effects of valproic acid on the placental barrier in the pregnant mouse: Optical imaging and transporter expression studies.
abstract: Our aim was to evaluate the effects of valproic acid (VPA) on the function of the placental barrier in vivo, in pregnant mice. Studies were conducted on gestational days 12.5 (mid-gestation) or 17.5 (late gestation), following intraperitoneal treatment with 200 mg/kg VPA or the vehicle. Indocyanine green (ICG; 0.167 mg, i.v.) was used as a marker for the placental barrier permeability. Transporter expression was evaluated by quantitative -PCR. VPA treatment was associated with a 40% increase (p < 0.05) in accumulation of ICG in maternal liver in mid-pregnancy and a decrease by one fifth (p < 0.05) in late pregnancy. Ex vivo, VPA treatment led to a 20% increase (p < 0.05) in fetal ICG emission in mid-pregnancy. Also in mid-pregnancy, the placental expression of the L-type amino acid transporter, the organic anion-transporting polypeptide (Oatp)4a1 (thyroid hormone transporter), and the reduced folate carrier was lower in VPA-treated mice (p < 0.05). In late pregnancy, hepatic Oatp4a1 levels were 40% less than in controls (p > 0.05). The observed changes in placental transporter expression and function support further research into the potential role of the placenta in the adverse pregnancy outcomes of VPA. Near-infrared imaging provides a noninvasive, nonradioactive tool for future studies on the effects of epilepsy and antiepileptic drugs on tissue transport functions.
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Meir
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Ameer
authors.initials: A
authors.lastname: Bishara
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Aniv
authors.initials: A
authors.lastname: Mann
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Udi
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Emma
authors.initials: E
authors.lastname: Portnoy
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Miri
authors.initials: M
authors.lastname: Shmuel
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Eyal
mesh_terms: D000367:Age Factors; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005260:Female; D005333:Fetus / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005865:Gestational Age; D007208:Indocyanine Green; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D061848:Optical Imaging; D010920:Placenta / Q000187:drug effects* / Q000503:physiopathology; D011247:Pregnancy; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D026901:Membrane Transport Proteins; D014635:Valproic Acid; D007208:Indocyanine Green
keywords: Indocyanine green; Near-infrared imaging; Organic anion-transporting polypeptides; Placenta; Pregnancy; Valproic acid