PPARdelta agonista enhance the levels of PGE2 and phospholipids in embryos from control and diabetic rats during early organogenesis

HIGA ROMINA; GONZÁLEZ ELIDA; WHITE VERÓNICA; CAPOBIANCO EVANGELINA; PUSTOVRH CAROLINA; MARTÍNEZ NORA; JAWERBAUM ALICIA

Facultad de Medicina, Buenos Aires.

Workshop; I Taller de interacción materno-fetal: De la fisiología a la patología.; 2005

Centro de Estudios Farmacológicos y Botánicos (CONICET), Facultad de Farmacia y Bioquímica, Facultad de Medicina (UBA)

Alterations in the maternal environment due to the diabetic disease induce congenital malformations, such as embryonic neural tube defects in both diabetic women and diabetic experimental models. Neural tube closure requires extensive growth and formation of lipid membranes. A reduction in embryonic PGE2 levels has been previously related to diabetes-induced neural tube defects. The aim of this research was to evaluate whether agonists of the nuclear receptor PPARdelta regulate the levels of phospholipids (main lipids constituent of membrane cells) and of PGE2 in embryos from control and diabetic rats, and to determine the levels of PGI2 (endogenous PPARdelta agonist) in these embryos. Methods: Embryos from control and diabetic rats (obtained through administration of streptozotocin 50 mg/kg preconceptionally) were explanted on day 10.5 of gestation, frozen for determination of 6-keto-PGF1alpha, stable metabolite of PGI2 (by EIA), or cultured for three hours in the presence of the PPARdelta agonist carboxyprostacyclin (cPGI2, stable analogue of  PGI2) for further determination of both phospholipid levels (by TLC and densitometry) and PGE2 (by RIA). Results: The addition of cPGI2 (1 uM) enhances phospholipid levels in embryos from control (52%) and diabetic (54%) rats. The addition of cPGI2 (1 uM) increases PGE2 levels in the embryos from control (196%) and diabetic (68%) rats. These effects seem to involve PPARdelta activation since embryonic PGE2 and phospholipid levels were also stimulated by PGA1, another PPARdelta activator. Levels of 6-keto-PGF1alpha, stable metabolite of PGI2, were reduced in embryos from diabetic rats (74%) when compared to controls. Conclusions: Activation of  PPARdelta results in enhanced levels of PGE2 and phospholipids, metabolites involved in the process of neural tube closure. These results, together with the maternal diabetes-induced alterations in the levels of the endogenous PPARdelta activator PGEI2, provide new insights into the mechanisms o diabetic embryopathy.