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

JAWERBAUM A; HIGA R; WHITE V; CAPOBIANCO E; PUSTOVRH C; MARTÍNEZ N; GONZÁLEZ E

Mykonos

Congreso; 37th Meeting of the Diabetes and Pregnancy Study Group (DPSG), European Association for the Study of Diabetes (EASD); 2005

Diabetes and Pregnancy Study Group, EASD.

Background: Neural tube defects are some of the main congenital malformations induced in pregnancies of both diabetic women and diabetic experimental models. During neural tube closure, apposition of neural folds 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 the present work 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 the 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 before mating) 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 mM) enhances phospholipid levels in the embryos from control (51%, p<0.005) and diabetic (54%, p<0.01) rats. The addition of cPGI2 (1 mM) increases PGE2 levels in the embryos from control (196%, p<0.01) and diabetic (68%, p<0.05) 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 the embryos from diabetic rats (74%, p<0.01) 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 PGI2, provide new insights into the mechanisms of diabetic embryopathy.