title: Reduction in embryonic malformations and alleviation of endoplasmic reticulum stress by nitric oxide synthase inhibition in diabetic embryopathy.
abstract: Maternal diabetes-induced neural tube defects (NTDs) are associated with increased programmed cell death (apoptosis) in the neuroepithelium, which is related to intracellular nitrosative stress. To alleviate nitrosative stress, diabetic pregnant mice were fed via gavage an inhibitor of nitric oxide (NO) synthase (NOS) 2, L-N6-(1-iminoethyl)-lysine (L-NIL; 80 mg/kg), once a day from embryonic (E) day 7.5 to 9.5 during early stages of neurulation. The treatment significantly reduced NTD rate in the embryos, compared with that in vehicle (normal saline)-treated diabetic group. In addition to alleviation of nitrosative stress, endoplasmic reticulum (ER) stress was also ameliorated, assessed by quantification of associated factors. Apoptosis was reduced, indicated by caspase 8 activation. These results show that nitrosative stress is important in diabetes-induced NTDs via exacerbating ER stress, leading to increased apoptosis. Oral treatment with NOS-2 inhibitor alleviates nitrosative and ER stress, decreases apoptosis, and reduces NTDs in the embryos, providing information for further interventional studies to reduce diabetes-associated birth defects.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. zzhao@upi.umaryland.edu
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
authors.forename: E Albert
authors.initials: EA
authors.lastname: Reece
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D005260:Female; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D008810:Mice, Inbred C57BL; D054259:Neural Tube / Q000201:enzymology / Q000473:pathology; D009436:Neural Tube Defects / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000201:enzymology*
chemical_list: C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D053181:Caspase 8; D008239:Lysine