Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes.
OBJECTIVE
Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy.


METHODS
Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetes-induced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocin-induced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos(-/-)).


RESULTS
ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetes-related congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos(-/-) mice and the incidence of other malformations was also markedly reduced.


CONCLUSIONS
We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.
Sugimura
Y
Y
Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya, Japan.
Murase
T
T
Oyama
K
K
Uchida
A
A
Sato
N
N
Hayasaka
S
S
Kano
Y
Y
Takagishi
Y
Y
Hayashi
Y
Y
Oiso
Y
Y
Murata
Y
Y
D000578:Amidines / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology*; D004195:Disease Models, Animal; D005260:Female; D005327:Fetal Resorption; D005333:Fetus; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use; D008098:Litter Size; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009436:Neural Tube Defects / Q000209:etiology / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D011247:Pregnancy
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D006574:Heterocyclic Compounds, 2-Ring; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester