[MAP kinase signal pathway in hyperglycemia-induced congenital neural tube defects].
The aim of the present study was to determine molecular mechanism in hyperglycemia-induced congenital neural tube defects and the its potential pharmacologic rescuing agents. In order to explore these questions, six study groups of Sprague-Dawley rats were employed: Group 1 was normal control rats with normal diet; group 2 represented streptozotocin (STZ) -induced diabetic rats with congenital neural tube defects in offspring; group 3 included STZ-induced diabetic rats with normal offspring; groups 4,5 and 6 included rats exposed to the same STZ-induced diabetic condition, but receiving daily oral supplementation of 80 microg/mL of the sodium salt of arachidonic acid (AA), 400mg of vitamin E and a cocktail of a polyunsaturated fatty acid (safflower oil) plus an antioxidant ( vitamin E) respectively. Yolk sac cells were harvested at gestational day 12 from each rat group. Changes in MAPK signaling pathways were detected by western blot analysis using special antibodies directed against phosphorylated forms of extracellular signal regulated kinase (ERK), Jun N-terminal/stress-activated protein kinase (JNK/SAPK). Furthermore, activity of RAF-1, an upstream kinase in ERK1/2 signaling cascade, was evaluated by immunoprecipitation assay. The results showed that in yolk sac cells in embryopathic offspring from experimentally-induced diabetic rats, activities of ERK1/2 were dramatically decreased (group 2). Consisted with these observation, reduction in RAF-1 kinase activity could be discerned in these diabetic yolk sac cells. In contrast, activities of JNK1/2 were significantly increased in yolk sac cells of group 2. Under rescuing circumstance,activations of ERK1/2 and RAF-1 were increased, and JNK1/2 were decreased. MAP kinase signal pathway plays a very important role in hyperglycemia induced neural tube defects. The supplementation of polyunsaturated fatty acid arachidonic acid, and antioxidant vitamin E rescued conceptuses from diabetic embryopathy by triggering a restoration of normal membrane signaling pathways.
Chen
Bi-Liang
BL
Department of Obstetrics & Gynecology, Xijing Hospital, Fourth Military Medical University, Xi'an 710 033, China. gynobs@fmmu.edu.cn
Ma
Xiang-Dong
XD
Xin
Xiao-Yan
XY
Wang
De-Tang
DT
Reece
E Albert
EA
D000818:Animals; D016718:Arachidonic Acid / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology; D004359:Drug Therapy, Combination; D005260:Female; D006943:Hyperglycemia / Q000150:complications*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology; D009436:Neural Tube Defects / Q000196:embryology / Q000201:enzymology / Q000209:etiology* / Q000517:prevention & control; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000188:drug therapy / Q000201:enzymology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012450:Safflower Oil / Q000627:therapeutic use; D015398:Signal Transduction; D014810:Vitamin E / Q000627:therapeutic use; D015017:Yolk Sac / Q000166:cytology / Q000201:enzymology
D014810:Vitamin E; D016718:Arachidonic Acid; D012450:Safflower Oil; D019908:Proto-Oncogene Proteins c-raf; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8