title: The essential role of endothelial nitric oxide synthase activation in insulin-mediated neuroprotection against ischemic stroke in diabetes.
abstract: BACKGROUND
  Stroke patients with diabetes have a higher mortality rate, worse neurologic outcome, and more severe disability than those without diabetes. Results from clinical trials comparing the outcomes of stroke seen with intensive glycemic control in diabetic individuals are conflicting. Therefore, the present study was aimed to identify the key factor involved in the neuroprotective action of insulin beyond its hypoglycemic effects in streptozotocin-diabetic rats with ischemic stroke.
  
  
  METHODS
  Long-Evans male rats were divided into three groups (control, diabetes, and diabetes treated with insulin) and subjected to focal cerebral ischemia-reperfusion (FC I/R) injury.
  
  
  RESULTS
  Hyperglycemia aggravated FC I/R injuries with an increase in cerebral infarction and neurologic deficits, inhibition of glucose uptake and membrane-trafficking activity of glucose transporter 1, and reduction of Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebrum. Insulin treatment alleviated hyperglycemia and the symptoms of diabetes in streptozotocin-diabetic rats. Insulin administration also significantly decreased cerebral infarction and neurologic deficits and increased phosphorylation of Akt and eNOS protein in the cerebrum of FC I/R-injured diabetic rats. However, the glucose uptake and membrane trafficking activity of glucose transporter 1 in the cerebrum were not restored by insulin treatment. Coadministration of the eNOS inhibitor, N-iminoethyl-L-ornithine, with insulin abrogated beneficial effects of insulin on cerebral infarct volume and neurologic deficits in FC I/R-injured diabetic rats without affecting the hypoglycemic action of insulin.
  
  
  CONCLUSIONS
  These results suggest that eNOS activation is required for the neuroprotection of insulin against ischemic stroke in patients with diabetes.
authors.affiliation: Department of Pharmacology and Institute of Medicine, Chung Shan Medical University and Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shiang-Suo
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Department and Graduate Institute of Biomedical Sciences and Healthy Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yi-Jhu
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Department and Graduate Institute of Biomedical Sciences and Healthy Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Jiung-Pang
authors.initials: JP
authors.lastname: Huang
authors.affiliation: Department and Graduate Institute of Biomedical Sciences and Healthy Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Yang-Tzu
authors.initials: YT
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University and Department of Anesthesiology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Day
authors.affiliation: Department and Graduate Institute of Biomedical Sciences and Healthy Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: lisahung@mail.cgu.edu.tw.
authors.forename: Li-Man
authors.initials: LM
authors.lastname: Hung
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051246:Glucose Transport Proteins, Facilitative / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020521:Stroke / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051246:Glucose Transport Proteins, Facilitative; D007004:Hypoglycemic Agents; D007328:Insulin; D018696:Neuroprotective Agents; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D051057:Proto-Oncogene Proteins c-akt