Shiang-Suo Huang1, Yi-Jhu Lu2, Jiung-Pang Huang2, Yang-Tzu Wu2, Yuan-Ji Day3, Li-Man Hung4. 1. Department of Pharmacology and Institute of Medicine, Chung Shan Medical University and Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. 2. Department and Graduate Institute of Biomedical Sciences and Healthy Aging Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. 3. Graduate Institute of Clinical Medical Sciences, Chang Gung University and Department of Anesthesiology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. 4. 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.
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.
BACKGROUND:Strokepatients 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-diabeticrats 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-diabeticrats. 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 diabeticrats. 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 diabeticrats 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: Charles E Amankwa; Sudershan R Gondi; Adnan Dibas; Courtney Weston; Arlene Funk; Tam Nguyen; Kytai T Nguyen; Dorette Z Ellis; Suchismita Acharya Journal: Antioxidants (Basel) Date: 2021-04-08
Authors: Irina O Zakharova; Liubov V Bayunova; Inna I Zorina; Tatiana V Sokolova; Alexander O Shpakov; Natalia F Avrova Journal: Int J Mol Sci Date: 2021-10-29 Impact factor: 5.923