Glycemic Control Confers Cerebrovascular Protection and Improves Neurological Outcomes in Diabetic Ischemic Brain Injury
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1
College of Pharmacy, University of Georgia, Program in Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, United States
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2
Van der Veer Institute for Parkinson's and Brain Research, Department of Physiology, United States
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3
Charlie Norwood Veterans Affairs Medical Center, United States
We have previously shown that temporary focal ischemia by middle cerebral artery occlusion (MCAO) causes greater hemorrhagic transformation (HT) and neurological deficits in diabetic Goto-Kakizaki (GK) rats, a model that presents with increased cerebrovascular MMP activity and tortuosity.
Purpose: The goals of this study were to test the hypotheses that 1) diabetes-induced cerebrovascular remodeling is MMP-dependant, and 2) prevention of vascular remodeling by glucose control reduces HT and functional outcomes in diabetes after focal ischemia.
Methods: Male Wistar control and diabetic GK rats were treated with vehicle, metformin (300 mg/kg/day) from the onset of diabetes in GK rats (6 weeks) till they reached the weight for MCAO (11 weeks, 270-300 g). A cohort was then sacrificed after injection of the resin Pu4ii to visualize the pial vessels and vascular tortuosity index, lumen diameter, number of collaterals between MCA and ACA and number of anostomoses within the MCA tree were measured as indices of remodeling. In a second cohort, MMP activity was evaluated by zymography of isolated MCAs. A third cohort was subjected to 3h MCAO/21h reperfusion and infarct size and HT were evaluated as indices of neurovascular injury.
Results: All remodeling markers including MMP-9 activity were increased in diabetes and treatment with metformin prevented these changes (see Table). There was no change in infarct size by metformin yet both severity of HT and neurological deficits were significantly reduced.
Conclusions: Thus diabetes-mediated stimulation of MMP-9 activity promotes cerebrovascular remodeling and augmented remodeling contributes to increased HT in diabetes. Glycemic control through metformin offers vascular protection and improves behavioral outcomes that has important clinical implications for patients with diabetes who are at a 4 to 6-fold higher risk for stroke.
Conference:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences, Atlanta , United States, 5 Mar - 7 Mar, 2010.
Presentation Type:
Oral Presentation
Topic:
Talks
Citation:
Prakash
R,
Elgebaly
MM,
Ogbi
S,
Kelly-Cobbs
A,
Li
W,
Fagan
SC and
Ergul
A
(2010). Glycemic Control Confers Cerebrovascular Protection and Improves Neurological Outcomes in Diabetic Ischemic Brain Injury.
Front. Neurosci.
Conference Abstract:
2010 South East Nerve Net (SENN) and Georgia/South Carolina Neuroscience Consortium (GASCNC) conferences.
doi: 10.3389/conf.fnins.2010.04.00017
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Received:
15 Mar 2010;
Published Online:
15 Mar 2010.
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Correspondence:
Roshini Prakash, College of Pharmacy, University of Georgia, Program in Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy, Athens, United States, roprakash@mcg.edu