Abstract 3216: Early Insulin Intervention Improves Tissue Plasminogen Activator Thrombolytic Therapy In A Focal Embolic Stroke Model Of Diabetic Rats
Background: Stroke patients with diabetes mellitus or post-stroke hyperglycemia are associated with resistance to tPA reperfusion, higher risk of intracerebral hemorrhage and worse neurological outcomes. Our laboratory has established an embolic focal stroke model in type I diabetic rats that closely mimic the clinical situation with worse neurological outcomes observed after tPA thrombolysis. Clinically insulin intervention did not show significant benefit to acute ischemic brain injury, perhaps due to the relatively late infusion time after stroke onset. In this study for the first time we aimed to test effects of early insulin intervention combined with following tPA thrombolytic therapy in neurological outcomes of focal embolic stroke model in type I diabetic rats.
Methods: Type I diabetic rats were induced by standard Streptozotocin i.p. injection. Six weeks type I diabetes rats were subjected into a focal embolic stroke. Four treatment groups: (1) saline at 1.5 hours after stroke; (2) standard rat dose 10 mg/kg of tPA at 1.5 hours after stroke; (3) insulin (i.h. 4 units and i.v. 2 units) at 1 hours plus saline at 1.5 hours; (4) insulin (i.h. 4 units and i.v. 2 units) at 1 hours plus 10 mg/kg tPA at 1.5 hours. Acute neurological outcomes were measured at 24 hours after stroke onset for brain infarction, hemispheric swelling, and hemorrhagic transformation.
Results: Blood glucose level of diabetic rats was 484±92 mg/dl at before stroke. Insulin infusion significantly decreased blood glucose levels. At 2.5 hours after stroke, blood glucose levels were 515±94 mg/dl for saline, 509±98 mg/dl for tPA alone, 325±77mg/dl for insulin plus saline, and 295±64 mg/dl for insulin plus tPA, respectively. At 24 hours after stroke, tPA slightly reduced infarction volume than saline group. Insulin significantly reduced 24% of brain infarction in tPA group, but not in saline group (11% reduction) compare to non-insulin controls. Insulin significantly decreased hemispheric swelling in both saline (40% reduction) and tPA groups (43% reduction). tPA treatment significantly increased hemorrhagic volume (6.23μ l/hemisphere), but insulin intervention eliminated the increased hemorrhagic volume (4.45μ l/hemisphere) elevated by tPA thrombolytics.
Discussion and Conclusion: Early insulin intervention may be safe and beneficial to tPA thrombolytics in reducing infarction volume, edema and intracerebral hemorrhage to ischemic stroke with diabetes mellitus or post-stroke hyperglycemia. Further investigations are needed for fully evaluating the early insulin intervention in preclinical settings and define underlying molecular mechanisms, in terms of optimizing its therapeutic effects in both safety and efficacy before clinical tests can be applied.
- © 2012 by American Heart Association, Inc.