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Comparative Analysis of Different Methods of Ischemia/Reperfusion in Hyperglycemic Stroke Outcomes: Interaction with tPA

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Abstract

Acute hyperglycemia (HG) exacerbates reperfusion injury and aggravates tissue plasminogen activator (tPA)-induced hemorrhagic transformation (HT). Previous experimental hyperglycemic stroke studies employed very high blood glucose levels and exclusively used suture occlusion model to induce ischemia. Only few studies evaluated HG in embolic stroke and mostly involving the use of 10-fold higher dose of tPA than that is used in patients. However, the interaction between acute HG and low (human) dose tPA in different experimental models of stroke has never been reported. We first tested the impact of the severity of acute HG on stroke outcome. Building upon our findings, we then compared the impact of mild acute HG on neurovascular injury in rats subjected to suture or thromboembolic occlusion with and without low dose tPA. We assessed cerebral blood flow, neurobehavioral outcomes, infarction, hemorrhage, and edema. tPA did not change the infarct size in either control or hyperglycemic animals when compared to no tPA groups. HG increased HT and worsened functional outcomes in both suture and embolic occlusion models. The combination of HG and tPA exacerbated the vascular injury and worsened the neurological deficits more than each individual treatment in both models. Our findings show that the interaction between HG and even low dose tPA has detrimental effects on the cerebrovasculature and functional outcomes independent of the method of reperfusion.

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Acknowledgments

Adviye Ergul is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, GA. This work was supported in part by VA Merit Award (BX000347), VA Research Career Scientists Award, and NIH (R01NS083559) to Adviye Ergul; VA Merit Award (BX000891) and NIH award (NS063965) to Susan C. Fagan; and American Heart Association Predoctoral Fellowship (13PRE17090026) to Sherif Hafez. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Compliance with Ethics Requirements

All institutional and national guidelines for the care and use of laboratory animals were followed.

Conflict of Interest

Sherif Hafez declares that he has no conflict of interest. Md Nasrul Hoda declares that he has no conflict of interest. Xinyue Guo declares that she has no conflict of interest. Maribeth H. Johnson declares that she has no conflict of interest. Susan C. Fagan declares that she has no conflict of interest. Adviye Ergul declares that she has no conflict of interest.

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Authors and Affiliations

  1. Charlie Norwood Veterans Administration Medical Center, Augusta, GA, USA

    Sherif Hafez, Xinyue Guo, Susan C. Fagan & Adviye Ergul

  2. Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Athens, GA, USA

    Sherif Hafez, Susan C. Fagan & Adviye Ergul

  3. Department of Neurology, Georgia Regents University, Augusta, GA, USA

    Md Nasrul Hoda & Susan C. Fagan

  4. Department of Medical Laboratory, Imaging and Radiologic Sciences, Georgia Regents University, Augusta, GA, USA

    Md Nasrul Hoda

  5. Department of Biostatistics, Georgia Regents University, Augusta, GA, USA

    Maribeth H. Johnson

  6. Department of Physiology, CA2094, Georgia Regents University, Augusta, GA, 30912, USA

    Xinyue Guo & Adviye Ergul

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  1. Sherif Hafez
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Correspondence to Adviye Ergul.

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Hafez, S., Hoda, M.N., Guo, X. et al. Comparative Analysis of Different Methods of Ischemia/Reperfusion in Hyperglycemic Stroke Outcomes: Interaction with tPA. Transl. Stroke Res. 6, 171–180 (2015). https://doi.org/10.1007/s12975-015-0391-0

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