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Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes

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Abstract

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tissue plasminogen activator (tPA) treatment. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT), and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low-dose tPA will improve the functional recovery after the embolic stroke in both control and diabetic male and female animals. Diabetes was induced in age-matched male and female Wistar rats with high fat diet and low-dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with clot occlusion of the middle cerebral artery (MCA). The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. An additional set of animals were subjected to 90 min MCAO with suture. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. In the control groups, female rats had smaller infarcts and better functional outcomes. tPA decreased infarct size in both sexes with a greater effect in males. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. In the diabetic groups, neuronal injury increased in females reaching that of the infarct sizes seen in male rats. tPA decreased infarct size in females but not males. HT was greater in female rats than in males and was not further increased with tPA. Diabetes worsened neurological deficits in both sexes. Male animals showed improved sensorimotor skills, especially with tPA treatment, but there was no improvement in females. These data suggest that diabetes amplifies neurovascular injury and neurological deficits in both sexes. Human dose tPA offers some degree of protection in male but not female rats. Given that control female animals experience less injury compared to male rats, the diabetes effect is more profound in females.

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Acknowledgements

Adviye Ergul is a Research Career Scientist at the Charlie Norwood Veterans Affairs Medical Center in Augusta, Georgia. This work was supported in part by the VA Merit Award (BX000347), VA Research Career Scientists Award, and NIH (R01NS083559) to Adviye Ergul, and VA Merit Award (BX000891) and NIH award (NS063965) to Susan C. Fagan. The contents do not represent the views of the Department of Veterans Affairs or the US Government.

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Authors and Affiliations

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

    Weiguo Li, Guangkuo Dong, Susan C. Fagan & Adviye Ergul

  2. Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Weiguo Li, John Paul Valenzuela, Guangkuo Dong & Adviye Ergul

  3. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Rebecca Ward

  4. Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA

    Susan C. Fagan & Adviye Ergul

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  1. Weiguo Li
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Correspondence to Adviye Ergul.

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All institutional and national guidelines for the care and use of laboratory animals were followed. All protocols were approved by the institutional animal care and use committee. This study was conducted in accordance with the National Institute of Health guidelines for the care and use of animals in research, and adhered to the current RIGOR guidelines for the translational research with respect to (1) blinding of the study, (2) randomization of treatment (intervention) groups, (3) power analysis, and (4) statistical analysis.

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The authors declare that they have no conflict of interest.

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Li, W., Ward, R., Valenzuela, J.P. et al. Diabetes Worsens Functional Outcomes in Young Female Rats: Comparison of Stroke Models, Tissue Plasminogen Activator Effects, and Sexes. Transl. Stroke Res. 8, 429–439 (2017). https://doi.org/10.1007/s12975-017-0525-7

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  • DOI: https://doi.org/10.1007/s12975-017-0525-7

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