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

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 (10mg/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 (30mg/kg, i.p.). Embolic stroke was induced with clot occlusion of the middle cerebral artery (MCA). The animals were treated with or without tPA (1mg/kg, i.v.) at 90min after surgery. An additional set of animals were subjected to 90min MCAO with suture. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3days 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.