Diabetic mice exhibit increased mortality and morbidity following stroke. Recent studies from our laboratory have indicated that increased morbidity in diabetic db/db mice relative to their non-diabetic db/+ littermates is associated with increased levels of MMP-9 protease activity, increased blood-brain barrier (BBB) permeability, and greater neutrophil infiltration following hypoxic/ischemic (H/I) insult. Neutrophils are a major source of proteases and reactive oxygen species and studies have reported neutrophil depletion/inhibition is protective in certain models of experimental stroke. The objective of the current study is to determine the role of neutrophils in the increased morbidity seen in db/db mice following acute ischemic stroke. In this study, we found a significant increase in circulating neutrophils in the db/db mice at 4 h post H/I, which bound to endothelial cells in the ipsilateral hemisphere and infiltrated into brain tissue by 24 h of recovery. Depletion of circulating neutrophils resulted in reduced neutrophil concentrations in blood and in the ipsilateral hemispheres of the brain of both db/+ and db/db mice and decreased the levels of MMP-9 within the infarcted area. This resulted in smaller infarct size in the db/db mice compared to non-treated controls but did not affect stroke outcome in db/+ mice. While there was a significant correlation between neutrophil number and the levels of MMP-9 in the ipsilateral hemisphere of control and diabetic mice, surprisingly, neutrophil depletion had no effect on BBB permeability in either group. Thus, the current study suggests that neutrophil depletion reduces MMP-9 protease levels and improves stroke outcome in db/db mice but not in their db/+ counterparts.

糖尿病小鼠中风后死亡率和发病率增加。我们实验室最近的研究表明，糖尿病db/db小鼠相对于非糖尿病db/+同窝小鼠的发病率增加与 MMP-9 蛋白酶活性水平增加、血脑屏障 (BBB) 通透性增加和更大的血脑屏障 (BBB) 通透性相关。缺氧/缺血（H/I）损伤后中性粒细胞浸润。中性粒细胞是蛋白酶和活性氧的主要来源，研究报告中性粒细胞消耗/抑制在某些实验性中风模型中具有保护作用。本研究的目的是确定中性粒细胞在db/db小鼠急性缺血性中风后发病率增加中的作用。在这项研究中，我们发现H/I 后 4 小时，db/db小鼠的循环中性粒细胞显着增加，这些中性粒细胞与同侧半球的内皮细胞结合，并在恢复 24 小时时渗透到脑组织中。循环中性粒细胞的消耗导致db/+和db/db小鼠血液和同侧大脑半球中的中性粒细胞浓度降低，并降低梗塞区域内的 MMP-9 水平。与未治疗的对照组相比，这导致db/db小鼠的梗塞面积更小，但不影响db/+小鼠的中风结果。虽然对照组和糖尿病小鼠同侧半球的中性粒细胞数量和 MMP-9 水平之间存在显着相关性，但令人惊讶的是，中性粒细胞耗竭对两组的 BBB 通透性均没有影响。因此，目前的研究表明，中性粒细胞耗竭会降低db/db小鼠的 MMP-9 蛋白酶水平并改善中风结果，但不会改善db/+小鼠的中风结果。