Dept of Neural & Behavioral Sciences, College of Medicine, Penn State University, Hershey Medical Center, Hershey, PA, USA.
Department of Neurology, College of Medicine, Penn State University, Hershey, PA, USA.
Neurochem Int. 2020 Oct;139:104790. doi: 10.1016/j.neuint.2020.104790. Epub 2020 Jul 9.
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.
糖尿病小鼠在中风后死亡率和发病率增加。我们实验室的最近研究表明，与非糖尿病 db/+同窝仔相比，糖尿病 db/db 小鼠的发病率增加与 MMP-9 蛋白酶活性增加、血脑屏障 (BBB) 通透性增加以及缺氧/缺血 (H/I) 损伤后中性粒细胞浸润增加有关。中性粒细胞是蛋白酶和活性氧的主要来源，研究报告称，在某些实验性中风模型中，中性粒细胞耗竭/抑制具有保护作用。本研究旨在确定中性粒细胞在急性缺血性中风后 db/db 小鼠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 小鼠循环中性粒细胞数量显著增加，这些中性粒细胞与同侧半球的内皮细胞结合，并在恢复 24 小时后渗透到脑组织中。循环中性粒细胞的耗竭导致 db/+ 和 db/db 小鼠血液和同侧半球中的中性粒细胞浓度降低，并降低了梗塞区域内的 MMP-9 水平。与未经治疗的对照组相比，这导致 db/db 小鼠的梗塞面积更小，但对 db/+ 小鼠的中风结局没有影响。虽然在对照组和糖尿病小鼠的同侧半球中，中性粒细胞数量与 MMP-9 水平之间存在显著相关性，但令人惊讶的是，中性粒细胞耗竭对两组的 BBB 通透性均无影响。因此，本研究表明，中性粒细胞耗竭可降低 MMP-9 蛋白酶水平并改善 db/db 小鼠的中风结局，但对其 db/+ 同窝仔没有影响。
