Background and Purpose: Diabetes mellitus increases stroke incidence and mortality and hampers functional recovery after stroke. Fingolimod has been shown to improve neurofunctional recovery and reduce brain infarction after ischemic injury in mice without comorbidities. In this work, we investigated the effects of fingolimod in diabetic mice after transient middle cerebral artery occlusion (tMCAO). Methods: Hyperglycemia was induced by a single bolus streptozotocin injection. Adult male ICR mice (n = 86) underwent 1-h tMCAO surgery and received intraperitoneal injection of fingolimod (1 mg/kg) or vehicle immediately after reperfusion. Clark neurological score, brain infarction and edema, blood–brain barrier (BBB) integrity, apoptosis, and inflammation were evaluated at 24 h after tMCAO. Results: Fingolimod treatment reduced the number of infiltrated inflammatory cells and lowered the mRNA level of Tnfα. It also increased the ratio of Bcl-2/Bax. However, fingolimod significantly aggravated brain edema and reduced the expression levels of tight junction proteins ZO-1 and Occludin. The negative impacts of fingolimod on BBB integrity outweighed its beneficial effects in anti-inflammation, which resulted in the lack of improvement in endpoint outcomes at 24 h after tMCAO. Conclusion: Caution should be taken in considering the acute treatment using fingolimod for ischemic stroke with diabetes comorbidity.

中文翻译：

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芬戈莫德抑制炎症但加剧糖尿病小鼠脑缺血急性期的脑水肿

背景和目的：糖尿病会增加卒中的发病率和死亡率，并阻碍卒中后的功能恢复。在没有合并症的小鼠中，芬戈莫德已被证明可以改善神经功能恢复并减少缺血性损伤后的脑梗塞。在这项工作中，我们研究了芬戈莫德对短暂大脑中动脉闭塞 (tMCAO) 后糖尿病小鼠的影响。方法：通过单次推注链脲佐菌素诱导高血糖症。成年雄性 ICR 小鼠 (n = 86) 接受 1 小时 tMCAO 手术，并在再灌注后立即接受腹腔注射芬戈莫德 (1 mg/kg) 或载体。在 tMCAO 后 24 小时评估克拉克神经学评分、脑梗塞和水肿、血脑屏障 (BBB) 完整性、细胞凋亡和炎症。结果：芬戈莫德治疗减少了浸润炎症细胞的数量并降低了 Tnfα 的 mRNA 水平。它还增加了 Bcl-2/Bax 的比率。然而，芬戈莫德显着加重脑水肿并降低紧密连接蛋白 ZO-1 和 Occludin 的表达水平。芬戈莫德对 BBB 完整性的负面影响超过了其抗炎作用，导致 tMCAO 后 24 小时终点结果没有改善。结论：考虑使用芬戈莫德治疗合并糖尿病的缺血性脑卒中的急性治疗应谨慎。芬戈莫德对 BBB 完整性的负面影响超过了其抗炎作用，导致 tMCAO 后 24 小时终点结果没有改善。结论：考虑使用芬戈莫德治疗合并糖尿病的缺血性脑卒中的急性治疗应谨慎。芬戈莫德对 BBB 完整性的负面影响超过了其抗炎作用，导致 tMCAO 后 24 小时终点结果没有改善。结论：考虑使用芬戈莫德治疗合并糖尿病的缺血性脑卒中的急性治疗应谨慎。