Li Wanlu, He Tingting, Jiang Lu, Shi Rubing, Song Yaying, Mamtilahun Muyassar, Ma Yuanyuan, Zhang Zhijun, Tang Yaohui, Yang Guo-Yuan, Wang Yongting
School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Neurosci. 2020 Aug 11;14:842. doi: 10.3389/fnins.2020.00842. eCollection 2020.
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). Hyperglycemia was induced by a single bolus streptozotocin injection. Adult male ICR mice ( = 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. Fingolimod treatment reduced the number of infiltrated inflammatory cells and lowered the mRNA level of α. 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. Caution should be taken in considering the acute treatment using fingolimod for ischemic stroke with diabetes comorbidity.
糖尿病会增加中风的发病率和死亡率，并阻碍中风后的功能恢复。在没有合并症的小鼠中，已证明芬戈莫德可改善缺血性损伤后的神经功能恢复并减少脑梗死。在这项研究中，我们研究了芬戈莫德对短暂性大脑中动脉闭塞（tMCAO）后糖尿病小鼠的影响。通过单次注射链脲佐菌素诱导高血糖症。成年雄性ICR小鼠（n = 86）接受1小时的tMCAO手术，并在再灌注后立即腹腔注射芬戈莫德（1 mg/kg）或赋形剂。在tMCAO后24小时评估克拉克神经学评分、脑梗死和水肿、血脑屏障（BBB）完整性、细胞凋亡和炎症。芬戈莫德治疗减少了浸润性炎症细胞的数量，并降低了α的mRNA水平。它还增加了Bcl-2/Bax的比率。然而，芬戈莫德显著加重了脑水肿，并降低了紧密连接蛋白ZO-1和闭合蛋白的表达水平。芬戈莫德对血脑屏障完整性的负面影响超过了其在抗炎方面的有益作用，这导致tMCAO后24小时的终点结局没有改善。在考虑对合并糖尿病的缺血性中风使用芬戈莫德进行急性治疗时应谨慎。
