Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

中文翻译：

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SGLT2抑制剂恩格列净促进糖尿病小鼠中风后功能恢复

2 型糖尿病 (T2D) 会恶化中风恢复，加剧中风后残疾。目前，还没有针对这一重要临床问题的疗法。钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 是有效的抗糖尿病药物，还可有效减少心血管死亡和心力衰竭。此外，SGLT2i 还可促进中风恢复中涉及的多个过程。然而，SGLT2i 改善 T2D 中风恢复的潜在功效尚未得到研究。因此，我们确定使用 SGLT2i Empagliflozin 进行中风后干预是否可以改善 T2D 小鼠的中风恢复。C57BL6J 小鼠通过 8 个月的高脂肪饮食喂养诱导 T2D。此后，对动物进行短暂的大脑中动脉闭塞，并从中风后第3天开始用媒介物或SGLTi Empagliflozin（10 mg/kg/天）进行治疗。在非糖尿病小鼠中也进行了类似的研究。使用前爪握力测试评估中风恢复。为了确定恩格列净介导作用的潜在机制，评估了几个代谢参数。此外，使用免疫组织化学/定量显微镜分析神经元存活、神经炎症、神经发生和脑血管化。恩格列净显着改善了 T2D 小鼠的中风恢复，但对非糖尿病小鼠没有影响。功能恢复的改善与血糖降低、成纤维细胞生长因子-21 (FGF-21) 血清水平升高以及 T2D 诱导的实质周细胞密度畸变正常化相关。全球 T2D 流行以及 T2D 是中风主要危险因素的事实正在急剧增加需要有效治疗以改善中风康复的人数。我们的数据为 SGLT2i 治疗 T2D 中风后后遗症的潜在用途提供了强有力的动力。