Department of Neurology, Ajou University School of Medicine, Ajou University Medical Center, Suwon, South Korea.
Department of Neurology, Ajou University School of Medicine, Ajou University Medical Center, Suwon, South Korea; Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, South Korea.
Exp Neurol. 2022 Feb;348:113922. doi: 10.1016/j.expneurol.2021.113922. Epub 2021 Nov 12.
Patients with diabetes suffer more severe ischemic stroke. A combination of metformin and dipeptidyl peptide-4 inhibitors is commonly prescribed to treat diabetes. Therefore, we aimed to determine if pretreatment with a combination of metformin and evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce cerebral infarct volume in rats with streptozotocin-induced diabetes. After confirming diabetes induction, the rats were treated with vehicle, evogliptin, metformin, or evogliptin/metformin combination for 30 days. Then, stroke was induced by transient middle cerebral artery occlusion (tMCAO). Infarct volume, oxidative stress, levels of methylglyoxal-modified protein, glucagon-like peptide-1 receptor (GLP-1R), AMPK, and Akt/PI3K pathway-related proteins, and post-stroke pancreatic islet cell volume were evaluated. Compared to vehicle, only the co-administration group had significantly reduced infarct volume from the effects of tMCAO; the regimen also improved glycemic control, whereas the individual treatments did not. Co-administration also significantly reduced methylglyoxal-modified protein level in the core of the brain cortex, and the expression of 4-HNE and 8-OHdG was reduced. Co-administration increased p-Akt levels in the ischemic core and mitigated the suppression of Bcl-2 expression. Plasma GLP-1 and dipeptidyl peptidase-4 levels and brain GLP-1R expression remained unaltered. In the pancreas, islet cell damage was reduced by co-administration. These results reveal that metformin and evogliptin co-administration ameliorates cerebral infarction associated with prolonged glycemic control and pancreatic beta cell sparing. Other potential protective mechanisms may be upregulation of insulin receptor signaling or reduction of methylglyoxal-induced neurotoxicity. The combination of metformin and evogliptin should be tested further for its potential against focal cerebral ischemia in diabetes patients.
患有糖尿病的患者会遭受更严重的缺血性中风。通常会开二甲双胍和二肽基肽酶-4 抑制剂的组合来治疗糖尿病。因此，我们旨在确定用二甲双胍和二肽基肽酶-4 抑制剂依格列净预处理是否可以减少链脲佐菌素诱导的糖尿病大鼠的脑梗死体积。在确认糖尿病诱导后，用载体、依格列净、二甲双胍或依格列净/二甲双胍组合治疗大鼠 30 天。然后，通过短暂性大脑中动脉闭塞（tMCAO）诱导中风。评估梗死体积、氧化应激、甲基乙二醛修饰蛋白、胰高血糖素样肽-1 受体（GLP-1R）、AMPK 和 Akt/PI3K 通路相关蛋白的水平，以及中风后胰岛细胞的体积。与载体相比，只有联合治疗组可显著减轻 tMCAO 的影响，从而降低梗死体积；该方案还改善了血糖控制，而单独治疗则没有。联合治疗还可显著降低大脑皮质核心中甲基乙二醛修饰蛋白的水平，并降低 4-HNE 和 8-OHdG 的表达。联合治疗可增加缺血核心中的 p-Akt 水平，并减轻 Bcl-2 表达的抑制。血浆 GLP-1 和二肽基肽酶-4 水平以及大脑 GLP-1R 表达保持不变。在胰腺中，联合治疗可减轻胰岛细胞损伤。这些结果表明，二甲双胍和依格列净联合治疗可改善与长期血糖控制和胰岛β细胞保护相关的脑梗死。其他潜在的保护机制可能是上调胰岛素受体信号或降低甲基乙二醛诱导的神经毒性。应该进一步测试二甲双胍和依格列净的联合用药，以评估其在糖尿病患者局灶性脑缺血中的潜在疗效。
