Department of Anesthesiology, Affiliated Taizhou Hospital, Wenzhou Medical University, Linhai 317000, Zhejiang, China; Department of Anesthesiology, Taizhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), Linhai 317000, Zhejiang, China.
Department of Anesthesiology, Affiliated Taizhou Hospital, Wenzhou Medical University, Linhai 317000, Zhejiang, China; Department of Anesthesiology, Taizhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), Linhai 317000, Zhejiang, China.
Life Sci. 2019 Oct 15;235:116553. doi: 10.1016/j.lfs.2019.116553. Epub 2019 Jun 8.
Dexmedetomidine (Dex) has been noted to have neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury. However, the effect of Dex in diabetic hyperglycemia-exacerbated cerebral I/R injury and its underlying mechanism remain unclear.
The infarct volume and brain edema were evaluated by 2,3,5-triphenyltetrazolium chloride staining and standard wet-dry method. Modified neurological severity score was utilized to assess the neurological deficits. The oxidative stress and inflammation were evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and cell count kit-8 were applied to measure cell apoptosis and viability.
Dex treatment reduced infarct volume, decreased brain water content and improved neurological deficit in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Dex treatment reduced the levels of ROS, MDA, TNF-α and IL-1β in the entire middle cerebral artery territory of diabetic mice subjected to MCAO/R, as well as in primary culture of mouse hippocampal neurons stimulated with 50 mM glucose and oxygen glucose deprivation/reperfusion. Dex treatment inhibited neuronal apoptosis induced by diabetic hyperglycemia-exacerbated cerebral I/R injury. Dex upregulated nuclear factor of activated T-cells 5 (NFAT5) and Sirtuin 1 (SIRT1) expression, induced NF-E2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and inhibited the acetylation of Nrf2. However, these changes triggered by Dex treatment were abrogated by NFAT5 knockdown.
Dex protects against diabetic hyperglycemia-exacerbated cerebral I/R injury through attenuation of oxidative stress, inflammation and apoptosis. The underlying mechanism is at least the NFAT5/SIRT1/Nrf2 signaling pathway dependent.
右美托咪定（Dex）已被证明具有对抗脑缺血再灌注（I/R）损伤的神经保护作用。然而，Dex 在糖尿病高血糖加重的脑 I/R 损伤中的作用及其潜在机制仍不清楚。
通过 2,3,5-三苯基氯化四氮唑染色和标准干湿法评估梗死体积和脑水肿。改良神经功能严重程度评分用于评估神经功能缺损。通过检测活性氧（ROS）、丙二醛（MDA）、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β来评估氧化应激和炎症。末端脱氧核苷酸转移酶 dUTP 缺口末端标记法和细胞计数试剂盒-8 用于测量细胞凋亡和活力。
Dex 治疗可减少大脑中动脉闭塞/再灌注（MCAO/R）小鼠的梗死体积、脑水含量和改善神经功能缺损。Dex 治疗可降低糖尿病 MCAO/R 小鼠整个大脑中动脉区域以及 50mM 葡萄糖刺激的原代培养小鼠海马神经元和氧葡萄糖剥夺/再灌注中 ROS、MDA、TNF-α和 IL-1β的水平。Dex 治疗可抑制糖尿病高血糖加重的脑 I/R 损伤引起的神经元凋亡。Dex 上调核因子活化 T 细胞 5（NFAT5）和 Sirtuin 1（SIRT1）的表达，诱导 NF-E2 相关因子 2（Nrf2）从细胞质向细胞核转位，并抑制 Nrf2 的乙酰化。然而，Dex 治疗引起的这些变化被 NFAT5 敲低所阻断。
Dex 通过减轻氧化应激、炎症和细胞凋亡来保护大脑免受糖尿病高血糖加重的 I/R 损伤。其潜在机制至少与 NFAT5/SIRT1/Nrf2 信号通路有关。
