Anesthesia Operation Department, Zhejiang Hospital, China.
School of Basic Medicine, Zhejiang Chinese Medical University, China.
J Toxicol Sci. 2022;47(5):169-181. doi: 10.2131/jts.47.169.
Dexmedetomidine (DEX) protects against acute stress-induced liver injury, but what's less clear lies in the specific mechanism. To elucidate the specific mechanism underlying DEX on acute stress-induced liver injury, an in vivo model was constructed on rats with acute stress-induced liver injury by 15 min of exhaustive swimming and 3 hr of immobilization. DEX (30 μg/kg) or miR-34a-5p agomir was injected into model rats. Open field test was used to verify the establishment of the model. Liver injury was observed by hematoxylin-eosin (H&E) staining. Contents of norepinephrine (NE), alanine aminotransfease (ALT) and aspartate aminotransferase (AST) in serum of rats were detected by enzyme-linked immunosorbent assay (ELISA) and those of oxidative stress markers (reactive oxygen species (ROS), Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPX)) were measured using commercial kits. Apoptosis of hepatocytes was detected by Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Western blot was performed to detect the expressions of SOD2, COX-2, cytochrome C, Cleaved caspase 3, Bax, Bcl-2, P-JNK, JNK, P-p38, p38 and c-AMP, p-PKA and PKA in liver tissues. As a result, liver injury in model rat was alleviated by DEX. DEX attenuated the increase in the levels of NE, ALT, AST, MDA, ROS, apoptosis, SOD2, COX-2, Cytochrome C, cleaved caspase 3, Bax, and P-JNK, P-p38, c-AMP, P-PKA and miR-34a-5p, and the decrease in the levels of SOD, GPX, GSH and Bcl-2 in model rats. Furthermore, miR-34a-5p overexpression could partly reverse the effects of DEX. Collectively, DEX could alleviate acute stress-induced liver injury through ROS/JNK/p38 signaling pathway via downregulation of miR-34a-5p.
右美托咪定（DEX）可预防急性应激诱导的肝损伤，但具体机制尚不清楚。为了阐明 DEX 对急性应激诱导的肝损伤的具体机制，通过 15 分钟的力竭游泳和 3 小时的固定构建了急性应激诱导的肝损伤的体内模型。DEX（30μg/kg）或 miR-34a-5p agomir 被注射到模型大鼠中。旷场试验用于验证模型的建立。通过苏木精-伊红（H&E）染色观察肝损伤。通过酶联免疫吸附试验（ELISA）检测大鼠血清中去甲肾上腺素（NE）、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）的含量，通过商业试剂盒检测氧化应激标志物（活性氧（ROS）、丙二醛（MDA）、谷胱甘肽（GSH）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GPX））的含量。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测肝细胞凋亡。通过 Western blot 检测肝组织中 SOD2、COX-2、细胞色素 C、Cleaved caspase 3、Bax、Bcl-2、P-JNK、JNK、P-p38、p38 和 c-AMP、p-PKA 和 PKA 的表达。结果，DEX 减轻了模型大鼠的肝损伤。DEX 降低了模型大鼠中 NE、ALT、AST、MDA、ROS、凋亡、SOD2、COX-2、细胞色素 C、Cleaved caspase 3、Bax 和 P-JNK、P-p38、c-AMP、P-PKA 和 miR-34a-5p 的水平，增加了 SOD、GPX、GSH 和 Bcl-2 的水平。此外，miR-34a-5p 的过表达可以部分逆转 DEX 的作用。综上所述，DEX 可通过下调 miR-34a-5p 减轻 ROS/JNK/p38 信号通路介导的急性应激诱导的肝损伤。
