右美托咪定通过抗炎和抗细胞凋亡机制减轻兔脊髓缺血再灌注损伤。

Dexmedetomidine attenuates spinal cord ischemia-reperfusion injury through both anti-inflammation and anti-apoptosis mechanisms in rabbits.

机构信息

Department of Anesthesiology, Shanghai Fengxian District Central Hospital, Southern Medical University, Shanghai, People's Republic of China.

Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, People's Republic of China.

出版信息

J Transl Med. 2018 Jul 21;16(1):209. doi: 10.1186/s12967-018-1583-7.

BACKGROUND

Dexmedetomidine (Dex) can improve neuronal viability and protect the spinal cord from ischemia-reperfusion (I/R) injury, but the underlying mechanisms are not fully understood. This study investigated the effects of dexmedetomidine on the toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NF-κB) inflammatory system and caspase-3 dependent apoptosis induced by spinal cord ischemia-reperfusion injury.

METHODS

Twenty-four rabbits were divided into three groups: I/R, Dex (10 µg/kg/h prior to ischemia until reperfusion), and Sham. Abdominal aortic occlusion was carried out for 30 min in the I/R and Dex groups. Hindlimb motor function was assessed using the Tarlov scoring system for gait evaluation. Motor neuron survival and apoptosis in the ventral grey matter were assessed by haematoxylin-eosin staining and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling staining. The expression and localisation of ionised calcium-binding adaptor molecule 1, TLR4, NF-κB and caspase-3 were assessed by immunoreactivity analysis. The levels of interleukin 1β and tumour necrosis factor α were assessed using enzyme-linked immunosorbent assays.

RESULTS

Perioperative treatment with dexmedetomidine was associated with a significant preservation of locomotor function following spinal cord ischemia-reperfusion injury with increased neuronal survival in the spinal cord compared to control. In addition, dexmedetomidine suppressed microglial activation, inhibited the TLR4-mediated NF-κB signalling pathway, and inhibited the caspase-3 dependent apoptosis.

CONCLUSIONS

Dexmedetomidine confers neuroprotection against spinal cord ischemia-reperfusion injury through suppression of spinal cord inflammation and neuronal apoptosis. A reduction in microglial activation and inhibition of both the TLR4-mediated NF-κB signalling pathway and caspase-3 dependent apoptosis are implicated.

背景

右美托咪定（Dex）可提高神经元活力并保护脊髓免受缺血再灌注（I/R）损伤，但作用机制尚不完全清楚。本研究旨在探讨右美托咪定对脊髓缺血再灌注损伤诱导的 Toll 样受体 4（TLR4）介导的核因子 κB（NF-κB）炎症系统和半胱氨酸天冬氨酸蛋白酶-3（caspase-3）依赖性细胞凋亡的影响。

方法

24 只兔随机分为 3 组：I/R 组、右美托咪定（10μg/kg/h，于缺血前至再灌注时给予）组和假手术（Sham）组。I/R 组和右美托咪定组采用腹主动脉夹闭法复制 30min 脊髓缺血再灌注模型。采用 Tarlov 步态评分系统评估后肢运动功能。苏木精-伊红（HE）染色和末端脱氧核苷酸转移酶介导的 dUTP 生物素缺口末端标记（TUNEL）染色评估脊髓腹侧灰质运动神经元存活和凋亡情况。免疫组织化学法检测离子钙结合衔接分子 1（Iba-1）、TLR4、NF-κB 和 caspase-3 的表达和定位。酶联免疫吸附试验（ELISA）检测白细胞介素 1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的水平。