高压利多卡因通过靶向 p38 MAPK/ERK 和 PINK1/Parkin 介导的自噬信号通路加重糖尿病神经病理性疼痛。

Hyperbaric Lidocaine Aggravates Diabetic Neuropathic Pain by Targeting p38 MAPK/ERK and PINK1/Parkin-Mediated Mitophagy Signaling Pathway.

机构信息

Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China.

Emergency Office, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China.

出版信息

Discov Med. 2024 May;36(184):992-1001. doi: 10.24976/Discov.Med.202436184.92.

DOI:10.24976/Discov.Med.202436184.92

PMID:38798258

Abstract

BACKGROUND

Diabetic neuropathic pain (DNP) is a complication of diabetes mellitus (DM). Hyperbaric lidocaine (HL), a local anesthetics drug, has neurotoxicity. The present study aims to study the effect and molecular mechanisms of HL on spinal nerve injury in DNP.

METHODS

The DNP rat model was established through a high-fat-glucose diet in combination with Streptozotocin (STZ) administration. SB203580 and PD98059 were utilized to inhibit p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The mechanical paw withdrawal threshold (PWT) and the thermal paw withdrawal latency (PWL) were tested to evaluate rats' mechanical allodynia and thermal hyperalgesia. Hematoxylin-eosin (H&E) and terminal deoxynucleotidyltransferase-mediated dUTP nick-end Labeling (TUNEL) staining were performed to evaluate the pathological changes and neuron apoptosis in spinal cord tissues of L4-5. Western blotting analysis and reverse transcription-polymerase chain reaction (RT-qPCR) assay were used to measure the levels of proteins and mRNAs, respectively.

RESULTS

PWT and PWL were decreased in DNP rats with serious spinal nerve injury. HL administration downregulated the PWT and PWL and aggravated spinal nerve injury in DNP rats, but isobaric lidocaine had no effects on these changes. Meanwhile, p38 MAPK/ERK signaling and PTEN-induced kinase 1 (PINK1)-mediated mitophagy were activated in DNP, which was enhanced by HL but not isobaric lidocaine. Blocking p38 MAPK/ERK signaling could effectively attenuate HL-induced spinal nerve injury and inhibit mitophagy.

CONCLUSION

In summary, HL can aggravate spinal cord tissue damage in DNP rats by inducing PINK1-mediated mitophagy via activating p38 MAPK/ERK signaling. Our data provide a novel insight that supports the potential role of p38 MAPK/ERK signaling in acting as a therapeutic target for HL-induced neurotoxicity.

摘要

背景

糖尿病性神经痛（DNP）是糖尿病（DM）的一种并发症。高压利多卡因（HL）作为一种局部麻醉药物，具有神经毒性。本研究旨在研究 HL 对 DNP 中脊髓神经损伤的作用及其分子机制。

方法

通过高脂肪-葡萄糖饮食联合链脲佐菌素（STZ）给药建立 DNP 大鼠模型。利用 SB203580 和 PD98059 抑制 p38 丝裂原活化蛋白激酶（p38 MAPK）和细胞外信号调节激酶（ERK）。通过机械性足底撤回阈值（PWT）和热足底撤回潜伏期（PWL）测试评估大鼠的机械性痛觉过敏和热痛觉过敏。苏木精-伊红（H&E）和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）染色评估 L4-5 脊髓组织的病理变化和神经元凋亡。Western blot 分析和逆转录-聚合酶链反应（RT-qPCR）检测分别用于测量蛋白和 mRNA 的水平。

结果

DNP 大鼠 PWT 和 PWL 降低，伴有严重的脊髓神经损伤。HL 给药可下调 PWT 和 PWL，并加重 DNP 大鼠的脊髓神经损伤，但等渗利多卡因无此作用。同时，DNP 中 p38 MAPK/ERK 信号和 PTEN 诱导的激酶 1（PINK1）介导的自噬被激活，HL 增强了这一激活，但等渗利多卡因没有。阻断 p38 MAPK/ERK 信号可有效减轻 HL 诱导的脊髓神经损伤，并抑制自噬。