转运蛋白（TSPO）通过激活大鼠L5脊神经结扎模型中的脊髓自噬和核SIRT1/PGC-1α信号通路减轻神经性疼痛。
Translocator Protein (TSPO) Alleviates Neuropathic Pain by Activating Spinal Autophagy and Nuclear SIRT1/PGC-1α Signaling in a Rat L5 SNL Model.
作者信息
Hao Can, Ma Bingjie, Gao Nan, Jin Tian, Liu Xiaoming
机构信息
Pain Management Center, Shanghai Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 210092, People's Republic of China.
出版信息
J Pain Res. 2022 Mar 24;15:767-778. doi: 10.2147/JPR.S359397. eCollection 2022.
PURPOSE
Recent studies showed promotion of astrocyte autophagy in the spinal cord would provide analgesic effects. Silent information regulator T1 (SIRT1) and α subunit of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) are two master regulators of endogenous antioxidant defense and mitochondrial biogenesis. They play vital roles in both autophagy and neuropathic pain (NP). Our previous study showed that TSPO agonist Ro5-4864 elicited potent analgesic effects against NP, but the mechanisms remain unclear. This study aims to investigate the effects of TSPO agonist Ro5-4864 on autophagy and nuclear SIRT1/PGC-1α signaling in spinal dorsal horn.
METHODS
A rat model of L5 spinal nerve ligation (SNL) was adopted. Rats were randomly assigned to the Sham group, the SNL group, the Ro (TSPO agonist Ro5-4864) group and the Ro+3-MA group. The behavior assessments were conducted at baseline, on Day 1, 3, 7 and 14 after SNL. The autophagy-related proteins (ATG7, Beclin1, LC3, and P62) in spinal dorsal horn were assayed and the nuclear SIRT1/PGC-1α and downstream factors were analyzed.
RESULTS
Ro5-4864 alleviated the mechanical allodynia induced by SNL (P < 0.01 vs the SNL group), which could be totally abrogated by autophagy inhibitor 3-MA (P < 0.01 vs the Ro group). SNL induced elevated ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.01) contents and P62 accumulation (P < 0.01) on Day 7 and Day 14, which suggested an autophagy flux impairment. Ro5-4864 augmented ATG7 (P < 0.01), Beclin1 (P < 0.01) and LC3-II/LC3-I (P < 0.05) with decreased P62 (P < 0.01), which indicated a more fluent autophagic process. These effects were also totally abrogated by 3-MA (P < 0.01). Furthermore, Ro5-4864 activated the spinal nuclear SIRT1/PGC-1α signaling pathway.
CONCLUSION
TSPO improved both autophagy impairment and mitochondrial biogenesis, which may provide a new strategy for the treatment of NP.
目的
近期研究表明，促进脊髓星形胶质细胞自噬可产生镇痛作用。沉默信息调节因子T1（SIRT1）和过氧化物酶体增殖物激活受体γ共激活因子1α亚基（PGC-1α）是内源性抗氧化防御和线粒体生物发生的两个主要调节因子。它们在自噬和神经性疼痛（NP）中均发挥着至关重要的作用。我们之前的研究表明，TSPO激动剂Ro5-4864对NP具有显著的镇痛作用，但其机制尚不清楚。本研究旨在探讨TSPO激动剂Ro5-4864对脊髓背角自噬及核SIRT1/PGC-1α信号通路的影响。
方法
采用L5脊髓神经结扎（SNL）大鼠模型。将大鼠随机分为假手术组、SNL组、Ro（TSPO激动剂Ro5-4864）组和Ro+3-MA组。在SNL术后第1、3、7和14天进行行为学评估。检测脊髓背角自噬相关蛋白（ATG7、Beclin1、LC3和P62），并分析核SIRT1/PGC-1α及其下游因子。
结果
Ro5-4864减轻了SNL诱导的机械性异常疼痛（与SNL组相比，P<0.01），自噬抑制剂3-MA可完全消除该作用（与Ro组相比，P<0.01）。SNL导致第7天和第14天ATG7（P<0.01）、Beclin1（P<0.01）和LC3-II/LC3-I（P<0.01）含量升高以及P62蓄积（P<0.01），提示自噬流受损。Ro5-4864增加了ATG7（P<0.01）、Beclin1（P<0.01）和LC3-II/LC3-I（P<0.05），同时降低了P62（P<0.01），表明自噬过程更顺畅。3-MA也完全消除了这些作用（P<0.01）。此外，Ro5-4864激活了脊髓核SIRT1/PGC-1α信号通路。
结论
TSPO改善了自噬损伤和线粒体生物发生，这可能为NP的治疗提供一种新策略。
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