Heat shock protein 22 (hsp22) plays a significant role in mitochondrial biogenesis and redox balance. Moreover, it’s well accepted that the impairment of mitochondrial biogenesis and redox imbalance contributes to the progress of neuropathic pain. However, there is no available evidence indicating that hsp22 can ameliorate mechanical allodynia and thermal hyperalgesia, sustain mitochondrial biogenesis and redox balance in rats with neuropathic pain. In this study, pain behavioral test, western blotting, immunofluorescence staining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Dihydroethidium staining are applied to confirm the role of hsp22 in a male rat model of spared nerve injury (SNI). Our results indicate that hsp22 was significantly decreased in spinal neurons post SNI. Moreover, it was found that intrathecal injection (i.t.) with recombinant heat shock protein 22 protein (rhsp22) ameliorated mechanical allodynia and thermal hyperalgesia, facilitated nuclear respiratory factor 1 (NRF1)/ mitochondrial transcription factor A (TFAM)-dependent mitochondrial biogenesis, decreased the level of reactive oxygen species (ROS), and suppressed oxidative stress via activation of spinal adenosine 5’monophosphate-activated protein kinase (AMPK)/ peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) pathway in male rats with SNI. Furthermore, it was also demonstrated that AMPK antagonist (compound C, CC) or PGC-1α siRNA reversed the improved mechanical allodynia and thermal hyperalgesia, mitochondrial biogenesis, oxidative stress, and the decreased ROS induced by rhsp22 in male rats with SNI. These results revealed that hsp22 alleviated mechanical allodynia and thermal hyperalgesia, improved the impairment of NRF1/TFAM-dependent mitochondrial biogenesis, down-regulated the level of ROS, and mitigated oxidative stress through stimulating the spinal AMPK/PGC-1α pathway in male rats with SNI.

Graphical Abstract

中文翻译：

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热休克蛋白 22 通过改善雄性大鼠线粒体生物发生和减少脊髓 AMPK/PGC-1α 通路介导的氧化应激来减轻神经损伤引起的神经性疼痛

热休克蛋白 22 (hsp22) 在线粒体生物合成和氧化还原平衡中发挥着重要作用。此外，人们普遍认为线粒体生物合成和氧化还原失衡的受损会导致神经性疼痛的进展。然而，没有证据表明 hsp22 可以改善神经性疼痛大鼠的机械异常性疼痛和热痛觉过敏，维持线粒体生物发生和氧化还原平衡。在本研究中，应用疼痛行为测试、蛋白质印迹、免疫荧光染色、定量聚合酶链反应、酶联免疫吸附测定和二氢乙锭染色来证实hsp22在雄性大鼠神经损伤（SNI）模型中的作用。我们的结果表明 SNI 后脊髓神经元中 hsp22 显着减少。此外，还发现鞘内注射重组热休克蛋白 22 蛋白 (rhsp22) 可改善机械异常性疼痛和热痛觉过敏，促进核呼吸因子 1 (NRF1)/线粒体转录因子 A (TFAM) 依赖性线粒体生物发生，减少SNI 雄性大鼠的活性氧 (ROS) 水平，并通过激活脊髓腺苷 5' 单磷酸激活蛋白激酶 (AMPK)/过氧化物酶体增殖激活受体 γ 共激活剂 1α (PGC-1α) 通路抑制氧化应激。此外，还证明 AMPK 拮抗剂（化合物 C、CC）或 PGC-1α siRNA 可逆转 SNI 雄性大鼠中机械异常性疼痛和热痛觉过敏、线粒体生物发生、氧化应激以及 rhsp22 诱导的 ROS 减少的改善。这些结果表明，hsp22 通过刺激雄性大鼠脊髓 AMPK/PGC-1α 通路，减轻机械性异常性疼痛和热痛觉过敏，改善 NRF1/TFAM 依赖性线粒体生物发生的损伤，下调 ROS 水平，并减轻氧化应激。 SNI。

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