Abstract：
Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.
摘要：
癌症诱导的骨痛（CIBP）由于其复杂且未完全阐明的病理生理机制而成为临床实践中最具挑战性的问题之一。现有证据表明，过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）下调在各种啮齿动物神经性疼痛模型中的疼痛行为中具有重要意义。在我们目前的研究中,我们旨在研究PGC-1α在CIBP中的作用。我们的结果揭示了CIBP大鼠脊髓内PGC-1α表达的减少，特别是在GABA能中间神经元中。值得注意的是,鞘内注射PGC-1α激活剂ZLN005抑制了脊髓GABA能中间神经元的丢失。这种抑制是通过抑制caspase-3介导的细胞凋亡来实现的，最终导致CIBP大鼠机械性异常疼痛的缓解。对机制的进一步探索表明，PGC-1α激活在减轻与线粒体功能障碍有关的ATP消耗和活性氧积累中起关键作用。这是通过线粒体生物发生的恢复和SIRT3-SOD2途径的激活来实现的。令人印象深刻的是,在使用特定的PGC-1α抑制剂SR18292时，观察到的效果显着逆转。总之,我们的发现强烈表明，PGC-1α激活是脊髓GABA能中间神经元凋亡的有效抑制剂。这种抑制是由线粒体功能的改善介导的，部分通过增强线粒体生物发生和SIRT3-SOD2途径的激活而促进。我们的研究结果揭示了治疗CIBP的潜在治疗途径。
