FGIN-1-27 Mitigates Radiation-induced Mitochondrial Hyperfunction and Cellular Hyperactivation in Cultured Astrocytes
FGIN-1-27 Mitigates Radiation-induced Mitochondrial Hyperfunction and Cellular Hyperactivation in Cultured Astrocytes
复制标题
DOI：
10.1016/j.neuroscience.2023.10.017
复制
发表时间：
2023-11-06
期刊：
影响因子：
3.3
通讯作者：
Huang，Haiwei
中科院分区：
文献类型：
--
作者：
Zhang，Shifeng;Deng，Zhezhi;Huang，Haiwei
放射性脑损伤（RBI）是颅内肿瘤放射治疗中的一个重大挑战，需要对其细胞和分子机制进行全面的了解。虽然先前的研究已经强调了星形胶质细胞激活和血管内皮生长因子过度产生在与RBI相关的微血管损伤中的作用，但关于辐射对星形胶质细胞影响的研究仍然很少，特别是关于线粒体等细胞器的影响。因此，我们的研究旨在阐明辐射暴露后星形细胞和线粒体功能的改变，并特别关注评估转运蛋白18kda （TSPO）配体的潜在改善作用。本研究将培养的星形胶质细胞置于x射线照射下，观察其细胞状态和线粒体功能，并与对照细胞进行比较。我们的研究结果显示，辐射诱导的星形细胞过度活化，将其转化为神经毒性的a1型，并伴有细胞增殖减少。此外，辐射引发线粒体功能亢进，提高线粒体膜电位，增加氧化代谢物的产生。然而，在用TSPO配体FGIN-1-27治疗后，我们观察到线粒体功能的恢复和氧化代谢物的产生减少。此外，这种干预减轻了星形胶质细胞的过度活跃，减少了a1型星形胶质细胞的数量，恢复了细胞的增殖能力。总之，我们的研究揭示了辐射诱导的星形胶质细胞功能障碍的其他表现，并验证了TSPO配体可能作为一种有希望的治疗策略来减轻这种功能障碍。它对RBI的治疗具有潜在的临床意义。
Radiation-induced brain injury (RBI) poses a significant challenge in the context of radiotherapy for intracranial tumors, necessitating a comprehensive understanding of the cellular and molecular mechanisms involved. While prior investigations have underscored the role of astrocyte activation and excessive vascular endothelial growth factor production in microvascular damage associated with RBI, there remains a scarcity of studies examining the impact of radiation on astrocytes, particularly regarding organelles such as mitochondria. Thus, our study aimed to elucidate alterations in astrocyte and mitochondrial functionality following radiation exposure, with a specific focus on evaluating the potential ameliorative effects of translocator protein 18 kDa (TSPO) ligands. In this study, cultured astrocytes were subjected to X-ray irradiation, and their cellular states and mitochondrial functions were examined and compared to control cells. Our findings revealed that radiation-induced astrocytic hyperactivation, transforming them into the neurotoxic A1-type, concomitant with reduced cell proliferation. Additionally, radiation triggered mitochondrial hyperfunction, heightened the mitochondrial membrane potential, and increased oxidative metabolite production. However, following treatment with FGIN-1-27, a TSPO ligand, we observed a restoration of mitochondrial function and a reduction in oxidative metabolite production. Moreover, this intervention mitigated astrocyte hyperactivity, decreased the number of A1-type astrocytes, and restored cell proliferative capacity. In conclusion, our study has unveiled additional manifestations of radiation-induced astrocyte dysfunction and validated that TSPO ligands may serve as a promising therapeutic strategy to mitigate this dysfunction. It has potential clinical implications for the treatment of RBI.