Department of Radiotherapy and Oncology, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, P. R. China.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, Jiangsu Province, 215004, P. R. China.
Sci Rep. 2017 Nov 27;7(1):16373. doi: 10.1038/s41598-017-16693-8.
Due to an increasing concern about radiation-induced cognitive deficits for brain tumor patients receiving radiation therapy, developing and evaluating countermeasures has become inevitable. Our previous study has found that minocycline, a clinical available antibiotics that can easily cross the blood brain barrier, mitigates radiation-induced long-term memory loss in rats, accompanied by decreased hippocampal neuron apoptosis. Thus, in the present study, we report an unknown mechanism underlying the neuroprotective effect of minocycline. We demonstrated that minocycline prevented primary neurons from radiation-induced apoptosis and promoted radiation-induced autophagy in vitro. Moreover, using an immortalized mouse hippocampal neuronal cell line, HT22 cells, we found that the protective effect of minocycline on irradiated HT22 cells was not related to DNA damage repair since minocycline did not facilitate DNA DSB repair in irradiated HT22 cells. Further investigation showed that minocycline significantly enhanced X-irradiation-induced AMPKα1 activation and autophagy, thus resulting in decreased apoptosis. Additionally, although the antioxidant potential of minocycline might contribute to its apoptosis-inhibitory effect, it was not involved in its enhancive effect on radiation-induced AMPKα1-mediated autophagy. Taken together, we have revealed a novel mechanism for the protective effect of minocycline on irradiated neurons, e.g. minocycline protects neurons from radiation-induced apoptosis via enhancing radiation-induced AMPKα1-mediated autophagy.
由于人们越来越关注接受放射治疗的脑肿瘤患者的放射性认知功能障碍，因此开发和评估对策已成为必然。我们之前的研究发现，米诺环素是一种临床可用的抗生素，很容易穿过血脑屏障，可减轻大鼠的放射性长期记忆丧失，同时减少海马神经元凋亡。因此，在本研究中，我们报告了米诺环素的神经保护作用的未知机制。我们证明米诺环素可防止原代神经元发生放射诱导的细胞凋亡，并促进体外放射诱导的自噬。此外，使用永生化的小鼠海马神经元细胞系 HT22 细胞，我们发现米诺环素对辐照 HT22 细胞的保护作用与 DNA 损伤修复无关，因为米诺环素不会促进辐照 HT22 细胞中的 DNA DSB 修复。进一步的研究表明，米诺环素可显著增强 X 射线照射诱导的 AMPKα1 激活和自噬，从而减少细胞凋亡。此外，尽管米诺环素的抗氧化潜力可能有助于其抑制细胞凋亡的作用，但它不参与其对辐射诱导的 AMPKα1 介导的自噬的增强作用。综上所述，我们揭示了米诺环素对辐照神经元的保护作用的新机制，例如，米诺环素通过增强辐射诱导的 AMPKα1 介导的自噬来保护神经元免受辐射诱导的细胞凋亡。
