Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430023, PR China.
Brain Res. 2010 Feb 26;1316:101-11. doi: 10.1016/j.brainres.2009.12.055. Epub 2010 Jan 4.
Irradiation-induced brain injury, leading to cognitive impairment several months to years after whole brain irradiation (WBI) therapy, is a common health problem in patients with primary or metastatic brain tumor and greatly impairs quality of life for tumor survivors. Recently, it has been demonstrated that a rapid and sustained increase in activated microglia following WBI led to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Tamoxifen, serving as a radiosensitizer and a useful agent in combination therapy of glioma, has been found to exert anti-inflammatory response both in cultured microglial cells and in a spinal cord injury model. In the present study, we investigated whether tamoxifen alleviated inflammatory damage seen in the irradiated microglia in vitro and in the irradiated brain. Irradiating BV-2 cells (a murine microglial cell line) with various radiation doses (2-10 Gy) led to the increase in IL-1 beta and TNF-alpha expression determined by ELISA, and the conditioned culture medium of irradiated microglia with 10 Gy radiation dose initiated astroglial activation and decreased the number of neuronal cells in vitro. Incubation BV-2 cells with tamoxifen (1 microM) for 45 min significantly inhibited the radiation-induced microglial inflammatory response. In the irradiated brain, WBI induced the breakdown of the blood-brain barrier permeability at day 1 post irradiation and tissue edema formation at day 3 post-radiation. Furthermore, WBI led to microglial activation and reactive astrogliosis in the cerebral cortex and neuronal apoptosis in the CA1 hippocampus at day 3 post-radiation. Tamoxifen administration (i.p., 5 mg/kg) immediately post radiation reduced the irradiation-induced brain damage after WBI. Taken together, these data support that tamoxifen can decrease the irradiation-induced brain damage via attenuating the microglial inflammatory response.
辐射诱导的脑损伤导致全脑照射（WBI）治疗后数月至数年的认知障碍，是原发性或转移性脑肿瘤患者的常见健康问题，并极大地损害了肿瘤幸存者的生活质量。最近，已经证明 WBI 后激活的小胶质细胞的快速和持续增加导致慢性炎症反应和海马神经发生相应减少。他莫昔芬作为一种放射增敏剂和胶质细胞瘤联合治疗的有用药物，已被发现对培养的小胶质细胞和脊髓损伤模型具有抗炎反应。在本研究中，我们研究了他莫昔芬是否减轻了体外照射的小胶质细胞和照射的大脑中观察到的炎症损伤。用不同辐射剂量（2-10 Gy）照射 BV-2 细胞（一种鼠小胶质细胞系）导致 ELISA 测定的 IL-1β和 TNF-α表达增加，并且 10 Gy 辐射剂量照射的小胶质细胞的条件培养基在体外引发星形胶质细胞激活并减少神经元细胞数量。用他莫昔芬（1 μM）孵育 BV-2 细胞 45 分钟可显著抑制辐射诱导的小胶质细胞炎症反应。在照射的大脑中，WBI 在照射后第 1 天诱导血脑屏障通透性破坏，在照射后第 3 天诱导组织水肿形成。此外，WBI 在照射后第 3 天导致大脑皮质中小胶质细胞激活和反应性星形胶质细胞增生以及 CA1 海马神经元凋亡。照射后立即给予他莫昔芬（腹腔内，5 mg/kg）可减少 WBI 后的照射性脑损伤。总之，这些数据支持他莫昔芬通过减弱小胶质细胞炎症反应来减少照射引起的脑损伤。
