Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo
Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo
复制标题
他莫昔芬通过减弱体外和体内小胶质细胞炎症反应来减轻辐射引起的脑损伤
DOI：
10.1016/j.brainres.2009.12.055
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发表时间：
2010-02-26
期刊：
影响因子：
2.9
通讯作者：
Wu, Gang
中科院分区：
文献类型：
--
作者：
Liu, Jun-Li;Tian, Dai-Shi;Wu, Gang
放射性脑损伤在全脑照射(WBI)治疗后数月至数年内导致认知功能障碍，是原发或转移性脑肿瘤患者常见的健康问题，严重影响肿瘤存活者的生活质量。最近，有研究表明，WBI后激活的小胶质细胞迅速而持续地增加，导致慢性炎症反应和相应的海马神经发生减少。在胶质瘤的联合治疗中，他莫昔芬作为放射增敏剂和有用的药物，已被发现在培养的小胶质细胞和脊髓损伤模型中都具有抗炎反应。在目前的研究中，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后的脑组织中的炎性损伤。用不同剂量(2~10GY)照射小胶质细胞系BV-2细胞后，用ELISA法检测IL-1β和肿瘤坏死因子-α的表达增加，10Gy射线照射的小胶质细胞条件培养液在体外启动星形胶质细胞活化，减少神经细胞的数量。BV-2细胞与三苯氧胺(1mU M)孵育45min可明显抑制辐射诱导的小胶质细胞炎症反应。在受照射的脑中，WBI在照射后第1天引起血脑屏障通透性的破坏，并在照射后第3天形成组织水肿。此外，在辐射后第3天，WBI导致大脑皮层小胶质细胞活化和反应性星形胶质细胞增生，以及CA1海马区神经元凋亡。照射后即刻ip他莫昔芬(5 mg/kg)可减轻WBI后放射性脑损伤。综上所述，这些数据支持他莫昔芬可以通过减轻小胶质细胞炎症反应来减轻放射性脑损伤。(C)2009爱思唯尔B.V.保留所有权利。
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 mu M) 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. (C) 2009 Elsevier B.V. All rights reserved.