Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits.
Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits.
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集落刺激因子 1 受体阻断可预防分段全脑照射引起的记忆缺陷。
DOI：
10.1186/s12974-016-0671-y
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发表时间：
2016-08-30
影响因子：
9.3
通讯作者：
Rosi S
中科院分区：
文献类型：
--
作者：
Feng X;Jopson TD;Paladini MS;Liu S;West BL;Gupta N;Rosi S
原发性中枢神经系统（CNS）肿瘤和脑转移瘤常规采用全脑放疗治疗。许多患者可以长期生存，但他们的生活质量受到认知缺陷发展的严重影响，并且没有治疗方法可以预防这些不良反应。与脑内驻留的小胶质细胞和浸润的单核细胞的激活相关的神经炎症在神经功能丧失中起关键作用，并且已被证明与脑辐射的急性和长期效应相关。集落刺激因子1受体（CSF-1 R）信号传导对于小胶质细胞和单核细胞的存活和分化是必不可少的。在这里，我们测试了PLX 5622阻断CSF-1 R对接受三次3.3戈伊全脑照射的小鼠认知功能的影响。年轻的成年C57 BL/6 J小鼠给予三个部分的3.3戈伊全脑照射，同时它们食用补充有PLX 5622的饮食，并评估对外周单核细胞积累、小胶质细胞数量和神经元功能的影响。小鼠在接受分次全脑照射后1个月和3个月出现了大脑依赖性认知缺陷。认知功能受损与CNS中外周单核细胞积聚数量增加和海马颗粒神经元树突棘密度降低相关。PLX 5622治疗导致小胶质细胞数量暂时减少，抑制单核细胞在大脑中的积累，并防止辐射诱导的认知缺陷。PLX 5622阻断CSF-1 R可预防分次全脑辐射诱导的记忆缺陷。CSF-1 R的治疗靶向可能为保护辐射诱导的记忆缺陷提供新的途径。本文的在线版本（doi：10.1186/s12974-016-0671-y）包含补充材料，可供授权用户使用。
Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation. Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed. The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits. Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits. The online version of this article (doi:10.1186/s12974-016-0671-y) contains supplementary material, which is available to authorized users.
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