The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation.
The PPARalpha agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation.
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DOI：
10.1016/j.ijrobp.2009.06.059
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发表时间：
2009-11-01
影响因子：
7
通讯作者：
Robbins, Mike E.
中科院分区：
文献类型：
--
作者：
Ramanan, Sriram;Kooshki, Mitra;Zhao, Weiling;Hsu, Fang-Chi;Riddle, David R.;Robbins, Mike E.
全脑照射（WBI）会导致辐射后数月至数年的认知障碍。大量研究表明，WBI诱导的脑损伤的发病机制与海马神经发生减少和小胶质细胞活化有关。本研究的目的是研究给予过氧化物酶体增殖物激活受体（PPAR）α激动剂非诺贝特是否可以预防WBI对海马神经发生的不利影响。喂食常规食物或含0.2%w/w非诺贝特食物的129 S1/SvImJ野生型（WT）和PPARα敲除（KO）小鼠接受假照射或WBI（10戈伊单剂量137 Cs γ射线）。WBI后1个月，小鼠腹腔注射溴脱氧尿苷（BrdU）以标记存活细胞，WBI后2个月，使用BrdU/NeuN双免疫荧光对新生神经元进行计数。分别使用Ki-67和CD 68免疫组化在WBI后1周和2个月测量颗粒下区（SGZ）的增殖和小胶质细胞活化。脑损伤后2个月新生海马神经元数量显著减少。非诺贝特通过促进齿状回（DG）中新生细胞的存活来防止这种减少。此外，非诺贝特治疗与WBI后DG中小胶质细胞活化减少相关。在KO小鼠中，非诺贝特的神经保护作用消失，表明存在PPARα依赖性机制。这些数据突出了PPARα配体在改善WBI后神经发生中的新作用，并为改善接受放射治疗的脑癌患者的生活质量提供了希望。
Whole-brain irradiation (WBI) leads to cognitive impairment months to years after radiation. Numerous studies suggest that decreased hippocampal neurogenesis and microglial activation are involved in the pathogenesis of WBI-induced brain injury. The goal of this study was to investigate whether administration of the peroxisomal proliferator-activated receptor (PPAR)α agonist, fenofibrate, would prevent the detrimental effect of WBI on hippocampal neurogenesis. 129S1/SvImJ wild-type (WT) and PPARα knock-out (KO) mice that were fed either regular or 0.2% w/w fenofibrate-containing chow received either sham irradiation or WBI (10 Gy single dose of 137Cs γ rays). Mice were injected i.p. with bromodeoxyuridine (BrdU) to label the surviving cells at 1 month post-WBI and the newborn neurons were counted at 2 months post-WBI using BrdU/NeuN double-immunofluorescence. Proliferation in the sub-granular zone (SGZ) and microglial activation were measured at 1 week and 2 months post-WBI using Ki-67 and CD68 immunohistochemistry, respectively. WBI led to a significant decrease in the number of newborn hippocampal neurons 2 months post-WBI. Fenofibrate prevented this decrease by promoting the survival of newborn cells in the dentate gyrus (DG). In addition, fenofibrate treatment was associated with decreased microglial activation in the DG following WBI. The neuroprotective effects of fenofibrate were abolished in the KO mice, indicating a PPARα-dependent mechanism(s). These data highlight a novel role for PPARα ligands in improving neurogenesis following WBI, and offer the promise of improving the quality of life for brain cancer patients receiving radiotherapy.
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影响因子：
82.9
作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
影响因子：
7.8
作者：
Bauer, S;Patterson, PH
通讯作者：
Patterson, PH
影响因子：
3
作者：
Grabacka, M;Placha, W;Slominski, A
通讯作者：
Slominski, A
DOI：
10.1073/pnas.2234031100
发表时间：
2003-11-11
影响因子：
11.1
作者：
Ekdahl, CT;Claasen, JH;Lindvall, O
通讯作者：
Lindvall, O
影响因子：
3.4
作者：
Fan, Yang;Liu, Zhengyan;Liu, Jialing
通讯作者：
Liu, Jialing