Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance.
Pentoxifylline alleviates ischemic white matter injury through up-regulating Mertk-mediated myelin clearance.
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五氧化氨基林通过上调MERTK介导的髓鞘清除来减轻缺血性白质损伤。
DOI：
10.1186/s12974-022-02480-4
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发表时间：
2022-05-31
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
血管性痴呆（VAD）是缺乏有效治疗的第二种最常见的痴呆类型。戊茶碱（PTX）是一种非选择性磷酸二酯酶抑制剂，在多种脑疾病中显示出保护作用。本研究旨在探讨PTX对VAD的治疗作用及其可能机制。建立双侧颈总动脉狭窄（BCAS）小鼠模型，模拟VAD。采用旷场实验、新物体识别实验、Y-迷宫和Morris水迷宫（MWM）实验检测小鼠行为学。组织学染色、磁共振成像（MRI）和电子显微镜检查用于确定白色物质的完整性。应用小胶质细胞特异性Mertk敲除小鼠、Mertk抑制剂和PPAR-γ抑制剂，通过免疫荧光、蛋白质印迹和流式细胞术评估PTX对小胶质细胞吞噬功能、过氧化物酶体增殖物激活受体-γ（PPAR-γ）活化和Mer受体酪氨酸激酶（Mertk）表达的影响。在这里，我们发现PTX治疗减轻了新物体识别测试、Y-迷宫和Morris水迷宫测试中的认知障碍。此外，PTX减轻胼胝体（CC）和内囊（IC）区域的白色损伤，如组织学染色和MRI分析所示。通过电子显微镜观察，PTX治疗组呈现比载体组更厚的髓鞘。在机制上，PTX通过上调BCAS模型和原代培养的小胶质细胞中Mertk的表达来促进小胶质细胞对髓鞘碎片的吞噬。重要的是，小胶质细胞特异性Mertk敲除阻断了PTX在BCAS模型中的治疗作用。此外，Mertk的表达受PPAR-γ核转位的调控。PTX通过调节PPAR-γ，促进Mertk的表达。总的来说，我们的研究结果表明，PTX在VAD中显示出治疗潜力，并通过调节小胶质细胞中Mertk介导的髓鞘清除来减轻缺血性白色损伤。在线版本包含补充材料，可通过10.1186/s12974-022-02480-4获得。
Vascular dementia (VAD) is the second most common type of dementia lacking effective treatments. Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, displays protective effects in multiple cerebral diseases. In this study, we aimed to investigate the therapeutic effects and potential mechanisms of PTX in VAD. Bilateral common carotid artery stenosis (BCAS) mouse model was established to mimic VAD. Mouse behavior was tested by open field test, novel object recognition test, Y-maze and Morris water maze (MWM) tests. Histological staining, magnetic resonance imaging (MRI) and electron microscopy were used to define white matter integrity. The impact of PTX on microglia phagocytosis, peroxisome proliferator-activated receptors-γ (PPAR-γ) activation and Mer receptor tyrosine kinase (Mertk) expression was assessed by immunofluorescence, western blotting and flow cytometry with the application of microglia-specific Mertk knockout mice, Mertk inhibitor and PPAR-γ inhibitor. Here, we found that PTX treatment alleviated cognitive impairment in novel object recognition test, Y-maze and Morris water maze tests. Furthermore, PTX alleviated white matter injury in corpus callosum (CC) and internal capsule (IC) areas as shown by histological staining and MRI analysis. PTX-treatment group presented thicker myelin sheath than vehicle group by electron microscopy. Mechanistically, PTX facilitated microglial phagocytosis of myelin debris by up-regulating the expression of Mertk in BCAS model and primary cultured microglia. Importantly, microglia-specific Mertk knockout blocked the therapeutic effects of PTX in BCAS model. Moreover, Mertk expression was regulated by the nuclear translocation of PPAR-γ. Through modulating PPAR-γ, PTX enhanced Mertk expression. Collectively, our results demonstrated that PTX showed therapeutic potentials in VAD and alleviated ischemic white matter injury via modulating Mertk-mediated myelin clearance in microglia. The online version contains supplementary material available at 10.1186/s12974-022-02480-4.
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影响因子：
4.6
作者：
Hattori Y;Enmi J;Iguchi S;Saito S;Yamamoto Y;Nagatsuka K;Iida H;Ihara M
通讯作者：
Ihara M
肌肽对小鼠皮质下缺血性血管性痴呆的保护作用
影响因子：
5.5
作者：
Ma, Jing;Xiong, Jia-Yan;Chen, Zhong
通讯作者：
Chen, Zhong
影响因子：
3.4
作者：
Dong, Jianqing;Yuan, Xinmei;Xie, Weiwei
通讯作者：
Xie, Weiwei
影响因子：
5.5
作者：
Lee, Janice;Hamanaka, Gen;Arai, Ken
通讯作者：
Arai, Ken
DOI：
10.1007/978-1-4939-8994-2_10
发表时间：
2019-01-01
期刊：
PRE-CLINICAL MODELS
影响因子：
--
作者：
Kraeuter, Ann-Katrin;Guest, Paul C.;Sarnyai, Zoltan
通讯作者：
Sarnyai, Zoltan