Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury.
Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury.
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DOI：
10.1186/1742-2094-11-59
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发表时间：
2014-03-27
影响因子：
9.3
通讯作者：
Lin JK
中科院分区：
文献类型：
--
作者：
Zhu HT;Bian C;Yuan JC;Chu WH;Xiang X;Chen F;Wang CS;Feng H;Lin JK
创伤性脑损伤（Traumatic brain injury，TBI）可引起神经元损伤和行为障碍，Toll样受体4（Toll like receptor 4，TLR 4）是这一级联反应的重要介导因子。在当前的研究中，我们检验了姜黄素（一种从姜黄根茎中提取的具有强效抗炎特性的植物化学化合物）减轻TBI后由TLR 4介导的急性炎性损伤的假设。在遭受重物跌落挫伤的TLR 4-/-小鼠中测试神经功能、脑含水量和细胞因子水平。在TBI后15分钟，用不同浓度的姜黄素或载体腹膜内注射野生型（WT）小鼠。伤后24 h，采用免疫组化法检测小胶质细胞/巨噬细胞和TLR 4的活化，FJB和TUNEL染色检测神经细胞凋亡，ELISA法检测细胞因子，Western blotting法检测TLR 4、MyD 88和NF-κB的表达。在体外，由小胶质细胞和神经元组成的共培养系统在脂多糖（LPS）刺激后用姜黄素处理。免疫组化法检测刺激后24 h小胶质细胞TLR 4表达、形态学活化及神经元形态学损伤。TBI后24 h，挫伤周围组织中TLR 4蛋白表达达到高峰。与WT小鼠相比，TLR 4-/-小鼠在TBI后表现出减弱的功能障碍、脑水肿和细胞因子释放。除了上述方面的改善之外，TBI后100 mg/kg姜黄素治疗显著减少了WT小鼠中TLR 4阳性小胶质细胞/巨噬细胞的数量以及炎性介质释放和神经元凋亡。此外，Western blot分析表明姜黄素处理后TLR 4及其已知的下游效应物（MyD 88和NF-κB）的水平也降低。在LPS刺激后用姜黄素处理后的小胶质细胞和神经元共培养物中观察到类似的结果。LPS增加了小胶质细胞中TLR 4的免疫反应性和形态学活化，并增加了神经元凋亡，而姜黄素使这种上调正常化。姜黄素可抑制小胶质细胞中TLR 4、MyD 88和NF-κB蛋白水平的升高。我们的研究结果表明，损伤后，姜黄素管理可能会改善患者的结果，通过减少急性激活的小胶质细胞/巨噬细胞和神经元凋亡的机制，涉及TLR 4/MyD 88/NF-κB信号通路的小胶质细胞/巨噬细胞在TBI。
Traumatic brain injury (TBI) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of thiscascade. In the current study, we tested the hypothesis that curcumin, a phytochemical compound with potent anti-inflammatory properties that is extracted from the rhizome Curcuma longa, alleviates acute inflammatory injury mediated by TLR4 following TBI. Neurological function, brain water content and cytokine levels were tested in TLR4-/- mice subjected to weight-drop contusion injury. Wild-type (WT) mice were injected intraperitoneally with different concentrations of curcumin or vehicle 15 minutes after TBI. At 24 hours post-injury, the activation of microglia/macrophages and TLR4 was detected by immunohistochemistry; neuronal apoptosis was measured by FJB and TUNEL staining; cytokines were assayed by ELISA; and TLR4, MyD88 and NF-κB levels were measured by Western blotting. In vitro, a co-culture system comprised of microglia and neurons was treated with curcumin following lipopolysaccharide (LPS) stimulation. TLR4 expression and morphological activation in microglia and morphological damage to neurons were detected by immunohistochemistry 24 hours post-stimulation. The protein expression of TLR4 in pericontusional tissue reached a maximum at 24 hours post-TBI. Compared with WT mice, TLR4-/- mice showed attenuated functional impairment, brain edema and cytokine release post-TBI. In addition to improvement in the above aspects, 100 mg/kg curcumin treatment post-TBI significantly reduced the number of TLR4-positive microglia/macrophages as well as inflammatory mediator release and neuronal apoptosis in WT mice. Furthermore, Western blot analysis indicated that the levels of TLR4 and its known downstream effectors (MyD88, and NF-κB) were also decreased after curcumin treatment. Similar outcomes were observed in the microglia and neuron co-culture following treatment with curcumin after LPS stimulation. LPS increased TLR4 immunoreactivity and morphological activation in microglia and increased neuronal apoptosis, whereas curcumin normalized this upregulation. The increased protein levels of TLR4, MyD88 and NF-κB in microglia were attenuated by curcumin treatment. Our results suggest that post-injury, curcumin administration may improve patient outcome by reducing acute activation of microglia/macrophages and neuronal apoptosis through a mechanism involving the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages in TBI.
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影响因子：
4.7
作者：
Laird MD;Sukumari-Ramesh S;Swift AE;Meiler SE;Vender JR;Dhandapani KM
通讯作者：
Dhandapani KM
影响因子：
9.1
作者：
Chearwae, Wanida;Bright, John J.
通讯作者：
Bright, John J.
影响因子：
4.1
作者：
King MD;McCracken DJ;Wade FM;Meiler SE;Alleyne CH Jr;Dhandapani KM
通讯作者：
Dhandapani KM
影响因子：
2.9
作者：
Li, Guang-Zhao;Zhang, Yang;Hang, Chun-Hua
通讯作者：
Hang, Chun-Hua
影响因子：
2.9
作者：
FEENEY, DM;BOYESON, MG;DAIL, WG
通讯作者：
DAIL, WG