Li Ying, Li Jia, Li Shanshan, Li Yi, Wang Xiangxiang, Liu Baolin, Fu Qiang, Ma Shiping
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198, PR China; Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, China Pharmaceutical University, 639, Longmian Road, Nanjing 211198, PR China.
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198, PR China; Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, China Pharmaceutical University, 639, Longmian Road, Nanjing 211198, PR China.
Toxicol Appl Pharmacol. 2015 Jul 1;286(1):53-63. doi: 10.1016/j.taap.2015.03.010. Epub 2015 Mar 16.
Curcumin is a natural polyphenolic compound in Curcuma longa with beneficial effects on neuronal protection. This study aims to investigate the action of curcumin in the hippocampus subjected to glutamate neurotoxicity. Glutamate stimulation induced reactive oxygen species (ROS), endoplasmic reticulum stress (ER stress) and TXNIP/NLRP3 inflammasome activation, leading to damage in the hippocampus. Curcumin treatment in the hippocampus or SH-SY5Y cells inhibited IRE1α and PERK phosphorylation with suppression of intracellular ROS production. Curcumin increased AMPK activity and knockdown of AMPKα with specific siRNA abrogated its inhibitory effects on IRE1α and PERK phosphorylation, indicating that AMPK activity was essential for the suppression of ER stress. As a result, curcumin reduced TXNIP expression and inhibited NLRP3 inflammasome activation by downregulation of NLRP3 and cleaved caspase-1 induction, and thus reduced IL-1β secretion. Specific fluorescent probe and flow cytometry analysis showed that curcumin prevented mitochondrial malfunction and protected cell survival from glutamate neurotoxicity. Moreover, oral administration of curcumin reduced brain infarct volume and attenuated neuronal damage in rats subjected to middle cerebral artery occlusion. Immunohistochemistry showed that curcumin inhibited p-IRE1α, p-PERK and NLRP3 expression in hippocampus CA1 region. Together, these results showed that curcumin attenuated glutamate neurotoxicity by inhibiting ER stress-associated TXNIP/NLRP3 inflammasome activation via the regulation of AMPK, and thereby protected the hippocampus from ischemic insult.
姜黄素是姜黄中的一种天然多酚化合物，对神经元保护具有有益作用。本研究旨在探讨姜黄素在遭受谷氨酸神经毒性的海马体中的作用。谷氨酸刺激诱导活性氧（ROS）、内质网应激（ER应激）和TXNIP/NLRP3炎性小体激活，导致海马体损伤。在海马体或SH-SY5Y细胞中进行姜黄素处理可抑制IRE1α和PERK磷酸化，并抑制细胞内ROS生成。姜黄素增加了AMPK活性，用特异性siRNA敲低AMPKα可消除其对IRE1α和PERK磷酸化的抑制作用，表明AMPK活性对于抑制ER应激至关重要。结果，姜黄素通过下调NLRP3和切割的caspase-1诱导来降低TXNIP表达并抑制NLRP3炎性小体激活，从而减少IL-1β分泌。特异性荧光探针和流式细胞术分析表明，姜黄素可预防线粒体功能障碍，并保护细胞免受谷氨酸神经毒性导致的死亡。此外，口服姜黄素可减少大脑中动脉闭塞大鼠的脑梗死体积并减轻神经元损伤。免疫组织化学显示，姜黄素抑制海马体CA1区的p-IRE1α、p-PERK和NLRP3表达。总之，这些结果表明，姜黄素通过调节AMPK抑制与ER应激相关的TXNIP/NLRP3炎性小体激活，从而减轻谷氨酸神经毒性，进而保护海马体免受缺血性损伤。
