title: Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK.
abstract: 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.
authors: 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.
authors: Ying
authors: Y
authors: Li
authors: 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.
authors: Jia
authors: J
authors: Li
authors: 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.
authors: Shanshan
authors: S
authors: Li
authors: 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.
authors: Yi
authors: Y
authors: Li
authors: 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.
authors: Xiangxiang
authors: X
authors: Wang
authors: 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.
authors: Baolin
authors: B
authors: Liu
authors: 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. Electronic address: fuqiang@cpu.edu.cn.
authors: Qiang
authors: Q
authors: Fu
authors: 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. Electronic address: spma@cpu.edu.cn.
authors: Shiping
authors: S
authors: Ma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D018698:Glutamic Acid / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018696:Neuroprotective Agents; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; C445672:Txnip protein, mouse; C577686:interleukin-6, mouse; D018698:Glutamic Acid; D013655:Taurochenodeoxycholic Acid; D013879:Thioredoxins; C031655:ursodoxicoltaurine; D055372:AMP-Activated Protein Kinases; D003474:Curcumin
keywords: AMPK; Curcumin; Endoplasmic reticulum stress; Glutamate neurotoxicity; Ischemia; NLRP3 inflammasome