Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK

Journal Article · Wed Jul 01 04:00:00 EDT 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.03.010· OSTI ID:22465781

Li, Ying; Li, Jia; Li, Shanshan; Li, Yi; Wang, Xiangxiang; Liu, Baolin ^[1]; Fu, Qiang ^[1]; Ma, Shiping ^[1]

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1. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 639, Longmian Road, Nanjing 211198 (China)

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. - Highlights: • Curcumin attenuates glutamate neurotoxicity in the hippocampus. • Curcumin suppresses ER stress in glutamate-induced hippocampus slices. • Curcumin inhibits TXNIP/NLRP3 inflammasome activation. • Regulation of AMPK by curcumin contributes to suppressing ER stress.

• OSTI ID: 22465781
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 286; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADENOSINE
AMP
CEREBRAL ARTERIES
CHLORIDES
CURCUMIN
DAMAGE
ENDOPLASMIC RETICULUM
FLUORESCENCE
HIPPOCAMPUS
INHIBITION
ISCHEMIA
MITOCHONDRIA
ORAL ADMINISTRATION
PHOSPHORYLATION
RATS
RECEPTORS
SECRETION
STRESSES