Curcumin attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling.
Glutamate induces cell death by upsetting the cellular redox homeostasis, termed oxidative glutamate toxicity, in a mouse hippocampal cell line, HT22. Extracellular signal-regulated kinases (ERK) 1/2 are known key players in this process. Here we characterized the roles of both MAP kinases and cell cycle regulators in mediating oxidative glutamate toxicity and the neuroprotective mechanisms of curcumin in HT22 cells. c-Jun N-terminal kinase (JNK) and p38 kinase were activated during the glutamate-induced HT22 cell death, but at a later stage than ERK activation. Treatment with a JNK inhibitor, SP600125, or a p38 kinase inhibitor, SB203580, partly attenuated this cell death. Curcumin, a natural inhibitor of JNK signaling, protected the HT22 cells from glutamate-induced death at nanomolar concentrations more efficiently than SP600125. These doses of curcumin affected neither the level of intracellular glutathione nor the level of reactive oxygen species, but inactivated JNK and p38 significantly. Moreover, curcumin markedly upregulated a cell-cycle inhibitory protein, p21cip1, and downregulated cyclin D1 levels, which might help the cell death prevention. Our results suggest that curcumin has a neuroprotective effect against oxidative glutamate toxicity by inhibiting MAP kinase signaling and influencing cell-cycle regulation.
Suh
Hyun-Woo
HW
Laboratory of Functional Proteomics, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Taejon, 305-333, Korea.
Kang
Seongman
S
Kwon
Ki-Sun
KS
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000873:Anthracenes; D000975:Antioxidants; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D019938:Cyclin D1; C432165:pyrazolanthrone; D018698:Glutamic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; D003474:Curcumin