Chloroquine inhibits glutamate‐induced death of a neuronal cell line by reducing reactive oxygen species through sigma‐1 receptor

J. Neurochem. (2011) 119, 839–847. Chloroquine, a widely used anti‐malarial and anti‐rheumatoid agent, has been reported to induce apoptotic and non‐apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy‐induced apo...

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Published in:	Journal of neurochemistry Vol. 119; no. 4; pp. 839 - 847
Main Authors:	Hirata, Yoko, Yamamoto, Hideko, Atta, Mostafa Shukry Moursy, Mahmoud, Shawky, Oh‐hashi, Kentaro, Kiuchi, Kazutoshi
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-11-2011 Wiley-Blackwell
Subjects:	Animals Anisoles - pharmacology Biological and medical sciences Cell Death - drug effects Cell Line, Transformed Cell Survival - drug effects Cells chloroquine Chloroquine - pharmacology Diseases of the osteoarticular system Dose-Response Relationship, Drug Drug Interactions Ethylenediamines - pharmacology Gangliosides - metabolism glutamate Glutamic Acid - toxicity Glutathione - metabolism HT22 cells Human protozoal diseases Infectious diseases Inflammatory joint diseases Malaria Medical sciences Mice Neurons Neurons - drug effects Neuroprotective Agents - pharmacology oxidative stress Oxidative Stress - drug effects Oxygen Parasitic diseases Piperazines - pharmacology Propylamines - pharmacology Protozoal diseases reactive oxygen species Reactive Oxygen Species - metabolism Receptors, sigma - agonists Receptors, sigma - antagonists & inhibitors Receptors, sigma - metabolism Sigma-1 Receptor Time Factors Oxidative stress Protozoal disease Diseases of the osteoarticular system Central nervous system Autoimmune disease Inflammatory joint disease sigma-1 receptor Blood brain barrier Encephalon chloroquine reactive oxygen species Antagonist Immunopathology Oxygen Malaria Induction Rodentia Sigma 1 receptor Parasitosis Malignant tumor Glutamate Infection HT22 cells Vertebrata Chemotherapy Chronic Mammalia Treatment Mouse Cell death Rheumatoid arthritis Excitatory aminoacid Neurotransmitter Hippocampus Cancer Apoptosis
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Summary:	J. Neurochem. (2011) 119, 839–847. Chloroquine, a widely used anti‐malarial and anti‐rheumatoid agent, has been reported to induce apoptotic and non‐apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy‐induced apoptosis by inhibiting autophagy. However, chloroquine is reported to induce GM1 ganglioside accumulation in cultured cells at low μM concentrations and prevent damage to the blood brain barrier in mice. It remains unknown whether chloroquine has neuroprotective properties at concentrations below its reported ability to inhibit lysosomal enzymes and autophagy. In the present study, we demonstrated that chloroquine protected mouse hippocampal HT22 cells from glutamate‐induced oxidative stress by attenuating production of excess reactive oxygen species. The concentration of chloroquine required to rescue HT22 cells from oxidative stress was much lower than that sufficient enough to induce cell death and inhibit autophagy. Chloroquine increased GM1 level in HT22 cells at low μM concentrations but glutamate‐induced cell death occurred before GM1 accumulation, suggesting that GM1 induction is not related to the protective effect of chloroquine against glutamate‐induced cell death. Interestingly, BD1047 and NE‐100, sigma‐1 receptor antagonists, abrogated the protective effect of chloroquine against glutamate‐induced cell death and reactive oxygen species production. In addition, cutamesine (SA4503), a sigma‐1 receptor agonist, prevented both glutamate‐induced cell death and reactive oxygen species production. These findings indicate that chloroquine at concentrations below its ability to inhibit autophagy and induce cell death is able to rescue HT22 cells from glutamate‐induced cell death by reducing excessive production of reactive oxygen species through sigma‐1 receptors. These results suggest potential use of chloroquine, an established anti‐malarial agent, as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases.
ISSN:	0022-3042 1471-4159
DOI:	10.1111/j.1471-4159.2011.07464.x