Abstract |
Oxidative stress induced by inhibition of glutathione (GSH) biosynthesis with D,L- buthionine-S,R-sulfoximine (BSO) causes human microglia, human astrocytes, THP-1 cells, and U373 cells to secrete materials toxic to human neuroblastoma SH-SY5Y cells and stimulates them to release TNF-alpha, IL-6, and nitrite ions. The effect is correlated with activation of the inflammatory pathways P38 MAP- kinase, Jun-N-terminal kinase, and NF-kappaB. The effect is reduced by adding to the medium GSH or clotrimazole (CTM), an inhibitor of Ca(2+)-influx through TRPM2 channels. It is also produced by inhibiting TRPM2 protein expression in microglia and astrocytes through introduction of its small inhibitory RNA ( siRNA). TRPM2 mRNA is expressed by glial cells but not by SH-SY5Y cells. BSO in the culture medium causes an almost 3-fold increase in [Ca(2+)](i) in microglia and astrocytes over a 24-h period, which is reduced to half by the addition of CTM. The data strongly suggest that inhibiting intracellular GSH synthesis induces a neuroinflammatory response in human microglia and astrocytes, which is linked to Ca(2+) influx through TRPM2 channels. It represents a new model for inducing neuroinflammation and suggests that increasing GSH levels in glial cells may confer neuroprotection in neurodegenerative diseases, such as Alzheimer disease, which have a prominent neuroinflammatory component.
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Authors | Moonhee Lee, Taesup Cho, Nattinee Jantaratnotai, Yu Tian Wang, Edith McGeer, Patrick L McGeer |
Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology
(FASEB J)
Vol. 24
Issue 7
Pg. 2533-45
(Jul 2010)
ISSN: 1530-6860 [Electronic] United States |
PMID | 20228251
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- TRPM Cation Channels
- TRPM2 protein, human
- Glutathione
- Calcium
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Topics |
- Aging
- Astrocytes
(metabolism, pathology)
- Calcium
(metabolism)
- Cells, Cultured
- Glutathione
(deficiency)
- Humans
- Inflammation
(metabolism)
- Neurodegenerative Diseases
- Neuroglia
(metabolism, pathology)
- Neurotoxicity Syndromes
(etiology)
- TRPM Cation Channels
(metabolism)
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