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SEA0400, a specific inhibitor of the Na + –Ca 2+ exchanger, attenuates sodium nitroprusside‐induced apoptosis in cultured rat microglia
Author(s) -
Nagano Takayuki,
Osakada Masakazu,
Ago Yukio,
Koyama Yutaka,
Baba Akemichi,
Maeda Sadaaki,
Takemura Motohiko,
Matsuda Toshio
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706104
Subject(s) - sodium nitroprusside , thapsigargin , microglia , apoptosis , endoplasmic reticulum , nitric oxide , endocrinology , biology , medicine , microbiology and biotechnology , chemistry , biochemistry , inflammation
1 Using SEA0400, a potent and selective inhibitor of the Na + –Ca 2+ exchanger (NCX), we examined whether NCX is involved in nitric oxide (NO)‐induced disturbance of endoplasmic reticulum (ER) Ca 2+ homeostasis followed by apoptosis in cultured rat microglia. 2 Sodium nitroprusside (SNP), an NO donor, decreased cell viability in a dose‐ and time‐dependent manner with apoptotic cell death in cultured microglia. 3 Treatment with SNP decreased the ER Ca 2+ levels as evaluated by measuring the increase in cytosolic Ca 2+ level induced by exposing cells to thapsigargin, an irreversible inhibitor of ER Ca 2+ ‐ATPase. 4 The treatment with SNP also increased mRNA expression of CHOP and GPR78, makers of ER stress. 5 SEA0400 at 0.3–1.0 μ M protected microglia against SNP‐induced apoptosis. 6 SEA0400 blocked not only the SNP‐induced decrease in ER Ca 2+ levels but also SNP‐induced increase in CHOP and GRP78 mRNAs. 7 SEA0400 did not affect capacitative Ca 2+ entry in the presence and absence of SNP. 8 SNP increased Na + ‐dependent 45 Ca 2+ uptake and this increase was blocked by SEA0400. 9 These results suggest that SNP induces apoptosis via the ER stress pathway and SEA0400 attenuates SNP‐induced apoptosis via suppression of the ER stress in cultured microglia. Our findings imply that NCX plays a role in ER Ca 2+ depletion under pathological conditions.British Journal of Pharmacology (2005) 144 , 669–679. doi: 10.1038/sj.bjp.0706104