論文 - 詳細
| RRC ID | 42187 |
|---|---|
| 著者 | Soeda S, Tsuji Y, Ochiai T, Mishima K, Iwasaki K, Fujiwara M, Yokomatsu T, Murano T, Shibuya S, Shimeno H. |
| タイトル | Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. |
| ジャーナル | Neurochem Int |
| Abstract |
Magnesium-dependent neutral sphingomyelinase (N-SMase) present in plasma membranes is an enzyme that can be activated by stress in the form of inflammatory cytokines, serum deprivation, and hypoxia. The design of small molecule N-SMase inhibitors may offer new therapies for the treatment of inflammation, ischemic injury, and cerebral infarction. Recently, we synthesized a series of difluoromethylene analogues (SMAs) of sphingomyelin. We report here the effects of SMAs on the serum/glucose deprivation-induced death of neuronally differentiated pheochromocytoma (PC-12) cells and on cerebral infarction in mice. SMAs inhibited the enhanced N-SMase activity in the serum/glucose-deprived PC-12 cells, and thereby suppressed the apoptotic sequence: ceramide formation, c-Jun N-terminal kinase phosphorylation, caspase-3 activation, and DNA fragmentation in the nuclei. Administration of SMA-7 (10 mg/kg i.v.) with IC50= 3.3 microM to mice whose middle cerebral arteries were occluded reduced significantly the size of the cerebral infarcts, compared to the control mice. These results suggest that N-SMase is a key component of the signaling pathways in cytokine- and other stress-induced cellular responses, and that inhibiting or stopping N-SMase activity is an important strategy to prevent neuron death from ischemia. |
| 巻・号 | 45(5) |
| ページ | 619-26 |
| 公開日 | 2004-10-1 |
| DOI | 10.1016/j.neuint.2004.04.001 |
| PII | S0197018604000786 |
| PMID | 15234103 |
| MeSH | Animals Blotting, Western Brain Ischemia / pathology* Caspase 3 Caspases / metabolism Cell Death / drug effects Cell Differentiation / drug effects Ceramides / biosynthesis DNA / analysis DNA / biosynthesis DNA Fragmentation Electrophoresis, Polyacrylamide Gel Enzyme Inhibitors / pharmacology* Glucose / deficiency Indicators and Reagents Infarction, Middle Cerebral Artery / pathology JNK Mitogen-Activated Protein Kinases Male Mice Mitogen-Activated Protein Kinases / metabolism Neurons / drug effects Neurons / enzymology* PC12 Cells Phosphorylation Rats Sphingomyelin Phosphodiesterase / antagonists & inhibitors* |
| IF | 3.881 |
| 引用数 | 41 |
| WOS 分野 | NEUROSCIENCES BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | PC-12(RCB0009) |