RRC ID 42187
Author Soeda S, Tsuji Y, Ochiai T, Mishima K, Iwasaki K, Fujiwara M, Yokomatsu T, Murano T, Shibuya S, Shimeno H.
Title Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress.
Journal 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.
Volume 45(5)
Pages 619-26
Published 2004-10
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 3.603
Times Cited 37
Human and Animal Cells