Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress.
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.
Soeda
Shinji
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Tsuji
Yoshiaki
Y
Ochiai
Takashi
T
Mishima
Ken-ichi
K
Iwasaki
Katsunori
K
Fujiwara
Michihiro
M
Yokomatsu
Tsutomu
T
Murano
Tetsuo
T
Shibuya
Shiroshi
S
Shimeno
Hiroshi
H
D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D053938:DNA Fragmentation; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D007202:Indicators and Reagents; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*
D002518:Ceramides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose