Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis |
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Authors: | Zai Fang Yu Mariana Nikolova-Karakashian Daohong Zhou Guanjun Cheng Edward H. Schuchman Mark P. Mattson |
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Affiliation: | (1) Sanders-Brown Research Center on Aging, University of Kentucky, 40536 Lexington, KY;(2) Department of Physiology, University of Kentucky, 40536 Lexington, KY;(3) Department of Medicine, University of Kentucky, 40536 Lexington, KY;(4) Department of Human Genetics, Mount Sinai School of Medicine, 10029 New York, NY;(5) Laboratory of Neurosciences, National Institute on Aging, 5600 Nathan Shock Drive, 21224 Baltimore, MD |
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Abstract: | Stroke is a major cause of long-term disability, the severity of which is directly related to the numbers of neurons that succumb to the ischemic insult. The signaling cascades activated by cerebral ischemia that may either promote or protect against neuronal death are not well-understood. One injury-responsive signaling pathway that has recently been characterized in studies of non-neural cells involves cleavage of membrane sphingomyelin by acidic and/or neutral sphingomyelinase (ASMase) resulting in generation of the second messenger ceramide. We now report that transient focal cerebral ischemia induces large increases in ASMase activity, ceramide levels, and production of inflammatory cytokines in wild-type mice, but not in mice lacking ASMase. The extent of brain tissue damage is decreased and behavioral outcome improved in mice lacking ASMase. Neurons lacking ASMase exhibit decreased vulnerability to excitotoxicity and hypoxia, which is associated with decreased levels of intracellular calcium and oxyradicals. Treatment of mice with a drug that inhibits ASMase activity and ceramide production reduces ischemic neuronal injury and improves behavioral outcome, suggesting that drugs that inhibit this signaling pathway may prove beneficial in stroke patients. |
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Keywords: | Apoptosis calcium excitotoxicity interleukin stroke tumor necrosis factor |
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