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Journal of Molecular Neuroscience

, Volume 15, Issue 2, pp 85–97 | Cite as

Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis

  • Zai Fang Yu
  • Mariana Nikolova-Karakashian
  • Daohong Zhou
  • Guanjun Cheng
  • Edward H. Schuchman
  • Mark P. Mattson
Article

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.

Index Entries

Apoptosis calcium excitotoxicity interleukin stroke tumor necrosis factor 

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Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Zai Fang Yu
    • 1
  • Mariana Nikolova-Karakashian
    • 2
  • Daohong Zhou
    • 3
  • Guanjun Cheng
    • 1
  • Edward H. Schuchman
    • 4
  • Mark P. Mattson
    • 1
    • 5
  1. 1.Sanders-Brown Research Center on AgingUniversity of KentuckyLexington
  2. 2.Department of PhysiologyUniversity of KentuckyLexington
  3. 3.Department of MedicineUniversity of KentuckyLexington
  4. 4.Department of Human GeneticsMount Sinai School of MedicineNew York
  5. 5.Laboratory of NeurosciencesNational Institute on AgingBaltimore

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