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

Stroke is a major cause of long-term disability, the severity of which is d irectly related to the numbers of neurons that succumb to the ischemic insu lt. The signaling cascades activated by cerebral ischemia that may either p romote or protect against neuronal death are not well-understood. One injur y-responsive signaling pathway that has recently been characterized in stud ies of non-neural cells involves cleavage of membrane sphingomyelin by acid ic and/or neutral sphingomyelinase (ASMase) resulting in generation of the second messenger ceramide. We now report that transient focal cerebral isch emia induces large increases in ASMase activity, ceramide levels, and produ ction of inflammatory cytokines in wild-type mice, but not in mice lacking ASMase. The extent of brain tissue damage is decreased and behavioral outco me improved in mice lacking ASMase. Neurons lacking ASMase exhibit decrease d vulnerability to excitotoxicity and hypoxia, which is associated with dec reased levels of intracellular calcium and oxyradicals. Treatment of mice w ith a drug that inhibits ASMase activity and ceramide production reduces is chemic neuronal injury and improves behavioral outcome, suggesting that dru gs that inhibit this signaling pathway may prove beneficial in stroke patie nts.