Figure 9

Process flow diagram of signaling pathway. Specific accumulation of ceramide in astrocytes can be induced by cerebral ischemia-reperfusion (I/R), of which activation of neutral sphingomyelinase 2 (nSMase2) by the A2B adenosine receptor (A_2BAR)/p38 mitogen-activated protein kinase (p38MAPK) pathway is the major mechanism for ceramide production. Meanwhile, the binding of the TNF-αR-RACK1-EED complex via their WD repeat domains with nSMase2 can initiate its activity only in part. More importantly, the ischemia-induced accumulation of ceramide in astrocytes can upregulate the generation of proinflammatory factors such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor α (TNF-α) mediated by nuclear factor κB (NF-κB), leading to secondary damage of hippocampal neurons.