Fructose-1,6-disphosphate (F1,6DP), a glycolytic intermediate, is known to have protective activities against ischemia / reperfusion injury and septic shock induced by bacterial lipopolysaccharide (LPS), a Gram-negative cell wall component. In this study, it was shown that F1,6DP could effectively reduce LPS-induced iNOS expression and NO production in BV-2 mouse microglia. F1,6DP attenuated iNOS expression through down-regulation of AP-1 DNA binding activity and interception of MAPKs, JAK / STAT and Akt / GSK-3β pathways. In consideration of ROS-contribution to iNOS expression and NO production, it was tested whether F1,6DP affects LPS-induced ROS production in BV-2 cells. F1,6DP significantly reduced LPS-induced ROS production in BV-2 cells. It was also found that F1,6DP enhanced LPS-induced activity of glucose-6-phopsphate dehydrogenase (G6PD), a key enzyme of PPP, which paralleled the enhancement of LPS-stimulated G6PD expression in the levels of mRNA and protein. Ectopic expression of G6PD resulted in the diminution of iNOS expression and NO production as well as ROS production. Considering PPP is one of the most important ROS scavenging mechanism, our data obtained hitherto suggest that F1,6DP can reduce the cellular ROS generation by increasing metabolic flux through PPP, that is, by providing substrate for G6PD, and up-regulation of G6PD. And also, it was suggested that ROS regulation by F1,6DP might be functionally linked to the down-regulation of LPS-induced iNOS expression and NO production in BV-2 microglia.
