A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like\r\nbehavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored\r\nby lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was\r\ninvestigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of\r\nproinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics\r\nwere constructed from transduction and indirect response models. A delay in the onset of increased\r\nproinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized\r\nby series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect\r\nresponse model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would\r\npeak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after\r\npeak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior\r\nindexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines\r\nlevel in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease\r\nprogression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in\r\nthe different time phases and conditions
Loading....