Abstract
A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like behavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored by lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was investigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of proinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics were constructed from transduction and indirect response models. A delay in the onset of increased proinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized by series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect response model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would peak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after peak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior indexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines level in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease progression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in the different time phases and conditions.
Highlights
Increased major depressive-like disorders occur in many diseases, all of which have a common inflammatory component [1]
It was reported that IDO could be activated by proinflammatory cytokines (PCs) [6,7], and its degree of activation was correlated to the intensity of depressive symptoms, as observed in cancer patients chronically treated with immunotherapy [7,8]
KYN was readily transported across the blood brain barrier into the brain where it could be further metabolized by perivascular macrophages, microglia and astrocytes to generate neuroactive glutamatergic compounds [9,10]
Summary
Increased major depressive-like disorders occur in many diseases (e.g., atherosclerosis, congestive heart failure, rheumatoid arthritis), all of which have a common inflammatory component [1]. Depressive-like behaviors were observed in patients undergoing cytokine immunotherapy for the treatment of cancers [2,3]. In these conditions, depressive symptoms were induced by proinflammatory cytokines (PCs), mainly interleukin1b (IL-1b), interleukin-6 (IL-6), interferon-c (IFN-c), and tumor necrosis factor-alpha (TNF-a) [4,5]. It was reported that IDO could be activated by PCs [6,7], and its degree of activation (indicated by increased KYN concentration) was correlated to the intensity of depressive symptoms, as observed in cancer patients chronically treated with immunotherapy [7,8]. We found that anti-inflammatory effects with AZI approach could abrogate LPS-induced depressive like behavior
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