Significant sex differences exist in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. These differences are thought to contribute to the disparity in the prevalence of various autoimmune and infectious diseases between males and females. We used a mathematical model of the HPA axis to evaluate the hypothesis that differential sensitivity and negative feedback of the HPA axis network are causal factors for the observed sex differences in its activity. In doing so, we implicitly accounted for the differential influence of gonadal hormones on the HPA axis. Furthermore, we determined whether the putative mechanisms responsible for differences in basal HPA axis activity might also contribute to the observed differences in its stimulus-driven response. Model simulations predicted that the female HPA axis has greater adrenal sensitivity and weaker negative feedback. We identified two distinct sex-specific parameter spaces that generate corticosterone profiles in qualitative agreement with experimental results. We propose that these parameter subspaces indicate the interindividual variability in the regulatory mechanisms of the HPA axis. Furthermore, the model predicts that the maintenance of homeostatic rhythms in response to chronic stress requires specific regulatory adaptations resulting in a phenotype of allostatically driven chronic stress-sensitization. We propose that these adaptations indicate a physiological cost of adaptation to chronic stress. Model simulations suggest that individuals with high adrenal sensitivity are more vulnerable to chronic stress sensitization and might be more susceptible to the development of neuropsychiatric disorders. These results contribute to the study of sex differences in physiological feedback systems within a quantitative framework.

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The hypothalamic-pituitary-adrenal (HPA) axis orchestrates the physiological response to unpredictable acute stressors. Moreover, the HPA axis exhibits prominent circadian activity and synchronizes peripheral circadian clocks to daily environmental cycles, thereby promoting homeostasis. Persistent disruption of homeostatic glucocorticoid circadian rhythmicity due to chronic stress exposure is correlated with the incidence of various pathological conditions including depression, diabetes and cancer. Allostatic habituation of the HPA axis, such that glucocorticoid levels retain homeostatic levels upon chronic exposure to stress, can therefore confer fitness advantages by preventing the sustained dysregulation of glucocorticoid-responsive signaling pathways. However, such allostatic adaptation results in a physiological cost (allostatic load) that might impair the homeostatic stress-responsive and synchronizing functions of the HPA axis. We use mathematical modeling to characterize specific chronic stress-induced allostatic adaptations in the HPA network. We predict the existence of multiple individualized regulatory strategies enabling the maintenance of homeostatic glucocorticoid rhythms, while allowing for flexible HPA response characteristics. We show that this regulatory variability produces a trade-off between the stress-responsive and time-keeping properties of the HPA axis. Finally, allostatic regulatory adaptations are predicted to cause a time-of-day dependent sensitization of the acute stress response and impair the entrainability of the HPA axis.

Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been studied widely, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. This study evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes. LPS was administered intravenously either alone or with curcumin to female Sprague-Dawley rats. Plasma samples were analysed for curcumin concentration and mRNA expression was quantified in lymphocytes. The relative gene expression of several inflammatory and epigenetic modulators was analysed. To investigate the relationship between curcumin concentration and iNOS, TNF-α, and IL-6 gene expression, PK/PD modeling using Jusko's indirect response model (IDR) integrating transit compartments (TC) describing the delayed response was conducted. The concentration-time profile of curcumin exhibited a bi-exponential decline, which was well described by a two-compartmental pharmacokinetic model. Importantly the results demonstrate that LPS induced gene expression of pro-inflammatory markers in lymphocytes, with peak expression at approximately 3 h and curcumin suppressed the gene expression in animals administered with LPS. These effects were well captured using the IDR model and an IDR model with the transit compartments. In summary, the PK/PD modeling approach could potentially provide a robust quantitative framework for evaluating the acute anti-inflammatory and epigenetic effects of curcumin in future clinical trials.

The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology.