Corticotropin-releasing hormone receptor antagonists

Zoumakis, Emmanouil; Grammatopoulos, Dimitris K.; Chrousos, George P.

doi:10.1530/eje.1.02259

Cited by 10 publications

(5 citation statements)

References 94 publications

(53 reference statements)

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“…3 a ). While an exhaustive evaluation of rescue strategies based on single-target interventions suggested that inhibition of CRH would also succeed, the latter is less widely used and somewhat more novel [ 16 ]. For this reason we focused this proof-of-principle on the more common inhibition of glucocortiocoid receptor R [ 17 ].…”

Section: Resultsmentioning

confidence: 99%

High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

et al. 2018

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BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis is a central regulator of stress response and its dysfunction has been associated with a broad range of complex illnesses including Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS). Though classical mathematical approaches have been used to model HPA function in isolation, its broad regulatory interactions with immune and central nervous function are such that the biological fidelity of simulations is undermined by the limited availability of reliable parameter estimates.MethodHere we introduce and apply a generalized discrete formalism to recover multiple stable regulatory programs of the HPA axis using little more than connectivity between physiological components. This simple discrete model captures cyclic attractors such as the circadian rhythm by applying generic constraints to a minimal parameter set; this is distinct from Ordinary Differential Equation (ODE) models, which require broad and precise parameter sets. Parameter tuning is accomplished by decomposition of the overall regulatory network into isolated sub-networks that support cyclic attractors. Network behavior is simulated using a novel asynchronous updating scheme that enforces priority with memory within and between physiological compartments.ResultsConsistent with much more complex conventional models of the HPA axis, this parsimonious framework supports two cyclic attractors, governed by higher and lower levels of cortisol respectively. Importantly, results suggest that stress may remodel the stability landscape of this system, favoring migration from one stable circadian cycle to the other. Access to each regime is dependent on HPA axis tone, captured here by the tunable parameters of the multi-valued logic. Likewise, an idealized glucocorticoid receptor blocker alters the regulatory topology such that maintenance of persistently low cortisol levels is rendered unstable, favoring a return to normal circadian oscillation in both cortisol and glucocorticoid receptor expression.ConclusionThese results emphasize the significance of regulatory connectivity alone and how regulatory plasticity may be explored using simple discrete logic and minimal data compared to conventional methods.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0599-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

High-fidelity discrete modeling of the HPA axis: a study of regulatory plasticity in biology

et al. 2018

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“…Resilient individuals likely have the capacity to effectively regulate CRH levels and/or the relative activity of both receptor subtypes. CRH receptor antagonists are currently under active investigation as potential new pharmacotherapies for anxiety and mood disorders as well as for stress-related gastrointestinal disorders such as irritable bowel syndrome (Tache & Bonaz, 2007;Zoumakis, Grammatopoulos, & Chrousos, 2006).…”

Section: Crhmentioning

confidence: 99%

Psychobiological mechanisms of resilience: Relevance to prevention and treatment of stress-related psychopathology

et al. 2007

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Resilience refers to the ability to successfully adapt to stressors, maintaining psychological well-being in the face of adversity. Recent years have seen a great deal of research into the neurobiological and psychological factors and mechanisms that characterize resilient individuals. This article draws from that research to outline some of the most important contributors to resilience. The authors hope that by contributing to a growing understanding of the genetic, developmental, neurobiological, and psychological underpinnings of resilience, researchers and clinicians in the field will move closer toward the goal of identifying and treating individuals at risk for developing posttraumatic psychopathology.

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“…This suggests an antireproductive role of CRH materialized via auto/paracrine inhibition of steroidogenesis and direct and/or indirect participation in follicular maturation, ovulation, and luteolysis (11). Antalarmin is a specific CRH-R1 antagonist used in investigations of the central and peripheral roles of CRH, including reproductive function (15,16).…”

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confidence: 99%