Augmented cortisol and antiglucocorticoid therapy in mood disorders: the hippocampus as a potential drug target

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Abstract

The pathophysiology of many mood disorders is closely related to abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, a key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide fairly firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on the hippocampus mitigating its dysfunction and neurodegeneration, neuroinflammation, and impairment of neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

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About the authors

N. V. Gulyaeva

Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences; Moscow Research and Clinical Center for Neuropsychiatry

Author for correspondence.
Email: nata_gul@ihna.ru
Russian Federation, Moscow; Moscow

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2. Fig. 1. The hypothalamic-pituitary-adrenal (HPA) axis and potential targets of antiglucocorticoid therapy [4, 5, 8, 15–17]. The schematic representation shows the cascading nature of the HPA axis, the major neuroendocrine axis underlying the stress response. Key events in this cascade include: release of the secretagogues corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the medial parvocellular paraventricular nucleus (PVN) of the hypothalamus into the pituitary portal circulation; cleavage of proopiomelanocortin (POMC) to adrenocorticotropic hormone (ACTH) and release of ACTH from the pituitary gland into the systemic circulation; synthesis of glucocorticoids (GCs) (cortisol in humans, or corticosterone in other species, including rodents) in the adrenal cortex and their release into the systemic circulation; binding of glucocorticoids (GCs) to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in central and peripheral target tissues, including the brain, after crossing the blood–brain barrier, thereby mediating the cellular effects of GCs. GRs are expressed in most HPA-related structures and regions of the brain, while limbic structures, primarily the hippocampus, also contain MRs. Multilevel feedback loops from the hypothalamus, pituitary gland, adrenal glands, and signals from the hippocampus and frontal cortex contribute to HPA regulation, in particular by tuning circadian changes in circulating GC levels and decreasing them after the end of a stressor. Excitatory hippocampal output provides inhibitory GABAergic input to the PVN, and gamma-aminobutyric acid (GABA) suppresses hypothalamic hormone secretion. Circulating GCs suppress hypothalamic CRH secretion and pituitary ACTH secretion, and circulating ACTH also suppresses hypothalamic CRH secretion. For a detailed discussion of potential targets for antiglucocorticoid therapy, see Section 2.

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3. Fig. 2. The main symptoms and processes that can be affected by antiglucocorticoid therapy of affective disorders [1, 3, 17, 25, 20, 36, 65, 78, 79]. AntiGC therapy (using mifepristone as an example) in clinical trials and rodent models of affective disorders can reduce affective symptoms, decrease cognitive impairment, overcome the side effects of traditional drugs, and reduce glucocorticoid and insulin resistance. In animal studies, antiGC drugs reverse or prevent hippocampal dysfunction and neurodegeneration, reduce neuroinflammation, and improve impaired neurogenesis.

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