Augmented Cortisol and Antiglucocorticoid Therapy in Mood Disorders: the Hippocampus as a Potential Drug Target

Pub Date : 2024-08-29 DOI:10.1134/s0022093024040203

N. V. Gulyaeva

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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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增强皮质醇和抗糖皮质激素疗法治疗情绪障碍：海马体是潜在的药物靶点

摘要许多情绪障碍的病理生理学与异常应激反应密切相关，而异常应激反应与下丘脑-垂体-肾上腺（HPA）轴功能障碍和皮质醇过度分泌有关。海马体是边缘系统的一个关键结构，负责认知和情感两个领域，它选择性地容易受到过量糖皮质激素（GCs）的影响，从而诱发神经炎症和神经变性。在其他方法中，以海马中大量存在的糖皮质激素受体为靶点被认为是非常有前景的。然而，尽管临床前数据为抗糖皮质激素治疗应激相关疾病的概念提供了相当坚实的证据，但临床研究仍处于概念验证阶段。值得注意的是，慢性 GC 过多不仅与情绪疾病有关，还与认知能力下降、代谢紊乱和糖尿病有关。抗 GC（调节 HPA 轴）疗法有可能通过对海马的有益影响，缓解其功能障碍和神经变性、神经炎症和神经发生障碍，从而减轻情感症状、认知障碍、GC 和胰岛素抵抗以及传统药物的不良副作用。由于应激/GC 相关的神经炎症介导的边缘系统，特别是海马体的病理变化是许多脑部疾病的典型特征，因此抗 GC 治疗的概念可以在更广泛的脑部病理变化中进行扩展、测试和验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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