de Kloet Edo Ronald
Leiden University Medical Center, Department of Clinical Medicine, Division of Endocrinology, Leiden University, Leiden, the Netherlands.
Neurosci Appl. 2024 Feb 14;3:104047. doi: 10.1016/j.nsa.2024.104047. eCollection 2024.
Glucocorticoid hormones cortisol and corticosterone (collectively called CORT), secreted as the end products of the hypothalamus-pituitary-adrenal (HPA)-axis, coordinate body and brain function over the circadian cycle and during adaptation to stress. For this purpose, the hormones bind to the mineralocorticoid receptors (MR) with the highest expression in the hippocampus/lateral septum neurons and a 10-fold lower affinity to the widely distributed glucocorticoid receptors (GR). MR and GR mediate opposing rapid non-genomic actions of CORT on neuronal excitability. MR and GR also mediate in a slower complementary manner the genomic actions on neuronal excitability, the management of energy resources, the control of defense reactions, and emotional, motivational, social, and valuation processes to gain control and adapt. The glucocorticoids perform this life-sustaining pleiotropic action in interaction with the neuropeptides of the HPA-axis, the central and autonomic nervous systems, and the immune system. Here, the progress is discussed in (i) detecting dysregulation and recovery in glucocorticoid secretion patterns, (ii) unraveling the complementary function of MR and GR in the mechanism underlying stress-coping and adaptation, and (iii) applying selective CORT receptor modulators for attenuating neurodegeneration and enhancing resilience.
作为下丘脑 - 垂体 - 肾上腺（HPA）轴的终产物分泌的糖皮质激素皮质醇和皮质酮（统称为CORT），在昼夜节律周期以及应激适应过程中协调身体和大脑功能。为此，这些激素与海马体/外侧隔神经元中表达最高的盐皮质激素受体（MR）结合，对广泛分布的糖皮质激素受体（GR）的亲和力低10倍。MR和GR介导CORT对神经元兴奋性的相反快速非基因组作用。MR和GR还以较慢的互补方式介导对神经元兴奋性、能量资源管理、防御反应控制以及情绪、动机、社交和评估过程的基因组作用，以实现控制和适应。糖皮质激素与HPA轴的神经肽、中枢和自主神经系统以及免疫系统相互作用，发挥这种维持生命的多效性作用。在此，讨论了以下方面的进展：（i）检测糖皮质激素分泌模式的失调和恢复；（ii）阐明MR和GR在应激应对和适应机制中的互补功能；（iii）应用选择性CORT受体调节剂减轻神经退行性变并增强恢复力。
