Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation

Abstract

Glucocorticoids (GCs) are an important component of adaptive response of an organism to stressogenic stimuli, a typical stress response being accompanied by elevation of GC levels in blood. Anti-inflammatory effects of GCs are widely used in clinical practice, while pro-inflammatory effects of GCs are believed to underlie neurodegeneration. This is particularly critical for the hippocampus, brain region controlling both cognitive function and emotions/affective behavior, and selectively vulnerable to neuroinflammation and neurodegeneration. The hippocampus is believed to be the main target of GCs since it has the highest density of GC receptors potentially underlying high sensitivity of hippocampal cells to severe stress. In this review, we analyzed the results of studies on pro- and anti-inflammatory effects of GCs in the hippocampus in different models of stress and stress-related pathologies. The available data form a sophisticated, though often quite phenomenological, picture of a modulatory role of GCs in hippocampal neuroinflammation. Understanding the dual nature of GC-mediated effects as well as causes and mechanisms of switching can provide us with effective approaches and tools to avert hippocampal neuroinflammatory events and as a result to prevent and treat brain diseases, both neurological and psychiatric. In the framework of a mechanistic view, we propose a new hypothesis describing how the anti-inflammatory effects of GCs may transform into the pro-inflammatory ones. According to it, long-term elevation of GC level or preliminary treatment with GC triggers accumulation of FKBP51 protein that suppresses activity of GC receptors and activates pro-inflammatory cascades, which, finally, leads to enhanced neuroinflammation.

Stress-Associated Molecular and Cellular Hippocampal Mechanisms Common for Epilepsy and Comorbid Depressive Disorders

“…Excessively secreted GCs in patients with TLE, especially in those with initially abnormal stress response due to the HPACS dysfunction, interact with the hippocampal GRs, inducing signaling pathways that stimulate neuroinflammation and other processes, such as neurodegeneration and changes in neurogenesis [21,41,60]. Functional and structural damages to the hippocampus, which is selectively vulnerable to extreme factors and responds to them by increasing cytokine secretion [115], form an individual basis for the develop ment of both epilepsy and depressive/anxiety disorders in each particular patient.…”

Neuroinflammation and Neuronal Loss in the Hippocampus Are Associated with Immediate Posttraumatic Seizures and Corticosterone Elevation in Rats

“…Mechanisms of these effects of GCs include suppression of glucose transport, glutamate reuptake by astrocytes, alternation of Ca2+ homeostasis and suppression of neurotrophic factors production [ 51 , 52 ]. GCs exhibit either pro- or anti-inflammatory properties, depending on specific features of the definite situation, including the degree and duration of GCs exposure, factors and characteristics of the injury and spatial/temporal aspects [ 53 ]. It is suggested that in the hippocampus GCs may act as pro-inflammatory agents [ 8 , 53 , 54 ].…”

“…GCs exhibit either pro- or anti-inflammatory properties, depending on specific features of the definite situation, including the degree and duration of GCs exposure, factors and characteristics of the injury and spatial/temporal aspects [ 53 ]. It is suggested that in the hippocampus GCs may act as pro-inflammatory agents [ 8 , 53 , 54 ]. Importantly, increased level of GCs before a pro-inflammatory stimulus has an additional pro-inflammatory effect [ 55 ].…”

“…In rats with prolonged seizures, CS was higher on days 3, 7 and 14. CS elevation on day 3 negatively correlated with microglial cells density in the hippocampus, reflecting a well-known anti-inflammatory effect of GCs [ 53 ] (IL-1β and microglial cells density on day 3 in TBI rats were not elevated). On day 7, microglial activation was detected in both hemispheres and it was accompanied by neuronal loss in the contralateral hippocampus.…”

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

“…In contrast, GRs are functionally active at stress-induced high GC levels and therefore orchestrate stress responses of the cells, organs, and the whole body. One of the main and most vulnerable targets of GCs is the brain, where excessive or chronic activation of GRs may be detrimental for neuronal function and survival [ 28 , 29 ].…”