Brain Trauma, Glucocorticoids and Neuroinflammation: Dangerous Liaisons for the Hippocampus

Abstract

Glucocorticoid-dependent mechanisms of inflammation-mediated distant hippocampal damage are discussed with a focus on the consequences of traumatic brain injury. The effects of glucocorticoids on specific neuronal populations in the hippocampus depend on their concentration, duration of exposure and cell type. Previous stress and elevated level of glucocorticoids prior to pro-inflammatory impact, as well as long-term though moderate elevation of glucocorticoids, may inflate pro-inflammatory effects. Glucocorticoid-mediated long-lasting neuronal circuit changes in the hippocampus after brain trauma are involved in late post-traumatic pathology development, such as epilepsy, depression and cognitive impairment. Complex and diverse actions of the hypothalamic–pituitary–adrenal axis on neuroinflammation may be essential for late post-traumatic pathology. These mechanisms are applicable to remote hippocampal damage occurring after other types of focal brain damage (stroke, epilepsy) or central nervous system diseases without obvious focal injury. Thus, the liaisons of excessive glucocorticoids/dysfunctional hypothalamic–pituitary–adrenal axis with neuroinflammation, dangerous to the hippocampus, may be crucial to distant hippocampal damage in many brain diseases. Taking into account that the hippocampus controls both the cognitive functions and the emotional state, further research on potential links between glucocorticoid signaling and inflammatory processes in the brain and respective mechanisms is vital.

Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury

“…Importantly, many of these post-injury stressors can also be exacerbated by recovery-related environmental stress, such as sleep loss, isolation, and medical anxiety (Jain et al, 2014 ; Agtarap et al, 2021 ). When the HPA axis has recently been activated by TBI, subsequent activation by other stressors can result in an impaired stress response (reviewed by Komoltsev and Gulyaeva, 2022 ). This impaired response during the vulnerable post-injury period can result in loss of essential immediate anti-inflammatory actions of GC, exacerbating the chronic inflammatory state (Komoltsev and Gulyaeva, 2022 ).…”

“…When the HPA axis has recently been activated by TBI, subsequent activation by other stressors can result in an impaired stress response (reviewed by Komoltsev and Gulyaeva, 2022 ). This impaired response during the vulnerable post-injury period can result in loss of essential immediate anti-inflammatory actions of GC, exacerbating the chronic inflammatory state (Komoltsev and Gulyaeva, 2022 ). Additionally, survivors of TBI have an increased likelihood of developing post-traumatic stress disorder (PTSD), which can amplify the stress and trauma experienced post-TBI (Spadoni et al, 2018 ).…”

Research progress on antidepressant effects and mechanisms of berberine

“…Chronic stress or the dysregulation of GC negative feedback receptors can result in elevated GC levels that can lead to significant damage to the hippocampus and hypothalamus ( Hu et al, 2016 ). Ultimately, this neurogenic damage can lead to the proliferation of oligodendrocytes and exacerbation of depressive symptoms ( Komoltsev and Gulyaeva, 2022 ). Chronic antidepressant treatment can restore the negative feedback function of the HPA axis, which either precedes or coincides with the relief of depression symptoms ( Gobinath et al, 2014 ).…”

Involvement of brain-derived neurotrophic factor signaling in the pathogenesis of stress-related brain diseases

“…In addition to their impact on AD pathology, glucocorticoids play a role in neuroinflammation and synaptic plasticity, which are integral processes in AD pathogenesis. Glucocorticoids can modulate the immune response in the brain, influencing microglial activation, cytokine release, and oxidative stress ( Pedrazzoli et al, 2019 ; Komoltsev and Gulyaeva, 2022 ; Correia et al, 2023 ). Chronic exposure to elevated glucocorticoid levels leads to a state of chronic neuroinflammation, promoting neuronal damage and impairing synaptic function ( Hu et al, 2016 ; Zhang et al, 2017 ).…”