Ischemic Stroke, Glucocorticoids, and Remote Hippocampal Damage: A Translational Outlook and Implications for Modeling

Abstract

Progress in treating ischemic stroke (IS) and its delayed consequences has been frustratingly slow due to the insufficient knowledge on the mechanism. One important factor, the hypothalamic-pituitary-adrenocortical (HPA) axis is mostly neglected despite the fact that both clinical data and the results from rodent models of IS show that glucocorticoids, the hormones of this stress axis, are involved in IS-induced brain dysfunction. Though increased cortisol in IS is regarded as a biomarker of higher mortality and worse recovery prognosis, the detailed mechanisms of HPA axis dysfunction involvement in delayed post-stroke cognitive and emotional disorders remain obscure. In this review, we analyze IS-induced HPA axis alterations and supposed association of corticoid-dependent distant hippocampal damage to post-stroke brain disorders. A translationally important growing point in bridging the gap between IS pathogenesis and clinic is to investigate the involvement of the HPA axis disturbances and related hippocampal dysfunction at different stages of SI. Valid models that reproduce the state of the HPA axis in clinical cases of IS are needed, and this should be considered when planning pre-clinical research. In clinical studies of IS, it is useful to reinforce diagnostic and prognostic potential of cortisol and other HPA axis hormones. Finally, it is important to reveal IS patients with permanently disturbed HPA axis. Patients-at-risk with high cortisol prone to delayed remote hippocampal damage should be monitored since hippocampal dysfunction may be the basis for development of post-stroke cognitive and emotional disturbances, as well as epilepsy.

A Comparative Study of Two Models of Intraluminal Filament Middle Cerebral Artery Occlusion in Rats: Long-Lasting Accumulation of Corticosterone and Interleukins in the Hippocampus and Frontal Cortex in Koizumi Model

“…Ischemia-induced HPA activation which represents a quick physiological response, resulting in a prolonged increase in blood glucocorticoid levels, was described about 3 decades ago [ 20 , 21 , 22 ]. The fact that the stress response mediated by the HPA axis is associated with ischemic stroke has been confirmed in numerous further clinical and preclinical studies (see [ 8 ] for a review). A prolonged excess of glucocorticoids is believed to aggravate ischemic brain injury via the unwarranted activation of their receptors and increase the vulnerability of neurons in selected brain regions to neurodegeneration and demise.…”

“…One of the main reasons for this continuous failure may be due to problems with the validity of the models used [ 6 , 7 ]. Though the involvement of the stress and neurohumoral system in strokes is well-documented in clinical studies, it is still neglected in rodent models of ischemic stroke [ 8 ], although increased cortisol is associated with a worse outcome and the development of delayed cognitive deficits. Limbic structures, primarily the hippocampus, which coordinate both cognitive and emotional functions, have a high density of corticosteroid receptors, and this may be related to their selective vulnerability to stress factors.…”

The association between serum glucose to potassium ratio on admission and short-term mortality in ischemic stroke patients

“…Thus, post-stroke hyperglycemia and hypokalemia may reflect the stress-related activation and a disorder of the hypothalamic–pituitary–adrenal (HPA) axis. HPA axis dysregulation believed to play a key role in the process of successive energy pump failure and various signaling cascades of IS 38 . In addition, a high cortisol level would activate the renin–angiotensin–aldosterone system (RAAS) to induce low serum potassium 39 .…”

“…Therefore, most treatment strategies currently followed that were developed by targeting known key pathogenetic links are often inadequately effective. The role of stress responses 38 and stress-related markers 3 has been proven to play a pivotal role in IS progression and has gained increasing attention. Our results suggested that comprehensive treatments including appropriate potassium supplementation, hypoglycemic treatment, and stress response blocker (β-blocker, RAAS inhibitor) may improve the short-term prognosis with high GPR levels.…”

Development of Post-Stroke Cognitive and Depressive Disturbances: Associations with Neurohumoral Indices

“…The HPA axis dysfunction associated with stroke is generally neglected, though both clinical data and the results from rodent models of IS show that glucocorticoids are tightly involved in IS-induced brain dysfunction (see [ 34 ] for review). Adrenal glucocorticoid stress response in acute stroke is harmful.…”