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

Natalia V Gulyaeva,Yulia V Moiseeva,Mikhail V Onufriev

doi:10.3389/fnins.2021.781964

Natalia V Gulyaeva, Yulia V Moiseeva + Show 1 more

Open Access

https://doi.org/10.3389/fnins.2021.781964

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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.

Highlights

Ischemic stroke (IS) accounting for approximately 87% of stroke cases (Virani et al, 2021) is a severe neurological pathology with high mortality and frequent post-stroke delayed sequelae
Since hyperglutamatergic transmission is regarded as key mechanism of hippocampus-dependent cognitive, affective, and epilepsyassociated disturbances, it is more than probable that it is one of the main players in the delayed consequences of IS (Gulyaeva, 2021b). Both in rats and in gerbils, adrenalectomy protected hippocampal pyramidal cells from transient ischemia (Morse and Davis, 1990). These findings suggest that GCs affect the rate of hippocampal pyramidal cell disappearance following ischemia
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 hippocampus-associated cognitive and emotional disorders remain obscure

Summary

INTRODUCTION

In acute IS patients, increased plasma cortisol was negatively correlated with plasma brain-derived neurotrophic factor (BDNF) levels, neurological condition, cognitive function, functional responses, and emotional status, suggesting a connection between the declines of clinical, behavioral and biochemical blood parameters with stress-induced cortisol elevation (Casas et al, 2017). It was suggested that high bedtime salivary cortisol levels in IS patients may provide information about dysregulation of diurnal HPA axis activity under acute challenge conditions, and predict worse cognitive outcome. These recent studies confirm the data reported earlier by Maeda et al (1991) who showed that HPA axis function was activated in demented patients and that this activation was related generally to dementation itself, not to the etiology of dementia. Stress response (cortisol levels, HPA axis activation) is among most promising prognostic biomarkers

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