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Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response

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Abstract

Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients’ individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.

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Abbreviations

ACTH:

adrenocorticotropic hormone

Aβ:

amyloid β

AD:

Alzheimer’s disease

BDNF:

brain derived neurotrophic factor

CNS:

central nervous system

CRH:

corticotropin-releasing hormone

CS:

cortisosteroid

GR:

glucocorticoid receptor

HPAA:

hypothalamic-pituitary-adrenocortical axis

11HSD:

11β-hydroxysteroid dehydrogenase

IL:

interleukin

MCI:

mild cognitive impairment

MR:

mineralocorticoid receptor

PSD:

poststroke depression

TNF-α:

tumor necrosis factor-α

TrkB:

tropomyosin receptor kinase B

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Funding

This work was supported by the Russian Foundation for Basic Research, grant no. 18-00-00125 (stress, depression), and the Russian Academy of Sciences Presidium Program “Fundamental bases of physiological adaptation technologies” (remote hippocampal damage).

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Authors and Affiliations

  1. Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485, Moscow, Russia

    N. V. Gulyaeva

  2. Healthcare Department of Moscow, Moscow Research and Clinical Center for Neuropsychiatry, 115419, Moscow, Russia

    N. V. Gulyaeva

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  1. N. V. Gulyaeva
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Correspondence to N. V. Gulyaeva.

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The author declares no conflict of interest.

Compliance with ethical norms

This article does not contain any studies with human participants or animals performed by the author.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 11, pp. 1622–1648.

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Gulyaeva, N.V. Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response. Biochemistry Moscow 84, 1306–1328 (2019). https://doi.org/10.1134/S0006297919110087

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  • DOI: https://doi.org/10.1134/S0006297919110087

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