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

N. V. Gulyaeva1,2,a

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

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

Received June 7, 2019; Revised August 24, 2019; Accepted August 24, 2019
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.
KEY WORDS: hippocampus, stress, stress response, hypothalamic-pituitary-adrenal axis, corticosteroids, cortisol, corticosterone, glucocorticoid receptor, mineralocorticoid receptor, cytokines, neuroinflammation, neurogenesis, BDNF, interleukins, focal brain injury, stroke, traumatic brain injury, depression, cognitive disturbances, dementia

DOI: 10.1134/S0006297919110087