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Cited by 738Stress Responses and CortisolNeuroscience and Neuropharmacology ResearchAdrenal Hormones and Disorders

Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion

Sapolsky, Robert M.·1996·Stress
DOI 10.3109/10253899609001092
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Abstract

An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.

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Crossref · 10.3109/10253899609001092

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  • Neurologic damage can be potentiated by an elevation in glucocorticoids, potentially complicating comparisons across labs.

    “Neurologic damage can be potentiated by an elevation in glucocorticoids,40 potentially complicating comparisons across labs.”

    From Ultrasonic Vocalization Analysis as a Novel Metric to Assess Cage Enrichment in Rats (2022) · cites this paper as [40]

  • Prolonged elevation in corticosterone levels is implicated in damage to the central nervous system, particularly the hippocampus.

    “Prolonged elevation in corticosterone levels is implicated in damage to the central nervous system, particularly the hippocampus.40”

    From Ultrasonic Vocalization Analysis as a Novel Metric to Assess Cage Enrichment in Rats (2022) · cites this paper as [40]

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Authors
Sapolsky, R. M.
Affiliations
Stanford University (US)
Corresponding author
Sapolsky, Robert M.
ORCID
Sapolsky, Robert M.
Venue
Stress
Publisher
Informa UK Limited
Published
1996-01
Volume
1
Issue
1
Pages
1-19
ISSN
  • 1025-3890 (ISSN-L)
  • 1607-8888
DOI
10.3109/10253899609001092
OpenAlex
W2127596344
Cited by
738
References
9
Citations by year
2026: 7 · 2025: 10 · 2024: 8 · 2023: 38 · 2022: 24 · 2021: 17 · 2020: 27 · 2019: 23 · 2018: 12 · 2017: 27 · 2016: 22 · 2015: 21 · 2014: 28 · 2013: 26 · 2012: 31
FWCI
11.63
Type
journal article
Language
en
Open access
closed
Locations
  • Stress (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
glucocorticoids, hippocampus, glucocorticoid neurotoxicity, glucose uptake inhibition, glutamate excitotoxicity, calcium mobilization, oxygen free radicals, neurotrophins, electrophysiological effects, corticosteroid receptors

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