Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity

Kimonides, V. G.; Khatibi, Nikan H.; Svendsen, Clive N.; Sofroniew, M.V.; Herbert, Joseph

doi:10.1073/pnas.95.4.1852

Cited by 412 publications

(258 citation statements)

References 25 publications

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“…It is clear that in both P20 and adult slices, DHEA can be metabolized fully to estrogens and 5α-reduced androgens in this region of the songbird brain. In other vertebrates, DHEA has been shown to influence neurite outgrowth, neuron survival, and adult neurogenesis (Cardounel et al, 1999;Fiore et al, 2004;Karishma and Herbert, 2002;Kimonides et al, 1998;Li et al, 2001;Marx et al, 2000;Suzuki et al, 2004). DHEA has now been detected circulating in the blood of several avian species (Goodson et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Activities of 3β-HSD and aromatase in slices of developing and adult zebra finch brain

Tam¹,

Schlinger²

2007

General and Comparative Endocrinology

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Sex steroids influence the development and function of the songbird brain. Developmentally, the neural circuitry underlying song undergoes masculine differentiation under the influence of estradiol. In adults, estradiol stimulates song behavior and the seasonal growth of song control circuits. There is good reason to believe that these neuroactive estrogens are synthesized in the brain. At all ages, estrogens could act at the lateral ventricle, during migration, or where song nuclei exist or will form. We investigated the activity of two critical steroidogenic enzymes, 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD) and aromatase, using a slice culture system. Sagittal brain slices were collected from juvenile (posthatch day 20) and adult zebra finches containing either the lateral ventricle, where neurons are born, or the telencephalic song nuclei HVC and RA. The slices were incubated with 3 H dehydroepiandrosterone or 3 H-androstenedione. Activity was determined by isolating certain products of 3βHSD (5α-androstanedione, 5β-androstanedione, estrone, and estradiol) and aromatase (estrone and estradiol). Activities of both 3βHSD and aromatase were detected in all slices and were confirmed using specific enzyme inhibitors. We found no significant difference in activity between adult males and females in either region for either enzyme. Juvenile female slices containing the lateral ventricle, however, showed greater levels of 3βHSD activity than did similar slices from age-matched males. Determination of the activity of these critical steroidogenic enzymes in slice culture has implications for the role of neurosteroids in brain development.

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Section: Discussionmentioning

confidence: 99%

Activities of 3β-HSD and aromatase in slices of developing and adult zebra finch brain

Tam¹,

Schlinger²

2007

General and Comparative Endocrinology

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“…As noted above, the vulnerability to excitotoxicity in hippocampal neurons has been related to increased calcium channel activity that develops with increasing age in culture (116). The cell culture approach has been extended recently to demonstrate the protective effects of another steroid that declines with age in humans, namely, dehydroepiandrosterone (DHEA), toward NMDA-induced neurotoxicity (65). A fourth strategy is to use targeted delivery of genetic material in viral vectors in order to overcome the restrictions of energy supply in the face of excitotoxic challenge using local enhancement of glucose transporter activity (55).…”

Section: How To Define Protective Factors In the Brainmentioning

confidence: 99%

Stress and the Aging Hippocampus

McEwen

1999

Frontiers in Neuroendocrinology

208

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The ''glucocorticoid cascade hypothesis'' of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain. KEY WORDS: stress; hippocampal aging; glucocorticoid cascade hypothesis. 1999 Academic Press INTRODUCTIONThe hippocampus is a particularly vulnerable and sensitive region of the brain that is also very important for declarative and spatial learning and memory (36). Hippocampal neurons are vulnerable to seizures, strokes, and head trauma, as well as responding to stressful experiences (27,92,130). At the same time they show remarkable plasticity, involving long-term synaptic potentiation and depression, dendritic remodeling, synaptic turnover, and neurogenesis in the case of the dentate gyrus (Fig 1) (17,27,92).The work of aus der Muhlen and Ockenfels (3) first drew attention to potentially toxic actions of adrenal steroids. The reported darkly stained neurons in the hippocampus of guinea pigs exposed to high levels of glucocorticoids, an observation that has been confirmed and extended to repeated stress in subsequent studies (41,100), although there are still some doubts as to whether ''dark neurons'' may be artifacts of tissue trauma (18). In 1968, we discovered receptors for adrenal steroids in hippocampus (95), and it is now known that two types of adrenal steroid receptors exist in the hippocampus and other brain regions and mediate a variety of adrenal steroid effects on excitability, neurochemistry, and structure (27). Landfield (68) and then Sapolsky (127,128) provided evidence for a role of adrenal steroids in neuronal aging in the hippocampus, leading to the formulation of the ''glucocorticoid cascade hypothesis '' (130). This hypothesis states that glucocorticoids participate in a ...

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“…Whereas high cortisol has catabolic properties, DHEA and its sulfate form DHEAS have been found to possess anabolic, neuroprotective and antiglucocorticoid effects, showing neurogenerative effects in the hippocampus (Karishma and Herbert, 2002) and protection against the neurotoxic effects of cortisol in studies in rodents (Kaminska et al, 2000;Kimonides et al, 1998Kimonides et al, , 1999. This may contribute to an upregulation of HPA-axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in PTSD (Rasmusson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The role of acute cortisol and DHEAS in predicting acute and chronic PTSD symptoms

Mouthaan

Sijbrandij²,

Luitse

et al. 2014

Psychoneuroendocrinology

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SummaryBackground: Decreased activation of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress is suspected to be a vulnerability factor for posttraumatic stress disorder (PTSD). Previous studies showed inconsistent findings regarding the role of cortisol in predicting PTSD. In addition, no prospective studies have examined the role of dehydroepiandrosterone (DHEA), or its sulfate form DHEAS, and the cortisol-to-DHEA(S) ratio in predicting PTSD. In this study, we tested whether acute plasma cortisol, DHEAS and the cortisol-to-DHEAS ratio predicted PTSD symptoms at 6 weeks and 6 months post-trauma. Methods: Blood samples of 397 adult level-1 trauma center patients, taken at the trauma resuscitation room within hours after the injury, were analyzed for cortisol and DHEAS levels. PTSD symptoms were assessed at 6 weeks and 6 months post-trauma with the Clinician Administered PTSD Scale. Results: Multivariate linear regression analyses showed that lower cortisol predicted PTSD symptoms at both 6 weeks and 6 months, controlling for age, gender, time of blood sampling, injury, trauma history, and admission to intensive care. Higher DHEAS and a smaller cortisol-to-DHEAS ratio predicted PTSD symptoms at 6 weeks, but not after controlling for the same variables, and not at 6 months. Conclusions: Our study provides important new evidence on the crucial role of the HPA-axis in response to trauma by showing that acute cortisol and DHEAS levels predict PTSD symptoms in survivors of recent trauma. #

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Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity

Cited by 412 publications

References 25 publications

Activities of 3β-HSD and aromatase in slices of developing and adult zebra finch brain

Activities of 3β-HSD and aromatase in slices of developing and adult zebra finch brain

Stress and the Aging Hippocampus

The role of acute cortisol and DHEAS in predicting acute and chronic PTSD symptoms

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