Metabolism of dehydroepiandrosterone by rat hippocampal cells in culture: possible role of aromatization and 7-hydroxylation in neuroprotection

Jellinck, Peter H.; Lee, Susan J.; McEwen, Bruce S.

doi:10.1016/s0960-0760(01)00106-6

Cited by 48 publications

(31 citation statements)

References 29 publications

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“…Circulating DHEA can be locally metabolized to sex steroids within peripheral target tissues (e.g., prostate, skin), a phenomenon Labrie and colleagues termed "intracrinology" . Interestingly, DHEA metabolism to sex steroids also occurs within the human brain (Milewich et al, 1991) and rodent brain (Zhao et al, 1991;Zwain and Yen, 1999;Jellinck et al, 2001). …”

Section: Intracrinologymentioning

confidence: 99%

Recent advances in behavioral neuroendocrinology: Insights from studies on birds

Goodson

Saldanha

Hahn

et al. 2005

Hormones and Behavior

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Ever since investigations in the field of behavioral endocrinology were hatched with experiments on roosters, birds have provided original insights into issues of fundamental importance for all vertebrate groups. Here we focus on more recent advances that continue this tradition, including 1) environmental regulation of neuroendocrine and behavioral systems, 2) steroidogenic enzyme functions that are related to intracrine processes and de novo production of neurosteroids, and 3) hormonal regulation of neuroplasticity. We also review recent findings on the anatomical and functional organization of steroid-sensitive circuits in the basal forebrain and midbrain. A burgeoning body of data now demonstrates that these circuits comprise an evolutionarily conserved network, thus numerous novel insights obtained from birds can be used (in a relatively straightforward manner) to generate predictions for other taxa as well. We close by using birdsong as an example that links these areas together, thereby highlighting the exceptional opportunities that birds offer for integrative studies of behavioral neuroendocrinology, and behavioral biology in general. Keywords aggression; reproduction; song; limbic system; vasotocin; photoperiod; neurosteroid; DHEA; aromatase; adult neurogenesis; estrogen; testosterone; thyroxin; hypothalamus; hippocampus; HVC; septum; GnRH; SCN; season; neuroplasticity Birds offer excellent opportunities for behavioral and neuroendocrine experiments in both the field and the laboratory, and studies conducted at this interface have historically placed avian models on the cutting edge of research (Konishi et al., 1989; also see Wingfield, this issue). Indeed, wild birds offer a combination of accessibility (being diurnal and terrestrial) and diversity (social and ecological) that makes them invaluable models for studying mechanistic and evolutionary questions that are not as tractable in other vertebrate groups. This diversity can be studied within the context of neural and endocrine systems that share many features with those of other taxa (thereby increasing the general relevance of avian studies) (Goodson, 2005), although these features are often more pronounced in birds. Such examples include exceptionally robust and widespread neural aromatase activity, and adult neurogenesis in the forebrain, both of which are considered further below (also see Ball and Balthazart, 2004;

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Section: Intracrinologymentioning

confidence: 99%

Recent advances in behavioral neuroendocrinology: Insights from studies on birds

Goodson

Saldanha

Hahn

et al. 2005

Hormones and Behavior

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“…Last, DHEA can serve as substrate for the production of more potent androgens such as androstenedione (AE) and, subsequently, T and DHT, in the presence of 3␤-HSD, 17␤-HSD, and 5␣-reductase (Garcia-Segura et al, 1996;Zwain and Yen, 1999;Plassart-Schiess and Baulieu, 2001), providing an indirect means for the production of androgenic effects through AR. In the CNS, however, competing metabolic pathways and regional variation in 3␤-HSD expression leave open the possibility that DHEA itself, which is structurally a steroid, may interact directly with AR (Jellinck et al, 2001). In light of these observations, it was evident that an examination of regulatory effects of DHEA on neural AR was needed.…”

Section: Introductionmentioning

confidence: 99%

Dehydroepiandrosterone upregulates neural androgen receptor level and transcriptional activity

et al. 2003

J. Neurobiol.

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The mechanism of action of dehydroepiandrosterone (DHEA), a neuroactive neurosteroid synthesized in the brains of humans and other mammals, has not been fully characterized in the adult brain. Although well known for modulatory effects on GABA(A), NMDA, and sigma(1) receptors, studies in both CNS and peripheral target cells suggest that DHEA also may exert genomic effects via the androgen receptor (AR). The current study tested the hypothesis that DHEA was capable of producing androgenic effects in the CNS by assaying its ability to induce three characteristic effects of an androgenic compound. These included the ability to upregulate neural AR protein level in mouse brain and immortalized GT1-7 hypothalamic cells, the capacity to induce transcriptional activity through AR in CV-1 cells transfected with an MMTV-ARE-CAT reporter, and competition for recombinant AR binding in a radioligand binding assay. The results showed that DHEA treatment significantly augmented AR both in vivo and in vitro, and that this effect was not blocked by trilostane (TRIL), a known 3beta-hydroxysteroid dehydrogenase (3beta-HSD) inhibitor. DHEA also promoted AR-mediated CAT reporter expression and competed with dihydrotestosterone (DHT) for binding to recombinant AR in a cell-free system. These data indicate that DHEA possesses intrinsic androgenic activity that is potentially independent of metabolic conversion to other androgens, and that it can affect gene function through the AR. In combination with its modulation of neurotransmitter receptors at the cell membrane level, the findings suggest that the mechanism of action of DHEA in the brain can involve a "crosstalk" cellular signaling system that involves both nongenomic and genomic components.

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“…Therefore, the neuroprotective effect of pregnenolone and DHEA may be, at least in part, exerted by their conversion to estradiol. This conclusion does not exclude alternative or complementary mechanisms for the neuroprotective effects of pregnenolone and DHEA, including the formation of 7-hydroxylated metabolites of DHEA (Jellinck et al, 2001), in other injury or neurodegenerative conditions. In addition, future studies aimed at the assessment of the levels of pregnenolone, DHEA, and estradiol in the brain after injury and in the presence or in the absence of fadrozole would help to determine the precise mechanism involved in the neuroprotective actions of aromatase.…”

Section: Figurementioning

confidence: 92%

Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase

2003

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Pregnenolone and dehydroepiandrosterone (DHEA) are sex hormone precursors and neuroprotective steroids. Effects of pregnenolone and DHEA may be in part mediated by their conversion to testosterone and by the consecutive conversion of testosterone to estradiol by the enzyme aromatase. This enzyme is induced in reactive astrocytes after different forms of neurodegenerative lesions and the resultant local production of estradiol in the brain has been shown to be neuroprotective. The participation of aromatase in the neuroprotective effect of pregnenolone and DHEA has been assessed in this study. The protective effect of different doses (12.5, 25, 50, and 100 mg/kg) of pregnenolone or DHEA, against systemic kainic acid (7 mg/kg b.w.), was assessed on hippocampal hilar neurons in gonadectomized Wistar male rats. To determine whether the neuroprotective effect of pregnenolone and DHEA was dependent on their conversion to estradiol, the aromatase inhibitor fadrozole (4.16 mg/ml) was administered using subcutaneous osmotic minipumps. The number of Nissl-stained neurons in the hilus of the dentate gyrus of the hippocampal formation was estimated by the optical disector method. The administration of kainic acid resulted in a significant decrease in the number of hilar neurons compared to rats injected with vehicles. Pregnenolone and DHEA showed a dose-dependent protective effect of hilar neurons against kainic acid. The administration of the aromatase inhibitor fadrozole blocked the neuroprotective effect of pregnenolone and DHEA. These findings suggest that estradiol formation by aromatase mediates neuroprotective effects of pregnenolone and DHEA against excitotoxic-induced neuronal death in the hippocampus.

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Metabolism of dehydroepiandrosterone by rat hippocampal cells in culture: possible role of aromatization and 7-hydroxylation in neuroprotection

Cited by 48 publications

References 29 publications

Recent advances in behavioral neuroendocrinology: Insights from studies on birds

Recent advances in behavioral neuroendocrinology: Insights from studies on birds

Dehydroepiandrosterone upregulates neural androgen receptor level and transcriptional activity

Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase

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