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Neuroscience. 1999 Mar;89(2):429-36.

Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures.

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  • 1Department of Anatomy, Physiology and MRC Cambridge Centre for Brain Repair, University of Cambridge, U.K.


Glucocorticoids are toxic to hippocampal neurons. We report here that the steroid dehydroepiandrosterone protects neurons of primary hippocampal cultures against the toxic effects of corticosterone. Corticosterone (20-500 nM) added for 24h to primary cultures of embryonic day 18 rat hippocampus resulted in significant neurotoxicity. Dissociated cells were grown for at least 10 days, initially in serum-containing medium, but serum was removed before adding steroids for 24 h. Neurotoxicity was measured by counting the number of cells stained either for beta-tubulin III or glial fibrillary acidic protein. Corticosterone-induced toxicity was prevented by co-treatment of the cultures with dehydroepiandrosterone (20-500 nM). Dehydroepiandrosterone on its own had little effect, though the highest concentration used (500 nM) was mildly toxic. Immunohistochemical studies on the nuclear translocation of a range of stress-activated protein kinases showed that stress-activated protein kinases 1, 2, 3 and 4 were all translocated by 10 min exposure to corticosterone (100 nM). Dehydroepiandrosterone (100 nM) attenuated the translocation of stress-activated protein kinase 3, but not the others. These experiments show that dehydroepiandrosterone has potent anti-glucocorticoid actions on the brain, and can protect hippocampal neurons from glucocorticoid-induced neurotoxicity. This protective action may involve stress-activated protein kinase 3-related intracellular pathways, though direct evidence for this has still to be obtained.

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