title: Dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEAS) regulate apoptosis during neurogenesis by triggering the Akt signaling pathway in opposing ways.
abstract: Dehydroepiandrosterone (DHEA) can function to protect neural precursors and their progeny targeted with toxic insults; however, the molecular mechanisms underlying the neuroprotective effects of DHEA are not understood. We cultured neural precursors from the embryonic forebrain of rats and examined the effects of DHEA and its sulfated derivative (DHEAS) on the activation of the serine-threonine protein kinase Akt, which is widely implicated in cell survival signaling. We found that DHEA activated Akt in neural precursor culture, in association with a decrease in apoptosis. In contrast, DHEAS decreased activated Akt levels and increased apoptosis. The effects of DHEA on neural cell survival and activation of Akt were not blocked by the steroid hormone antagonists flutamide and tamoxifen, but both were blocked by a PI3-K inhibitor, LY294002. These findings suggest that during neurogenesis in the developing cortex, DHEA and DHEAS regulate the survival of neural precursors and progeny through the Akt signaling pathway.
authors.affiliation: Behavioral Endocrinology Branch, National Institute of Mental Health, Building 36, Room 2C02, Bethesda, MD 20892, USA. zhangl@codon.nih.gov
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Bing shen
authors.initials: Bs
authors.lastname: Li
authors.forename: Wu
authors.initials: W
authors.lastname: Ma
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Barker
authors.forename: Yoong H
authors.initials: YH
authors.lastname: Chang
authors.forename: Weiqin
authors.initials: W
authors.lastname: Zhao
authors.forename: David R
authors.initials: DR
authors.lastname: Rubinow
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005326:Fetal Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005485:Flutamide / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology; D013687:Telencephalon / Q000166:cytology / Q000196:embryology*
chemical_list: D000726:Androgen Antagonists; D002867:Chromones; D004791:Enzyme Inhibitors; D005326:Fetal Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005485:Flutamide; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt