title: Improvement of neuronal bioenergetics by neurosteroids: implications for age-related neurodegenerative disorders.
abstract: The brain has high energy requirements to maintain neuronal activity. Consequently impaired mitochondrial function will lead to disease. Normal aging is associated with several alterations in neurosteroid production and secretion. Decreases in neurosteroid levels might contribute to brain aging and loss of important nervous functions, such as memory. Up to now, extensive studies only focused on estradiol as a promising neurosteroid compound that is able to ameliorate cellular bioenergetics, while the effects of other steroids on brain mitochondria are poorly understood or not investigated at all. Thus, we aimed to characterize the bioenergetic modulating profile of a panel of seven structurally diverse neurosteroids (progesterone, estradiol, estrone, testosterone, 3α-androstanediol, DHEA and allopregnanolone), known to be involved in brain function regulation. Of note, most of the steroids tested were able to improve bioenergetic activity in neuronal cells by increasing ATP levels, mitochondrial membrane potential and basal mitochondrial respiration. In parallel, they modulated redox homeostasis by increasing antioxidant activity, probably as a compensatory mechanism to a slight enhancement of ROS which might result from the rise in oxygen consumption. Thereby, neurosteroids appeared to act via their corresponding receptors and exhibited specific bioenergetic profiles. Taken together, our results indicate that the ability to boost mitochondria is not unique to estradiol, but seems to be a rather common mechanism of different steroids in the brain. Thus, neurosteroids may act upon neuronal bioenergetics in a delicate balance and an age-related steroid disturbance might be involved in mitochondrial dysfunction underlying neurodegenerative disorders.
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland; Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000 Strasbourg, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland.
authors.forename: Karen
authors.initials: K
authors.lastname: Schmitt
authors.affiliation: Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland.
authors.forename: Undine E
authors.initials: UE
authors.lastname: Lang
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Bâtiment 3 de la Faculté de Médecine, 11 rue Humann, 67 000 Strasbourg, France.
authors.forename: Ayikoe Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular & Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, CH-4012 Basel, Switzerland. Electronic address: anne.eckert@upkbs.ch.
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D015113:Androstane-3,17-diol / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D004970:Estrone / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology*; D010101:Oxygen Consumption; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology
chemical_list: D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D015113:Androstane-3,17-diol; D004970:Estrone; D013739:Testosterone; D003687:Dehydroepiandrosterone; D011374:Progesterone; D004958:Estradiol; D000255:Adenosine Triphosphate; D011280:Pregnanolone; D013482:Superoxide Dismutase
keywords: Bioenergetics; Mitochondria; Neurosteroid; Redox homeostasis