title: Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement.
abstract: Allopregnanolone (AP) is supposed to exert beneficial actions including anxiolysis, analgesia, neurogenesis and neuroprotection. However, although mitochondrial dysfunctions are evidenced in neurodegenerative diseases, AP actions against neurodegeneration-induced mitochondrial deficits have never been investigated. Also, the therapeutic exploitation of AP is limited by its difficulty to pass the liver and its rapid clearance after sulfation or glucuronidation of its 3-hydroxyl group. Therefore, the characterization of novel potent neuroprotective analogs of AP may be of great interest. Thus, we synthesized a set of AP analogs (ANS) and investigated their ability to counteract APP-overexpression-evoked bioenergetic deficits and to protect against oxidative stress-induced death of control and APP-transfected SH-SY5Y cells known as a reliable cellular model of Alzheimer's disease (AD). Especially, we examined whether ANS were more efficient than AP to reduce mitochondrial dysfunctions or bioenergetic decrease leading to neuronal cell death. Our results showed that the ANS BR 297 exhibits notable advantages over AP with regards to both protection of mitochondrial functions and reduction of oxidative stress. Indeed, under physiological conditions, BR 297 does not promote cell proliferation but efficiently ameliorates the bioenergetics by increasing cellular ATP level and mitochondrial respiration. Under oxidative stress situations, BR 297 treatment, which decreases ROS levels, improves mitochondrial respiration and cell survival, appears more potent than AP to protect control and APP-transfected cells against H2O2-induced death. Our findings lend further support to the neuroprotective effects of BR 297 emphasizing this analog as a promising therapeutic tool to counteract age- and AD-related bioenergetic deficits.
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; Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland.
authors.forename: Imane
authors.initials: I
authors.lastname: Lejri
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland.
authors.forename: Amandine
authors.initials: A
authors.lastname: Grimm
authors.affiliation: Université de Strasbourg, Institut de Chimie - UMR 7177, 1 rue Blaise Pascal, 67008 Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Miesch
authors.affiliation: Université de Strasbourg, Institut de Chimie - UMR 7177, 1 rue Blaise Pascal, 67008 Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Geoffroy
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Transfaculty Research Platform, Molecular and Cognitive Neuroscience, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland; Psychiatric University Clinics, University of Basel, Wilhelm Klein-Str. 27, 4012 Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
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. Electronic address: gmensah@unistra.fr.
authors.forename: Ayikoe-Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D011280:Pregnanolone
keywords: Allopregnanolone; Alzheimer's disease; Bioenergetics; Mitochondria; Neuroprotection; Oxidative stress