DOCSLIB.ORG

Mitochondria, Neurosteroids and Biological Rhythms: Implications in Health and Disease States

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Mitochondria, neurosteroids and biological rhythms : implications in health and disease states Amandine Grimm To cite this version: Amandine Grimm. Mitochondria, neurosteroids and biological rhythms : implications in health and disease states. Neurobiology. Université de Strasbourg, 2015. English. NNT : 2015STRAJ002. tel-01280544 HAL Id: tel-01280544 https://tel.archives-ouvertes.fr/tel-01280544 Submitted on 29 Feb 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSIT DE STRASBOURG Ecole Doctorale des Sciences de la Vie et de la Sant (ED 414) INSERM UMR_S U1119 M Biopathologies de la My line, Neuroprotection et Strat gies Th rapeutiques THSE En cotutelle avec lRUniversit de Ble, Suisse pr sent e par : Amandine GRIMM soutenue le 14 janvier 2015 pour obtenir le grade de : Docteur de lRUniversit de Strasbourg Sp cialit : Neurosciences Mitochondria, neurosteroids and biological rhythms: implications in health and disease states. THSE dirig e par : M. MENSAH-NYAGAN Ayiko , Guy Professeur, Universit de Strasbourg, France Mme ECKERT Anne Professeur, Universit de Ble, Suisse RAPPORTEURS : M. HAMBURGER Matthias Professeur, Universit de Ble, Suisse M. REICHERT Heinrich Professeur, Universit de Ble, Suisse AUTRES MEMBRES DU JURY : Mme MATHIS Chantal Docteur, Universit de Strasbourg, France Mme PATTE-MENSAH Christine Docteur, Universit de Strasbourg, France À +#1 .0#,21 À +#1 $0L0#1 #2 130 À 2-31 !#36 /3# (_'+# #2 /3' +_-,2 1-32#,3 2-32 3 *-,% "3 !&#+', ACKNOWLEDGMENTS The present thesis has been performed between the Neurobiology Laboratory for Brain Aging and Mental Health of the Psychiatric University Clinics of Basel (UPK), University of Basel, under the supervision of Prof. Dr. Anne Eckert, and the INSERM unit U1119, Biopathologie de la My line, Neuroprotection et Strat gies Th rapeutiques, Universit de Strasbourg, under the supervision of Prof. Dr. Ayikoe Guy Mensah-Nyagan. My warmest thanks go to Prof. Dr. Anne Eckert who allowed me to be part of her team for this joint-PhD thesis. Thanks for your trust, your support and all the scientific opportunities you gave me (congresses, publications...). You have allowed me to develop my scientific skills by giving me new technical and intellectual challenges that helped me to grow up both professionally and personally. I would like to express my gratitude to Prof. Dr. Ayikoe Guy Mensah-Nyagan who always believed in my scientific skills since the Master degree. First, you gave me the opportunity to perform my Master training in Montreal which was one of the best experiences in my life. Then, you advised me as a PhD student to Prof. Dr. Anne Eckert and allowed me to do this joint-PhD thesis with your lab. I am indebted for your teaching, your availability, your advices and your constant support. My thanks go to Prof. Dr. Matthias Hamburger who accepted to be my Faculty representative and to Dr. Chantal Mathis for making herself available as a co-referee. I also wish to acknowledge Prof. Dr. Heinrich Reichert and Dr. Christine Patte-Mensah for their participation in my dissertation. I would like to express my thanks and my sympathy for my colleagues in Basel: First, a big thank goes for Karen, my colleague and shill, for all the time we spent together in the lab (even during night work), in congresses and in private. Thanks for all the outstanding scientific (and less scientific) conversations. Thanks a lot Fides for your help (especially the administrative part) and your humor that was always a breath of fresh air in critical periods. Thanks to Ginette and Imane for these moments of conviviality during the coffee break. We shared joy, tears, blues but, above all, happiness. Thanks for all these moments that make me think of you all a little bit like a second family. I would like also to thank all the "zivis" who stopped by our lab for a few months, in particular Stefano, Fabio, Ricky and Jonas, for their help in the lab or with informatic tasks that made my life much easier at the end! Thanks also to Virginie and Julien for all the "afterwork meetings" where we shared interesting (and funny) scientific (or not) conversations. Toute ma sympathie va galement mes coll gues de Strasbourg: Dr. V ronique Kemmel pour tous les changes scientifiques que l'on a pu avoir, Dr. Christine Patte-Mensah pour ses conseils et son ind fectible bonne humeur, Dr. Laurence Meyer, Dr. Christian Klein, David Hollinger, et bien sr tous les autres (Professeurs, docteurs, postdocs, techniciens et tudiants...) pour l'aide et les conseils qu'ils ont pu m'apporter. ACKNOWLEDGMENTS Un grand merci au Dr. Guillaume Wendt, mon binme depuis le Master, pour son soutien moral dans les moments difficiles et sa bonne humeur communicative! La route n'a pas t facile mais on y est finalement arriv ! Du fond du cLur , je voudrais remercier mes amis et ma famille: Merci Diane, lose et Sandrine pour tous ces bons moments pass s ensemble depuis le coll ge et le lyc e. Merci pour votre coute et votre soutien qui ont contribu faire de moi celle que je suis aujourd'hui. Merci ma cousine, Eve et ses adorables enfants, ainsi qu' mon groupe de danse du jeudi soir pour ces moments d' vasion et de convivialit loin du labo. Votre soutien et votre bonne humeur ont t pour moi une incroyable bouff e d'air frais! Merci mes grands-m res et grands-p res, ma marraine et mon parrain (partis trop tt), et tous les autres pour leur foi en moi qui m'a port aussi loin. Un immense merci toi, Benjamin, pour toutes ces ann es pass es mes ct s. Merci pour ton ind fectible soutient dans les moments de doute, merci pour ton humour qui me remonte toujours le moral, merci ta patience quand moi j'en manquais, et merci d'tre l pour en voir le fruit! Je tiens galement chaleureusement remercier Mado, Joseph et C cilia pour leur coute, leur soutien et leur gentillesse. Merci vous! Et enfin, comme il est coutume de garder le meilleur pour la fin, je ne remercierai jamais assez mes parents pour avoir toujours cru en moi et m'avoir soutenu depuis le tout d but. Vous m'avez donn l'envie et la motivation de vouloir aller toujours plus haut, toujours plus loin, et vous m'avez transmis la force et les qualit s n cessaires pour y arriver. Merci galement mes fr res et sLur , en particulier Maxime, qui a t un super stagiaire pendant quelques semaines et qui m'a toujours soutenu, et Laura, toujours prte rendre service (merci petite sLur !). La route a t longue mais votre amour et votre confiance m'ont permis de me construire petit petit. Aujourd'hui je suis tr s fi re et tr s heureuse de partager cet aboutissement avec vous. Ainsi, je d die cette th se ceux que j'aime et qui m'ont port jusqu'ici. TABLE OF CONTENT TABLE OF ILLUSTRATIONS: INTRODUCTION AND CONCLUSION ................................. 3 LIST OF APPENDICES ........................................................................................................ 4 SUMMARY ............................................................................................................................ 5 I. INTRODUCTION ........................................................................................................ 9 A. Mitochondria...........................................................................................................10 1. Mitochondrial structure and pivotal roles within cells ...........................................10 a) Mitochondria: versatile organelles ...................................................................11 (i) Mitochondrial fission ....................................................................................13 (ii) Mitochondrial fusion .....................................................................................13 (iii) Mitophagy ....................................................................................................15 b) Orchestrating cellular energy production .........................................................15 (i) Cellular glycolysis ........................................................................................16 (i) Mitochondrial respiration ..............................................................................17 (ii) Bioenergetic state and mitochondrial shape.................................................19 c) Mitochondrial: paradoxical organelles .............................................................20 (i) Mitochondria: source and target of reactive oxygen and nitrogen species ...20 (ii) Antioxidant defenses: weapons against oxidative stress ..............................22 (iii) Mitochondria and cell suicide .......................................................................23 2. Mitochondrial dysfunction in AlzheimerRs disease ...............................................25 a) Clinical symptoms and etiological factors ........................................................26 b) Histopathological hallmarks .............................................................................28 (i) Neurofibrillary tangles and hyperphosphorylated tau ...................................28 (ii) Amyloidogenic
Recommended publications
  • Exploring the Activity of an Inhibitory Neurosteroid at GABAA Receptors

    Exploring the Activity of an Inhibitory Neurosteroid at GABAA Receptors

    1 Exploring the activity of an inhibitory neurosteroid at GABAA receptors Sandra Seljeset A thesis submitted to University College London for the Degree of Doctor of Philosophy November 2016 Department of Neuroscience, Physiology and Pharmacology University College London Gower Street WC1E 6BT 2 Declaration I, Sandra Seljeset, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I can confirm that this has been indicated in the thesis. 3 Abstract The GABAA receptor is the main mediator of inhibitory neurotransmission in the central nervous system. Its activity is regulated by various endogenous molecules that act either by directly modulating the receptor or by affecting the presynaptic release of GABA. Neurosteroids are an important class of endogenous modulators, and can either potentiate or inhibit GABAA receptor function. Whereas the binding site and physiological roles of the potentiating neurosteroids are well characterised, less is known about the role of inhibitory neurosteroids in modulating GABAA receptors. Using hippocampal cultures and recombinant GABAA receptors expressed in HEK cells, the binding and functional profile of the inhibitory neurosteroid pregnenolone sulphate (PS) were studied using whole-cell patch-clamp recordings. In HEK cells, PS inhibited steady-state GABA currents more than peak currents. Receptor subtype selectivity was minimal, except that the ρ1 receptor was largely insensitive. PS showed state-dependence but little voltage-sensitivity and did not compete with the open-channel blocker picrotoxinin for binding, suggesting that the channel pore is an unlikely binding site. By using ρ1-α1/β2/γ2L receptor chimeras and point mutations, the binding site for PS was probed.
  • Antinociceptive Activity of a Neurosteroid Tetrahydrodeoxycorticosterone (5Cx-Pregnan-3Cx-21-Diol-20-One) and Its Possible Mechanism(S) of Action

    Antinociceptive Activity of a Neurosteroid Tetrahydrodeoxycorticosterone (5Cx-Pregnan-3Cx-21-Diol-20-One) and Its Possible Mechanism(S) of Action

    Indian Journal of Experimental Biology Vol. 39, December 2001, pp. 1299-1301 Antinociceptive activity of a neurosteroid tetrahydrodeoxycorticosterone (5cx-pregnan-3cx-21-diol-20-one) and its possible mechanism(s) of action P K Mediratta, M Gambhir, K K Sharma & M Ray Department of Pharmacology, University College of Medical Sciences and GTB Hospital, Delhi II 0095, India Fax: 91-11-2299495; E-mail: [email protected]/[email protected] Received 9 Apri/2001; revised 2 July 2001 The present study investigates the effects of a neurosteroid tetrahydrodeoxycorticosterone (5a-pregnan-3a-21-diol-20- one) in two experimental models of pain sensitivity in mice. Tetrahydrodeoxycorticosterone (2.5, 5 mg!kg, ip) dose dependently decreased the licking response in formalin test and increased the tail flick latency (TFL) in tail flick test. Bicuculline (2 mg/kg, ip), a GABAA receptor antagonist blocked the antinociceptive effect of tetrahydrodeoxy­ corticosterone in TFL test but failed to modulate licking response in formalin test. Naloxone (I mglkg, ip), an opioid antagonist effectively attenuated the analgesic effect of tetrahydrodeoxycorticosterone in both the models. Tetrahydrodeoxycorticosterone pretreatment potentiated the anti nociceptive response of morphine, an opioid compound and nimodipine, a calcium channel blocker in formalin as well as TFL test. Thus, tetrahydrodeoxycorticosterone exerts an analgesic effect, which may be mediated by modulating GABA-ergic and/or opioid-ergic mechanisms and voltage-gated calcium channels. It is now well known that some of the steroids like Allopregnanolone has been shown to exhibit progesterone can act on central nervous system (CNS) antinociceptive effect against an aversive thermal to produce a number of endocrine and behavioral stimulus 10 and in a rat mechanical visceral pain 11 effects.
  • Neurosteroid Metabolism in the Human Brain

    Neurosteroid Metabolism in the Human Brain

    European Journal of Endocrinology (2001) 145 669±679 ISSN 0804-4643 REVIEW Neurosteroid metabolism in the human brain Birgit Stoffel-Wagner Department of Clinical Biochemistry, University of Bonn, 53127 Bonn, Germany (Correspondence should be addressed to Birgit Stoffel-Wagner, Institut fuÈr Klinische Biochemie, Universitaet Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany; Email: [email protected]) Abstract This review summarizes the current knowledge of the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization and the putative effects of neurosteroids. Molecular biological and biochemical studies have now ®rmly established the presence of the steroidogenic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC), aromatase, 5a-reductase, 3a-hydroxysteroid dehydrogenase and 17b-hydroxysteroid dehydrogenase in human brain. The functions attributed to speci®c neurosteroids include modulation of g-aminobutyric acid A (GABAA), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT3), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines and synaptogenesis. The ®rst clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, post partum depression, catamenial epilepsy, depressive disorders and dementia disorders. Better knowledge of the biochemical pathways of neurosteroidogenesis and
  • Site-Specific Effects of Neurosteroids on GABA(A) Receptor Activation and Desensitization

    Site-Specific Effects of Neurosteroids on GABA(A) Receptor Activation and Desensitization

    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2020 Site-specific effects of neurosteroids on GABA(A) receptor activation and desensitization Yusuke Sugasawa Washington University School of Medicine in St. Louis Wayland W.L. Cheng Washington University School of Medicine in St. Louis John R. Bracamontes Washington University School of Medicine in St. Louis Zi-Wei Chen Washington University School of Medicine in St. Louis Lei Wang Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Sugasawa, Yusuke; Cheng, Wayland W.L.; Bracamontes, John R.; Chen, Zi-Wei; Wang, Lei; Germann, Allison L.; Pierce, Spencer R.; Senneff, Thomas C.; Krishnan, Kathiresan; Reichert, David E.; Covey, Douglas F.; Akk, Gustav; and Evers, Alex S., ,"Site-specific effects of neurosteroids on GABA(A) receptor activation and desensitization." Elife.,. (2020). https://digitalcommons.wustl.edu/open_access_pubs/9682 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Yusuke Sugasawa, Wayland W.L. Cheng, John R. Bracamontes, Zi-Wei Chen, Lei Wang, Allison L. Germann, Spencer R. Pierce, Thomas C. Senneff, Kathiresan Krishnan, David E. Reichert, Douglas F. Covey,
  • Physiological Roles of Endogenous Neurosteroids at Α2 Subunit-Containing GABAA Receptors

    Physiological Roles of Endogenous Neurosteroids at Α2 Subunit-Containing GABAA Receptors

    Physiological roles of endogenous neurosteroids at α2 subunit-containing GABAA receptors Elizabeth Jane Durkin A thesis submitted to University College London for the degree of Doctor of Philosophy October 2012 Department of Neuroscience, Physiology and Pharmacology University College London Gower Street London WC1E 6BT Declaration 2 Declaration I, Elizabeth Durkin, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis Abstract 3 Abstract Neurosteroids are important endogenous modulators of the major inhibitory neurotransmitter receptor in the brain, the γ-amino-butyric acid type A (GABAA) receptor. They are involved in numerous physiological processes, and are linked to several central nervous system disorders, including depression and anxiety. The neurosteroids allopregnanolone and allo-tetrahydro-deoxy-corticosterone (THDOC) have many effects in animal models (anxiolysis, analgesia, sedation, anticonvulsion, antidepressive), suggesting they could be useful therapeutic agents, for example in anxiety, stress and mood disorders. Neurosteroids potentiate GABA-activated currents by binding to a conserved site within α subunits. Potentiation can be eliminated by hydrophobic substitution of the α1Q241 residue (or equivalent in other α isoforms). Previous studies suggest that α2 subunits are key components in neural circuits affecting anxiety and depression, and that neurosteroids are endogenous anxiolytics. It is therefore possible that this anxiolysis occurs via potentiation at α2 subunit-containing receptors. To examine this hypothesis, α2Q241M knock-in mice were generated, and used to define the roles of α2 subunits in mediating effects of endogenous and injected neurosteroids. Biochemical and imaging analyses indicated that relative expression levels and localization of GABAA receptor α1-α5 subunits were unaffected, suggesting the knock- in had not caused any compensatory effects.
  • Bioenergetic Abnormalities in Schizophrenia

    Bioenergetic Abnormalities in Schizophrenia

    Bioenergetic abnormalities in schizophrenia A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Program in Neuroscience of the College of Medicine by Courtney René Sullivan B.S. University of Pittsburgh, 2013 Dissertation Committee: Mark Baccei, Ph.D. (chair) Robert McCullumsmith, M.D., Ph.D. (advisor) Michael Lieberman, Ph.D. Temugin Berta, Ph.D. Robert McNamara, Ph.D. ABSTRACT Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and displays a wide range of psychotic symptoms, as well as cognitive deficits and profound negative symptoms that are often treatment resistant. Cognition is intimately related to synaptic function, which relies on the ability of cells to obtain adequate amounts of energy. Studies have shown that disrupting bioenergetic pathways affects working memory and other cognitive behaviors. Thus, investigating bioenergetic function in schizophrenia could provide important insights into treatments or prevention of cognitive disorders. There is accumulating evidence of bioenergetic dysfunction in chronic schizophrenia, including deficits in energy storage and usage in the brain. However, it is unknown if glycolytic pathways are disrupted in this illness. This dissertation employs a novel reverse translational approach to explore glycolytic pathways in schizophrenia, effectively combining human postmortem studies with bioinformatic analyses to identify possible treatment strategies, which we then examine in an animal model. To begin, we characterized a major pathway supplying energy to neurons (the lactate shuttle) in the dorsolateral prefrontal cortex (DLPFC) in chronic schizophrenia. We found a significant decrease in the activity of two key glycolytic enzymes in schizophrenia (hexokinase, HXK and phosphofructokinase, PFK), suggesting a decrease in the capacity to generate bioenergetic intermediates through glycolysis in this illness.
  • Biochemical Fossils of the Ancient Transition from Geoenergetics to Bioenergetics in Prokaryotic One Carbon Compound Metabolism☆

    Biochemical Fossils of the Ancient Transition from Geoenergetics to Bioenergetics in Prokaryotic One Carbon Compound Metabolism☆

    BBABIO-47248; No. of pages: 18; 4C: 4, 6, 7, 9 Biochimica et Biophysica Acta xxx (2014) xxx–xxx Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbabio Biochemical fossils of the ancient transition from geoenergetics to bioenergetics in prokaryotic one carbon compound metabolism☆ Filipa L. Sousa, William F. Martin ⁎ Institute for Molecular Evolution,University of Düsseldorf, 40225 Düsseldorf, Germany article info abstract Article history: The deep dichotomy of archaea and bacteria is evident in many basic traits including ribosomal protein compo- Received 26 October 2013 sition, membrane lipid synthesis, cell wall constituents, and flagellar composition. Here we explore that deep di- Received in revised form 31 January 2014 chotomy further by examining the distribution of genes for the synthesis of the central carriers of one carbon Accepted 3 February 2014 units, tetrahydrofolate (H F) and tetrahydromethanopterin (H MPT), in bacteria and archaea. The enzymes un- Available online xxxx 4 4 derlying those distinct biosynthetic routes are broadly unrelated across the bacterial–archaeal divide, indicating Keywords: that the corresponding pathways arose independently. That deep divergence in one carbon metabolism is mir- Pterins rored in the structurally unrelated enzymes and different organic cofactors that methanogens (archaea) and Hydrothermal vents acetogens (bacteria) use to perform methyl synthesis in their H4F- and H4MPT-dependent versions, respectively, Origin of life of the acetyl-CoA pathway. By contrast, acetyl synthesis in the acetyl-CoA pathway — from a methyl group, CO2 Methanogens and reduced ferredoxin — is simpler, uniform and conserved across acetogens and methanogens, and involves Acetogens only transition metals as catalysts.
  • Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids

    Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids

    Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Rebas, Elzbieta, Tomasz Radzik, Tomasz Boczek, and Ludmila Zylinska. 2017. “Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.” Current Neuropharmacology 15 (8): 1174-1191. doi:10.2174/1570159X15666170329091935. http:// dx.doi.org/10.2174/1570159X15666170329091935. Published Version doi:10.2174/1570159X15666170329091935 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160234 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA 1174 Send Orders for Reprints to [email protected] Current Neuropharmacology, 2017, 15, 1174-1191 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Impact Factor: 3.365 Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids BENTHAM SCIENCE Elzbieta Rebas1, Tomasz Radzik1, Tomasz Boczek1,2 and Ludmila Zylinska1,* 1Department of Molecular Neurochemistry, Faculty of Health Sciences, Medical University of Lodz, Poland; 2Boston Children’s Hospital and Harvard Medical School, Boston, USA Abstract: Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.
  • THDOC) Abolishes the Behavioral and Neuroendocrine Consequences of Adverse Early Life Events

    THDOC) Abolishes the Behavioral and Neuroendocrine Consequences of Adverse Early Life Events

    Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events. V K Patchev, … , F Holsboer, O F Almeida J Clin Invest. 1997;99(5):962-966. https://doi.org/10.1172/JCI119261. Research Article Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20- one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life. Find the latest version: https://jci.me/119261/pdf
  • Revolutionizing Neurodegenerative Disease Using Bioenergetic Nanotherapeutics to Improve Patients‘ Lives

    Revolutionizing Neurodegenerative Disease Using Bioenergetic Nanotherapeutics to Improve Patients‘ Lives

    CLENE INC. ANNUAL REPORT 2020 REPORT ANNUAL REVOLUTIONIZING NEURODEGENERATIVE DISEASE USING BIOENERGETIC NANOTHERAPEUTICS TO IMPROVE PATIENTS‘ LIVES ANNUAL REPORT 2020 Breakthrough Needed for Patients Eective treatment of patients with neurodegenerative disorders requires a therapeutic breakthrough. The World Health Organization predicts diseases of neurodegeneration will become the second-most prevalent cause of death within the next 20 years1. Bioenergetic Opportunity Bioenergetic failure underlies the pathophysiology of many neurodegenerative diseases2. However, rescuing failing bioenergetic systems in these diseases has historically been extremely challenging3. Bioenergetic Nanotherapeutics Clene® is rapidly advancing a pipeline of bioenergetic nanotherapeutics, the first of those is CNM-Au8, designed to enhance naturally occurring cellular metabolism with the goal of reversing neurodegeneration. This new class of drugs called bioenergetic nanocatalysts has been created to accelerate neurorepair, improve neuroprotection, and enhance remyelination4. Innovative Platform The innovative platform is an electrochemistry approach to growing clean-surfaced, metallic nanocrystal therapeutics. The nanotherapeutic CNM-Au8 is designed to optimize cellular health and repair through energy enhancing bioenergetic catalysis. Using pure, clean-surfaced gold nanocrystals, we are able to amplify healthy, intracellular reactions necessary for cells to function and defend CLENE themselves from disease4. INNOVATE PROTECT REPAIR BIOENERGETIC NANOTHERAPEUTICS CNM-Au8 Clene Team Clene carefully engineered its lead drug Behind every innovative platform is a candidate, CNM-Au8, a bioenergetic team of inventive minds. Clene nanocatalyst which enhances critical enlisted a leadership team of intracellular bioenergetic reactions seasoned industry veterans united by necessary for repairing and reversing their appetite for innovation and neuronal damage. Orally administered, committed to advancing the CNM-Au8 has demonstrated safety in Phase company’s pipeline rapidly.
  • Estrogen: a Master Regulator of Bioenergetic Systems in the Brain and Body ⇑ Jamaica R

    Estrogen: a Master Regulator of Bioenergetic Systems in the Brain and Body ⇑ Jamaica R

    Frontiers in Neuroendocrinology 35 (2014) 8–30 Contents lists available at ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne Review Estrogen: A master regulator of bioenergetic systems in the brain and body ⇑ Jamaica R. Rettberg a, Jia Yao b, Roberta Diaz Brinton a,b,c, a Neuroscience Department, University of Southern California, Los Angeles, CA 90033, United States b Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, United States c Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States article info abstract Article history: Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the Available online 29 August 2013 brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regu- Keywords: lates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with Adipokine decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory Adipose tissue bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s Aging disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indi- Alzheimer’s disease cate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral meta- Biomarker Insulin bolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and Menopause cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as Metabolism indicators of efficacy of hormone therapy or other preventative interventions.
  • Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

    Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

    International Journal of Molecular Sciences Review Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant Rachida Guennoun U 1195 Inserm and University Paris Saclay, University Paris Sud, 94276 Le kremlin Bicêtre, France; [email protected] Received: 4 May 2020; Accepted: 22 July 2020; Published: 24 July 2020 Abstract: Progesterone has a broad spectrum of actions in the brain. Among these, the neuroprotective effects are well documented. Progesterone neural effects are mediated by multiple signaling pathways involving binding to specific receptors (intracellular progesterone receptors (PR); membrane-associated progesterone receptor membrane component 1 (PGRMC1); and membrane progesterone receptors (mPRs)) and local bioconversion to 3α,5α-tetrahydroprogesterone (3α,5α-THPROG), which modulates GABAA receptors. This brief review aims to give an overview of the synthesis, metabolism, neuroprotective effects, and mechanism of action of progesterone in the rodent and human brain. First, we succinctly describe the biosynthetic pathways and the expression of enzymes and receptors of progesterone; as well as the changes observed after brain injuries and in neurological diseases. Then, we summarize current data on the differential fluctuations in brain levels of progesterone and its neuroactive metabolites according to sex, age, and neuropathological conditions. The third part is devoted to the neuroprotective effects of progesterone and 3α,5α-THPROG in different experimental models, with a focus on traumatic brain injury and stroke. Finally, we highlight the key role of the classical progesterone receptors (PR) in mediating the neuroprotective effects of progesterone after stroke. Keywords: progesterone; PR; allopregnanolone; neuroprotection; neurosteroid; stroke; traumatic brain injury; TBI 1. Introduction Steroid hormones are synthesized by adrenal glands, gonads, and placenta and influence the function of many target tissues including the nervous system.