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UNIVERSITÀ DEGLI STUDI DI MILANO Dipartimento Di Scienze Biomediche Per La Salute Corso Di Dottorato in Ricerca Biomedica Integrata XXIX CICLO

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UNIVERSITÀ DEGLI STUDI DI MILANO Dipartimento Di Scienze Biomediche Per La Salute Corso Di Dottorato in Ricerca Biomedica Integrata XXIX CICLO UNIVERSITÀ DEGLI STUDI DI MILANO Dipartimento di Scienze Biomediche per la salute Corso di dottorato in Ricerca biomedica integrata XXIX CICLO SHORT-TERM DIABETES IN THE BRAIN: EFFECTS ON NEUROACTIVE STEROIDS, CHOLESTEROL HOMEOSTASIS, AND MITOCHONDRIAL FUNCTIONALITY Coordinatore: Chiar.ma Prof.ssa Chiarella SFORZA Tutor: Chiar.mo Prof. Roberto C. MELCANGI Tesi di Dottorato di: Dott. Simone ROMANO Matricola: R10561 Index Index Abbreviations .............................................................................................................................. 4 Summary ..................................................................................................................................... 5 Introduction ................................................................................................................................ 7 Steroids, not only peripheral messengers .............................................................................. 7 Neurosteroids and neuroactive steroids ............................................................................ 7 Synthesis and metabolism of neurosteroids ...................................................................... 9 Neuroactive steroids, role in the central nervous system ............................................... 18 Cholesterol: regulation and role in the nervous system ...................................................... 24 Biosynthesis of cholesterol ............................................................................................... 25 Metabolism of cholesterol ............................................................................................... 30 Trafficking of cholesterol .................................................................................................. 36 Mitochondria ........................................................................................................................ 40 Mitochondrial bioenergetics system ................................................................................ 40 Reactive oxygen species in neurodegeneration disease .................................................. 43 Mitochondrial biogenesis ................................................................................................. 45 Mitochondrial dysfunction in cholesterol efflux .............................................................. 46 Diabetes encephalopathy ..................................................................................................... 48 Glucose Excitotoxicity ....................................................................................................... 49 Diabetes induces oxidative stress .................................................................................... 50 Effects of diabetes on cholesterol homeostasis ............................................................... 51 Diabetes alters neuroactive steroids ................................................................................ 52 Effects of diabetic encephalopathy .................................................................................. 53 Aim ............................................................................................................................................ 55 Page | 2 Index Methods.................................................................................................................................... 56 Animals ................................................................................................................................. 56 Diabetic induction and characterization .............................................................................. 56 Liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) ............. 57 Assessment of neuroactive steroids ................................................................................. 57 Assessment of cholesterol and oxysterols ....................................................................... 58 Real-time Polymerase Chain Reaction ................................................................................. 59 Mitochondrial DNA content ................................................................................................. 59 Western blotting ................................................................................................................... 61 Tiobarbituric Acid Reactive Substances (TBARS) .................................................................. 62 Statistical analysis ................................................................................................................. 62 Results....................................................................................................................................... 63 Short-term diabetes induces hyperglycemia and decreases body weight .......................... 63 Short-term diabetes affects the levels of neuroactive steroids in the hippocampus and cerebral cortex ........................................................................................................... 64 Short-term diabetes affects gene expression of steroidogenic molecules in the hippocampus and cerebral cortex ........................................................................................ 65 Short-term diabetes alters the levels of cholesterol and its metabolites in hippocampus and cerebral cortex ...................................................................................................................... 67 Short-term diabetes alters the gene expression of molecules involved in the biosynthesis and metabolism of cholesterol ............................................................................................. 69 Short-term diabetes alters cholesterol trafficking ............................................................... 72 Short-term diabetes induces oxidative stress and mitochondrial alterations ..................... 75 Discussion ................................................................................................................................. 81 References ................................................................................................................................ 87 Page | 3 Abbreviations Abbreviations 36B4: ribosomal protein 36B4 LC-MS/MS: liquid chromatography-tandem mass 3α-diol: 5α-androstane-3α,17β-diol spectrometry analysis 3β-diol: 5α-androstane-3β,17β-diol LDLR: Low density lipoprotein receptor 3β-HSD: 3β-hydroxysteroid dehydrogenase LXRs: Liver X receptors 3α-HSOR: 3α-hydroxysteroid oxidoreductase MAM: mitochondria-associated endoplasmic 5α-R 1: 5α-reductase type 1 reticulum membrane 7α-OH: 7α-hydroxycholesterol mt-COX II: mitochondrial-cytochrome C 7β-OH: 7β-hydroxycholesterol oxidoreductase 7-keto: 7-ketocholesterol MS: multiple sclerosis 17β-HSD: 17β-hydroxysteroid dehydrogenase NDD: neurodegenerative disorders 24(S)-OH: 24(S)-hydroxycholesterol NCEH: neutral cholesteryl esters 25-OH: 25-hydroxycholesterol NMDA: N-Methyl-D-aspartate 27-OH: 27-hydroxycholesterol NO: nitric oxide ABCA1: ATP-binding cassette A1 NRF: nuclear respiratory factors ABCG1: ATP-binding cassette G1 OMM: outer mitochondrial membrane ACAT: cholesterol acyl transferase OXPHOS: functional subunits of respiratory chain AD: Alzheimer’s disease complexes ANTs: nucleotide translocators P450scc or CYP11A1: cytochrome P450 side chain ApoE: Apolipoprotein E cleavage AR: androgen receptors PD: Parkinson’s disease CEs: cholesteryl esters PGC-1α: proliferator-activated receptor gamma-1 CHO: Chinese hamster ovary cell line alpha CNS: central nervous system PKA: cAMP-dependent protein kinase A CSF: cerebrospinal fluid PNS: peripheral nervous system CYP27A1: cholesterol 27-hydroxylase PR: progesterone receptors CYP46A1: cholesterol 24-hydroxyase PREG: pregnenolone CYP19: aromatase PROG: progesterone DE: diabetic encephalopathy ROS: oxygen reactive species DHCR24: 24-deydrocholesterol reductase; RNS: reactive nitrogen species DHCR7: 7-dehydrocholesterol reductase RR-MS: relapsing remitting multiple sclerosis DHDOC: dihydrodeoxycorticosterone SOAT1: sterol O-acyltransferase 1 DHEA: dehydroepiandrosterone SOD: superoxide dismutase DHP: dihydroprogesterone SREs: Sterol-responsive elements DHT: dihydrotestosterone SREBPs: Sterol regulatory binding elements EAE: experimental autoimmune encephalomyelitis SCAP: SREBP cleavage-activating protein ERs: estrogen receptors StAR: steroidogenic acute regulatory protein ER: endoplasmic reticulum STZ: streptozotocin ETS: electron transport system T: testosterone GABA-A/B: gamma aminobutyric acid-A/B TBARS: thiobarbituric acid reactive substances GLUTs: glucose transporters TCA: tricarboxylic acid cycle GSH: glutathione TFAM: mitochondrial transcription factor A HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A THP: tetrahydroprogesterone HMG-CoA R: 3-hydroxy-3-methylglutaryl coenzyme A TNF-α: tumor necrosis α reductase TSPO: 18 kDa translocator protein HSL: hormone-sensitive lipase UCP2: Uncoupling protein 2 IL: interleukin VDAC2: voltage-dependent anion channel 2 IMM: inner mitochondrial membrane i.p.: intra-peritoneal ISOPREG: isopregnanolone Page | 4 Summary Summary Diabetes may induce neurophysiological and structural changes in the central nervous system (i.e., diabetic encephalopathy). Neuroactive steroids (i.e. molecules derived from cholesterol which exert their actions in the nervous system directly or after metabolization) are key regulators of the central nervous system and are affected in several
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