Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action
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| Sprache: | English |
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2015
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| 100 | 1 | |a Karout, Mona |e Verfasser |4 aut | |
| 245 | 1 | 0 | |a Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone |b evidence for a proliferative, neurogenic and neuroprotective action |c présentée par: Mona Karout |
| 264 | 1 | |c 2015 | |
| 300 | |a 187 Seiten |b Illustrationen, Diagramme |c 30 cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |b Dissertation |c Albert-Ludwigs-Universität Freiburg |d 2015 |g Université de Strassbourg | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
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| 943 | 1 | |a oai:aleph.bib-bvb.de:BVB01-028794638 | |
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TABLE OF CONTENTS
TABLE OF CONTENTS
FIGURES AND TABLES LISTS 1
1. FIGURES LIST 1
2. TABLES LIST 3
ABREVIATIONS 4
INTRODUCTION 9
1. NEURODEGENERATIVE DISEASES 9
2. ALZHEIMER S DISEASE 10
2.1. NEUROFIBRILLARY TANGLES 11
2.2. AMYLOID PEPTIDE 12
2.2.1. THE NON-AMYLOIDOGENIC PATHWAY 12
2.2.2. THE AMYLOIDOGENIC PATHWAY 13
2.2.3. ENZYMES IMPLICATED IN PROTEOLYTIC PROCESSING OF APP 14
2.2.4. THE AMYLOID CASCADE HYPOTHESIS AND ITS EVOLUTION 14
2.2.5. TOXICITY OF AMYLOID BETA OLIGOMERS 15
2.2.6. AMYLOID BETA
INDUCED APOPTOTIC PATHWAYS 17
3. ADULT NEUROGENESIS IN THE RODENT BRAIN 20
3.1. NEURAL STEM CELLS IN THE ADULT MAMMALIAN BRAIN 21
3.2. THE SUBVENTRICULAR ZONE (SVZ) 22
3.3. THE SUBGRANULAR ZONE (SGZ) 23
3.4. IMMUNOHISTOLOGICAL MARKERS FOR PROLIFERATION EVENTS, GLIOGENESIS
AND
NEUROGENESIS IN THE ADULT HIPPOCAMPUS 26
3.4.1. MARKERS FOR NEURAL STEM CELLS 26
3.4.2. MARKERS FOR PROLIFERATIVELY ACTIVE CELLS 26
3.4.3. MARKERS FOR THE NEURONAL LINEAGE 27
3.4.4. MARKERS FOR THE GLIAL LINEAGE 28
*3.5. FUNCTIONAL SIGNIFICANCE OF ADULT NEUROGENESIS 28
3.6. ADULT NEUROGENESIS DURING AGING AND NEURODEGENERATIVE DISEASES 29
3.7. CONTRIBUTION OF NEURAL STEM/PROGENITOR CELLS TO BRAIN REPAIR 31
4. NEUROSTEROIDS 32
4.1. DEFINITION 32
4.2. BIOSYNTHESIS 33
4.3. MECHANISMS OF ACTION 34
5. ALLOPREGNANOLONE (AP) 36
5.1. BIOSYNTHESIS 36
5.2. MECHANISMS OF ACTION 38
TABLE OF CONTENTS
5.3. ROLE OF ALLOPREGNANOLONE IN PSYCHIATRIC DISORDERS 42
5.4. NEUROPROTECTIVE EFFECTS OF ALLOPREGNANOLONE IN NEURODEGENERATIVE
DISORDERS 44
5.5. ALLOPREGNANOLONE AS A
THERAPEUTIC CANDIDATE FOR THE TREATMENT OF
NEUROPATHIC PAIN 45
5.6. ALLOPREGNANOLONE AS A REGENERATIVE THERAPEUTIC IN ALZHEIMER S
DISEASE... 46
5.6.1. ALLOPREGNANOLONE PROMOTES NEUROGENESIS IN VITRO 46
5.6.2. ALLOPREGNANOLONE REVERSES NEUROGENIC AND COGNITIVE DEFICITS IN
AGED
AND ALZHEIMER S DISEASE MUTANT MICE 47
6. PHD PROJECT 50
6.1. HYPOTHESIS 50
6.2. OBJECTIVES 51
6.3. EXPERIMENTAL MODELS 51
MATERIALS AND METHODS 53
1. IN VITRO EXPERIMENTS 53
1.1. ADULT NEURAL STEM CELL CULTURES (NEUROSPHERE CULTURE) 53
1.2. PRIMARY HIPPOCAMPAL CELL CULTURES 55
1.3. HUMAN NEURAL STEM CELLS (HNSC 100) 55
1.4. MATERIAL 56
1.4.1. ANTIBODIES 56
1.4.2. RNA OLIGONUCLEOTIDES ...: 56
1.4.3. REAGENTS, CHEMICALS AND MATERIAL 57
1.5. CELL CULTURE 60
1.5.1. PREPARATION OF PRIMARY NEUROSPHERE CULTURES 60
1.5.2. PASSAGING OF NEUROSPHERE CULTURES 62
1.5.3. PROLIFERATION AND DIFFERENTIATION OF ANSC CULTURES 62
1.5.4. ISOLATION, CULTURING AND PROLIFERATION OF PRIMARY HIPPOCAMPAL
CELL
CULTURES. 63
1.5.5. HUMAN NEURAL STEM CELL
CULTURES 65
1.6. MTT CELL VIABILITY ASSAY 66
1.7. IMMUNOCYTOCHEMISTRY 68
1.7.1. COATING OF COVERSLIPS 68
1.7.2. CELL FIXATION 68
1.7.3. IMMUNOCYTOCHEMICAL STAINING (ICC) 68
1.7.4. IDENTIFICATION OF PROLIFERATING CELLS BY INCORPORATION OF BRDU
AND EDU
. 69
1.7.5. CASPASE-3/7 ASSAY, QUANTIFICATION OF APOPTOTIC CELLS BY CELL
COUNTING. 71
1.8. CASPASE-3/7 ASSAY, QUANTIFICATION BY FLUOROMETRIC MEASUREMENT 71
TABLE OF CONTENTS
1.9. BRDU CELL
PROLIFERATION ELISA 72
1.10. REAL-TIME REVERSE
TRANSCRIPTION POLYMERASE CHAIN REACTION (QRT-PCR)... 73
1.10.1. RNA EXTRACTION 73
1.10.2. RNA CONCENTRATION MEASUREMENT AND QUALITY DETERMINATION 74
1.10.3. REVERSE TRANSCRIPTION 74
1.10.4. REAL-TIME REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION 75
1.11. CELL COUNTING AND STATISTICAL ANALYSIS 76
2. IN VIVO
EXPERIMENTS 76
2.1. ANIMALS 76
2.2. ANESTHESIA AND
PERFUSION OF THE ANIMALS 78
2.3. BRAIN FREEZING 78
2.4. MORPHOLOGICAL ANALYSIS 79
2.4.1. VIBRATOME SECTIONING 79
2.4.2. IMMUNOHISTOCHEMISTRY (IHC) 79
2.4.3. QUANTIFICATION OF IMMUNOLABELED CELLS IN HIPPOCAMPAL SECTIONS 81
2.5. DETERMINATION OF A(340 AND A042 CONCENTRATION
BY ELISA 81
2.5.1. SAMPLE PREPARATION 81
2.5.2. HUMAN A|340
AND A(342 ELISA 82
2.6. STATISTICAL ANALYSIS 83
RESULTS 84
1. PROLIFERATION-STIMULATING EFFECTS OF AP ANALOGS IN ANSCS 84
1.1. GROWTH OF ANSC NEUROSPHERES IN THE PRESENCE OF NEUROSTEROIDS 84
1.2. EFFECTS OF AP ANALOGS ON ANSCS PROLIFERATION: EDU INCORPORATION 86
1.2.1. 12 OXO-AP AND O-ALLYL-AP STIMULATE PROLIFERATION OF ANSCS 86
1.2.2. PHENOTYPE OF PROLIFERATING CELLS 88
I
1.2.3. PROLIFERATION-PROMOTING EFFECTS OF AP ANALOGS ARE MEDIATED VIA
L-TYPE CALCIUM CHANNELS 90
1.2.4. EFFECTS OF AP ANALOGS ON TUJ-1 AND GFAP EXPRESSION IN ANSCS 91
2. STIMULATORY EFFECT
OF O-ALLYL-AP ON NEURONAL DIFFERENTIATION IN ANSC CULTURES ... 92
3. PROTECTIVE EFFECTS OF AP ANALOGS AGAINST BETA AMYLOID PEPTIDE 1-42
TOXICITY IN
ANSCS 95
3.1. EFFECT OF MONOMERIC
A{342 ON ANSCS VIABILITY 95
3.2. A(342 INDUCES APOPTOSIS IN ANSC CULTURES 96
3.3. PROTECTIVE EFFECTS OF AP ANALOGS AGAINST A(342-INDUCED TOXICITY 97
3.4. MECHANISMS OF ACTION OF THE
PROTECTIVE EFFECT OF AP ANALOGS AGAINST
AP42-INDUCED TOXICITY 101
TABLE OF CONTENTS
4. PROLIFERATION-PROMOTING EFFECTS OF AP AND
ITS ANALOGS IN RAT AND
MOUSE
PRIMARY HIPPOCAMPAL
CELL CULTURES 102
4.1. PROLIFERATION-PROMOTING EFFECT OF AP ANALOGS IN POSTNATAL
HIPPOCAMPAL
CULTURES 103
4.2. PHENOTYPE OF PROLIFERATING CELLS IN RAT PRIMARY HIPPOCAMPAL CELL
CULTURES. 105
4.3. IS
AP
ANALOGS-INDUCED NEURAL PROGENITOR CELL PROLIFERATION IN MOUSE
PRIMARY HIPPOCAMPAL CELL
CULTURES MEDIATED VIA
GABA
A
RS
? 107
5. PROLIFERATION-PROMOTING EFFECTS OF O-ALLYL-AP ON HUMAN NEURAL STEM
CELLS 108
6. EFFECTS OF O-ALLYL-AP ON PROLIFERATION AND NEUROGENESIS IN THE AGED
ADULT
BRAIN 109
6.1. EFFECT OF O-ALLYL-AP ON NEURAL STEM AND
PROGENITOR CELLS 110
6.1.1. SOX2 LABELLING 110
6.1.2. BLBP LABELLING 111
6.2. O-ALLYL-AP EFFECT ON PROLIFERATING CELLS 112
6.3. O-ALLYL-AP EFFECT ON NEWBORN
NEURONS 113
7. EFFECTS OF AP ANALOGS IN AN AD
MOUSE MODEL (TG2576) 115
7.1. EFFECTS ON PROLIFERATION 115
7.1.1. O-ALLYL-AP TREATMENT 115
7.1.2. O-ALLYL-EPIAP TREATMENT 117
7.2. EFFECTS OF AP ANALOGS ON AP BURDEN
IN TG2576 MUTANT MICE 119
DISCUSSION 122
1. EFFECT OF AP ANALOGS ON PROLIFERATION AND DIFFERENTIATION 123
2. PROTECTIVE EFFECTS OF AP
ANALOGS AGAINST A(342-INDUCED TOXICITY ON ANSCS 126
3. THE DIFFERENTIAL
PATTERN OF BIOLOGICAL ACTIVITIES EFFICACY OF AP ANALOGS 128
4. MECHANISMS OF ACTION
OF AP ANALOGS 129
5. EFFECTS OF O-ALLYL-AP ON NEUROGENESIS IN THE AGED BRAIN 133
6. EFFECTS OF O-ALLYL-AP AND
O-ALLYL-EPIAP IN TG2576 135
CONCLUSIONS AND PERSPECTIVES 139
REFERENCES 143
DESCRIPTIF SYNTHETIQUE EN FRANQAIS DES TRAVAUX DE LA THESE... 165
ZUSAMMENFASSENDE BESCHREIBUNG DER ARBEIT AUF DEUTSCH 177
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| author | Karout, Mona |
| author_facet | Karout, Mona |
| author_role | aut |
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| building | Verbundindex |
| bvnumber | BV043375810 |
| ctrlnum | (OCoLC)945578346 (DE-599)DNB1081952512 |
| dewey-full | 570 610 |
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| dewey-ones | 570 - Biology 610 - Medicine and health |
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| dewey-search | 570 610 |
| dewey-sort | 3570 |
| dewey-tens | 570 - Biology 610 - Medicine and health |
| discipline | Biologie Medizin |
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| language | English |
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| spellingShingle | Karout, Mona Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action |
| subject_GND | (DE-588)4113937-9 |
| title | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action |
| title_auth | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action |
| title_exact_search | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action |
| title_full | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action présentée par: Mona Karout |
| title_fullStr | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action présentée par: Mona Karout |
| title_full_unstemmed | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative, neurogenic and neuroprotective action présentée par: Mona Karout |
| title_short | Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone |
| title_sort | multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone evidence for a proliferative neurogenic and neuroprotective action |
| title_sub | evidence for a proliferative, neurogenic and neuroprotective action |
| topic_facet | Hochschulschrift |
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