Molecular and cellular mechanisms of Ginkgo biloba extract [EGb 761] in improving age-related and β-amyloid [beta-amyloid] induced neuronal dysfunctions [Elektronische Ressource] / von Reham Mahmoud Abdel-Kader

Reham

Sujets

• Gesundheit

Informations

• Publié par: goethe_universitat_frankfurt_am_main
• Publié le: 01 janvier 2009
• Nombre de lectures: 33
• Langue: Deutsch
• Poids de l'ouvrage: 3 Mo

Extrait

Molecular and cellular mechanisms of Ginkgo biloba
®extract [EGb 761 ] in improving age-related and
ß-amyloid induced neuronal dysfunctions











Dissertation
zur Erlangung des
Doktorgrades der Naturwissenschaften




Vorgelegt im Fachbereich
Biochemie, Chemie und Pharmazie
der Johann Wolfgang Goethe-Universität
in Frankfurt am Main




von
Reham Mahmoud Abdel-Kader
aus Kairo, Ägypten

Frankfurt am Main 2009

[D30]










vom Fachbereich Chemische und Pharmazeutische Wissenschaften der Johann Wolfgang
Goethe-Universitaet als Dissertation angenommen.




































Dekan: Prof. Dr. Steinhilber

1. Gutachter: Prof.Dr. W.E. Mueller

2. Gutachter: Prof. Dr. M. Schubert-Zsilavecz

Datum der Disputation: 26.10.2009


Table of contents
Abbreviations....................................................................................................................................................4
1 Introduction ...................................................................................................................................................6
1.1 Alzheimer’s disease .........................................................................................................................6
1.1.1 A century of Alzheimer’s disease ....................................................................................................6
1.1.2 Prevalence........................................................................................................................................8
1.1.3 Diagnosis .........................................................................................................................................9
1.1.4 Risk Factors ...................................................................................................................................12
1.1.4.1 Sporadic AD...........................................................................................................................12
1.1.4.2 Familial AD............................................................................................................................13
1.1.5 Neuropathology..............................................................................................................................15
1.1.5.1 Neurofibrillary tangles ...........................................................................................................16
1.1.5.2 Amyloid plaques ....................................................................................................................18
1.1.6 Amyloid beta: first the making… ..................................................................................................19
1.1.6.1 Alpha secretase.......................................................................................................................21
1.1.6.2 Beta secretase.........................................................................................................................22
1.1.6.3 Gamma secretase....................................................................................................................23
1.1.6.4 Amyloid beta…“the peptide from Hell” ................................................................................24
1.1.7 Amyloid beta…first the making…then the breaking… .................................................................28
1.1.7.1 Neprilysin [NEP]....................................................................................................................29
1.1.7.2 Insulin degrading enzyme IDE...............................................................................................30
1.1.7.3 Endothelin converting enzyme [ECE]....................................................................................31
1.1.8 Role of oxidative and nitrosative stress in AD...............................................................................33
1.1.9 Mitochondrial dysfunction and AD ...............................................................................................36
1.1.10 Therapeutic interventions.............................................................................................................41
1.1.10.1 Acetylcholinesterase inhibitors ............................................................................................41
1.1.10.2 Memantine............................................................................................................................42
1.1.10.3 Piracetam..............................................................................................................................43
1.1.10.4 Ginkgo Biloba extract ..........................................................................................................44
1.1.11 Novel therapeutic strategies .........................................................................................................45
1.1.11.1 Targeting secretases: Gamma secretase ...............................................................................45
1.1.11.2 Targeting secretases: Beta secretase inhibitors ....................................................................46
1.1.11.3 Aß clearance.........................................................................................................................46
1.1.11.4 Immunotherapy ....................................................................................................................46
1.2 Ginkgo Biloba................................................................................................................................49
1.2.1 Medicinal History ..........................................................................................................................51
®1.2.2 Production of EGb 761 ................................................................................................................52
1.2.2.1 Harvesting and cultivation......................................................................................................52
1.2.2.2 Extraction and standardization ...............................................................................................52
1.2.3 Chemical composition....................................................................................................................54
1.2.3.1 Flavonoids..............................................................................................................................54
1.2.3.2 Terpeniods..............................................................................................................................55
1.2.3.3 Ginkgolides ............................................................................................................................55
1.2.3.4 Bilobalide ...............................................................................................................................55
1.2.3.5 Organic acids..........................................................................................................................57
1.2.4 Pharmacokinetics ...........................................................................................................................58
®
1.2.4.1 EGb 761 ...............................................................................................................................58
1.2.4.2 Flavonoids..............................................................................................................................58
1.2.4.3 Ginkgolides ............................................................................................................................59
1.2.5 Medicinal properties of Ginkgo biloba ..........................................................................................60
1.2.6 Pharmacological effects .................................................................................................................61
1.2.6.1 Free radical scavenging effect................................................................................................61
1.2.6.2 Mitochondrial protection and anti-apoptotic effects...............................................................64
1.2.6.3 Neurotransmitter systems.......................................................................................................66
1.2.6.4 Receptors: Platelet activating factor receptor.........................................................................68
1.2.6.5 Receptors: Glycine receptor ...................................................................................................69
1
1.2.6.6 Amyloid precursor protein and Amyloid beta........................................................................70
1.2.6.7 Gene Expression.....................................................................................................................72
1.2.7 Clinical evidence................................................................................................................