Systems pharmacology and blood-brain barrier functionality in Parkinson's disease
Ravenstijn, P.G.M.
Citation
Ravenstijn, P. G. M. (2009, December 16). Systems pharmacology and blood- brain barrier functionality in Parkinson's disease. Retrieved from
https://hdl.handle.net/1887/14514
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/14514
Note: To cite this publication please use the final published version (if
applicable).
Systems Pharmacology and Blood-Brain Barrier Functionality
in Parkinson's Disease
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit van Leiden, op gezag van Rector Magnificus prof. mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties te verdedigen op woensdag 16 december 2009
klokke 10.00 uur
door
Paulien Gerarda Maria Ravenstijn geboren te Terneuzen
in 1977
Systems Pharmacology and Blood-Brain Barrier Functionality
in Parkinson's Disease
Promotiecommissie
Promotor : Prof. dr. M. Danhof Co-promotor : Dr. E.C.M. de Lange
Overige Leden : Prof. dr. Y. Michotte Prof. dr. J.J. van Hilten Prof. dr. J. Bouwstra Prof. dr. T. Hankemeier Prof. dr. M.S. Oitzl
The research described in this thesis was sponsored by Lilly and conducted at the Division of Pharmacology of the Leiden/Amsterdam Center for Drug Research, Leiden University, the Neurodegeneration Drug Hunting Team of Eli Lilly & Co Ltd. in Windlesham, United Kingdom and the Department of Drug Disposition of Lilly Development Centre S.A. in Mont- Saint-Guibert, Belgium.
The only true wisdom is in knowing you know nothing Socrates (470 B.C. - 399 B.C.)
The printing of this thesis was financially supported by:
Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium Aurora Borealis Control BV, Schoonebeek, The Netherlands
ISBN 978-90-8570-424-9
Printed by : Wöhrmann Print Service
© Paulien Ravenstijn
No part of this thesis may be reproduced or transmitted in any form or by any means without written permission from the author.
Section I
Chapter 1 Chapter 2
Chapter 3
General Introduction
Scope and Outline of the Investigations Understanding Drug Response in Parkinson's Disease -
the Role of the Blood-Brain Barrier1. Introduction 2. Parkinson's disease
3. Current drug treatments for Parkinson's disease
4. Mechanisms involved in target site ditribution of CNS drugs 5. Sources of variation in mechanisms contributing to the
response profile
6. The BBB in neurodegeneration: implications for PK-PD relationships of antiparkinson drugs
7. Summary and concluding remarks 8. References
Animal Models as a Tool in Systems Pharmacology Research on Parkinson's Disease
1. Introduction
2. Animal models of Parkinson's disease
3. Measuring target site distribution and BBB functionality in animal models of Parkinson's disease
4. Measuring behaviour and drug effects in animal models of Parkinson's disease
5. Mechanism-based PK-PD modelling techniques 6. Conclusions
7. References
9 11 19
20 21 29 34 46
56
59 60
91
92 95 107
109
112 115 118
Section II Chapter 4
Chapter 5
Section III Chapter 6
The Rotenone Rat Model of Parkinson's Disease The Exploration of Rotenone as a Toxin for
Inducing Parkinson's Disease in Rats -
Application in BBB Transport and PK-PD Experiments 1. Introduction2. Materials and methods 3. Results
4. Discussion 5. References
The Intracerebral Rotenone Model of Parkinson's Disease in Rats -
Altered Conversion of L-DOPA into DOPAC and HVA Without Changes in BBB Transport 1. Introduction2. Materials and methods 3. Results
4. Discussion 5. References
Conclusions and General Discussions Summary, Conclusions and Perspectives
137 139
140 144 151 164 168 173
174 175 183 190 195 199 201
213 225 229 231
