The effects of simvastatin on central dopaminergic systems

THE EFFECTS OF SIMVASTATIN ON CENTRAL DOPAMINERGIC SYSTEMS WANG QING, DENNIS NATIONAL UNIVERSITY OF SINGAPORE 2005 THE EFFECTS OF SIMVASTATIN ON CENTRAL DOPAMINERGIC SYSTEMS WANG QING, DENNIS (M.D. M.S.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY MEDICINE OF FACULTY NATIONAL UNIVERSITY OF SINGAPORE August, 2005 Acknowledgements i ACKNOWLEDGEMENTS Firstly, I would like to express my deepest appreciation and thanks to my supervisor Associate Professor Wong Tsun Hon, Peter, Department of Pharmacology, NUS, for his excellent guidance and immerse support throughout the course of this study. Secondly, I wish to give my great thanks to Prof (Dr.). Tan Benny K.H Dr. Zhu Yi Zhun, and Dr. Robert Yang for their proficient guidance and constant encouragement in many aspects of this project. Thirdly, I am most grateful to my cooperator Dr. Wang Ling Zhi, Department of Pharmacology, for his expert direction and stimulating discussion on the dopamine transmission measurement. My deepest gratitude also goes out to Mrs. Ting Wee Lee for her expert technical assistance and suggestions, with which I have gone smoothly on many procedures and experiments. I am also greatly thankful to my pal Dr. Wang Peng Hua, Department of Biochemistry, for his encouragement, valuable discussion, and technical support. I must also greatly thank Professor Philip Keith Moore, the Head of Pharmacology Department, and all of the staffs in the Department of Pharmacology for providing very much comfortable experimental environment and assistance where necessary. Lastly, I would like to express my most heartfelt gratitude to my parents and elder brother for their earnest love, constant encouragement and the complete support throughout my career. This work was supported by a grant (R-184-000-039-112) from the National University of Singapore. Publications and main honors ii PUBLICATIONS AND MAIN HONORS 1. Wang Q, Wang Ling-Zhi, Boon-Cher Goh, How-Sung Lee, P. T.-H. Wong. Effects of simvastatin on levels of dopamine and its re-uptake in prefrontal cortex and striatum among SD rats. Submitted 2. Wang Q, Wang P.H, MacLachlan C , and Wong P. T.-H (2005). Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats. Brain Research 1045 (1-2), 229-233; 3. Wang Q, Ting W. L., Yang H. Y. and Wong P. T.-H. (2005). High doses of simvastatin up-regulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase. (British Journal of Pharmacology 144(7):933-9); 4. Farook JM, Wang Q, Moochhala SM, Zhu ZY, Lee L, Wong PT (2004) Distinct regions of periaqueductal gray (PAG) are involved in freezing behavior in hooded PVG rats on the cat-freezing test apparatus. Neurosci Lett. 354(2):139-42. 5. Farook JM, Zhu YZ, Wang Q, Moochhala SM, Lee L, Wong PT (2004) Analysis of strain difference in behavior to Cholecystokinin (CCK) receptor mediated drugs in PVG hooded and Sprague-Dawley rats using elevated plus-maze test apparatus. Neurosci Lett. 358(3):215-9. Main honors and awards: 1. 7th NUS-NUH Annual Scientific Meeting (Oct 2nd -5th, 2003, Republic of Singapore): The Young Scientist Award (merit). 2. The Third International Congress on Vascular Dementia (October 23rd - 26th, 2003, Prague, Czech Republic): Oral presentation for 15 minutes. 3. The 6th Biennial Meeting of the Asia Pacific Society for Neurochemistry (Feb 4th -7th, 2004, Hong Kong): The travel award iii Table of Contents TABLE OF CONTENTS Acknowledgements i Publications ii Table of contents iii Abbreviations ix Summary xi List of tables and figures XiV Chapter 1: Introduction 1.1 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors, or statins’ properties and their subtypes. 1.2 1.1.1. Cholesterol biosynthesis and the inhibition mechanism of statins. 1.1.2 Several types of statins and their properties 1.1.3 Statins and brain diseases Dopaminergic systems: Dopamine receptors and transmission 10 1.2.1 Dopamine receptors characteristics and their distribution in the brain. 10 1.2.2 cAMP---- the hallmark for the functional measurement of G-protein coupled receptors. 1.2.3 Dopaminergic pathways and their functions 17 19 iv Table of Contents .1.3. The central dopaminergic systems and neurological disorders. 23 1.4. Animal models of Parkinson disease. 28 1.5. Nitric oxide synthases and their clinical relevance. 30 Chapter 2: Chronic treatment with simvastatin in SD rats 38 2.1. Introduction 38 2.2. Methods 39 2.2.1 Animals and statins pretreatment 39 2.2.2 Serum cholesterol and triglyceride measurement 40 2.2.3.Preparation of RNA from prefrontal cortex and striata of SD rats. 40 2.2.4. Reverse transcription-polymerase chain reaction (RT-PCR). 41 2.2.5. Quantification of PCR products. 42 2.2.6. Western Blot analysis for D1 and D2 receptors and β-actin. 43 2.3. Results 44 2.3.1. Serum cholesterol measurement by kits from ThermoTrace. 44 2.3.2. D1 and D2 receptor expression after statin treatment. 45 2.4. Discussion 45 2.5. Figures 49 Chapter 3: The effects of Simvastatin on the expression of (e,n,i)NOS, D1 and D2 receptors. 57 v Table of Contents 3.1. Introduction: 57 3.2. Methods 59 3.2.1. Animal and statins pretreatment 59 3.2.2. Preparation of RNA from prefrontal cortices and striata of SD rats or mice. 59 3.2.3. Reverse transcription-ploymerase chain reaction (RT-PCR) for (e, n, i) NOS (rats), D1 and D2 dopamine receptor (mice) expression. 59 3.2.4. Quantification of PCR products. 60 3.2.5. Western Blot analysis for eNOS protein. 61 3.3. Results 61 3.3.1. NOS mRNA expression measured by RT-PCR in the prefrontal cortex and striatum after simvastatin treatment. 61 3.3.2. D1 and D2 dopamine receptor mRNA expression measured by RTPCR in the prefrontal cortex of eNOS knockout mice. 62 3.3.3. eNOS mRNA expression in the prefrontal cortex of SD rats after dopamine receptor D1 and D2 receptors blockade. 62 3.4. Discussion 63 3.5. Figures 65 Chapter 4: Functional study of D1 and D2 by measuring cAMP levels in the synaptosomes of the prefrontal cortex in SD rats after the simvastatin treatment. 72 Table of Contents vi 4.1. Introduction 72 4.2. Methods 73 4.2.1. Animal and statins pretreatment. 73 4.2.2. Different reagents and drugs preparation. 74 4.2.3. Preparation of rat prefrontal cortex synaptosomal membranes. 74 4.2.4. Synaptosome cAMP measurement after D1 and D2 antagonist or agonist treatment. 75 4.3. Results for cAMP measurement 75 4.4. Discussion 76 4.5. Figures 79 Chapter 5: Dopamine content and its re-uptake in the prefrontal cortex and striatum in SD rats after simvastatin treatment. 80 5.1. Introduction 80 5.2. Methods 81 5.2.1. Dopamine transmission measurement by HPLC-MS/MS 81 5.2.1.1. Animal and statins pretreatment. 81 5.2.1.2. Reagents and standards. 82 5.2.1.3. HPLC-MS instrumentation. 82 5.2.1.4. Sampling of prefrontal cortex and striatum. 82 5.2.1.5. Solid phase extraction. 83 Table of Contents 5.2.2. Dopamine re-uptake experiment vii 83 5.2.2.1. Animal and statin pretreatment 83 5.2.2.2. Synaptosome preparation. 83 5.2.2.3. Dopamine re-uptake measurement. 84 5.3. Results 85 5.4. Discussion 85 5.5. Figures 88 Chapter 6: Effects of simvastatin on dopamine D1 and D2 receptor expressions in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats 93 6.1. Introduction 93 6.2. Methods 95 6.2.1. Parkinson disease animal model—6-OHDA lesioned rats--set up 95 6.2.2. Circling behavior and simvastatin pre-treatment 96 6.3. Results 96 6.4. Discussion 97 6.5. Figures 100 Table of Contents Chapter 7: General discussion References viii 105 References Ponzio F, Calderini G., Lomuscio G, Vantini G, Toffano G. and Algeri S. (1982) Changes in monoamines and their metabolite levels in some brain regions of aged rats. Neurobiol. Aging 3: 23–29 . Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL, Dawson TM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci U S A 93(10):4565-71. 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J Neurol Sci 128:22-27. 155 [...]... expression of striatum by RT-PCR among control, 6-OHDA lesioned PD rats, and 6-OHDA lesioned PD rats with simvastatin treatment Figure 6.4 The β-actin and D2 receptor mRNA expression of striatum by RT-PCR among control, 6-OHDA lesioned PD rats, and 6-OHDA lesioned PD rats with simvastatin treatment Figure 6.5 The β-actin and D1 receptor protein level expression of prefrontal cortex by Western blot among control,... up-regulation of dopamine receptors These results strongly indicated that up-regulation of the dopamine receptors after simvastatin treatment occurs independently of the up-regulation of eNOS In vitro studies showed that dopamine content decreased in the prefrontal cortex but increased in the striatum while DA re-uptake in these brain regions remained unchanged xiii Summary SD rats with unilateral lesion of. .. List of tables and figures xvii Figure 6.1 The β-actin and D1 receptor mRNA expression of prefrontal cortex by RTPCR among control, 6-OHDA lesioned PD rats, and 6-OHDA lesioned PD rats with simvastatin treatment Figure 6.2 The β-actin and D2 receptor mRNA expression of prefrontal cortex by RTPCR among control, 6-OHDA lesioned PD rats, and 6-OHDA lesioned PD rats with simvastatin treatment Figure 6.3 The. .. selective D1 antagonist SCH-23390 (25μM) D2 receptor activation by quinpirole (5μM) had no effect on the basal cAMP levels in synaptosomes prepared from the prefrontal cortex of control and simvastatin- treated rats, while the same concentration of quinpirole completely abolished the D1 receptormediated increase Concurrent with the up-regulation of dopamine receptor D1 and D2 in the prefrontal cortex, eNOS... in advanced PD In short, chronic treatment with simvastatin for 4 weeks significantly altered the dopaminergic systems in the prefrontal cortex of SD rats The up-regulation of dopamine receptors expression with concurrent increase in receptor function may have specific implication on cognitive deficits in advanced Parkinson’s disease List of tables and figures xiv LIST OF TABLES/FIGURES Table 1.1... its agonist, Gαi will be activated so as to inhibit adenylyl cyclase and lower the level of cAMP (Stoof et al 1981; Stoof et al 1982; Huff 1997) As an intracellular second messenger that is triggered by hormones or other signaling molecules, cAMP exerts hormonal responses such as the mobilization of stored energy, conservation of water by the kidney, Ca2+ homeostasis, increased rate and force of contraction... Parkinson’s disease This work is mainly to explore the effects of simvastatin on central dopaminergic systems and its possible mechanism of action Since statins include two subtypes: lipophilic and hydrophilic First we choose pravastatin and simvastatin (at dosage of 1.0mg/kg/day, 10mg/kg/day and 30mg/kg/day), which represent these two different types respectively, to test if both of them affect the central. .. after simvastatin treatment The mechanism of protection may be associated with augmented blood flow owing to up-regulation of eNOS by simvastatin 9 Chapter 1: Introduction but may also stem from other known NO-mediated effects such inhibition of platelet aggregation or leukocyte adhesion 1.2 Dopaminergic systems: Dopamine receptors and transmission 1.2.1 Dopamine (DA) receptors characteristics and their... of the medial forebrain bundle by 6hydroxydopamine showed marked decrease in the expression of dopamine D1 and D2 receptors in the prefrontal cortex Simvastatin treatment (10 mg/kg/day for 4 weeks) restored receptor expression to control levels Therefore, these observations suggest that simvastatin may have an effect on cognitive deficits associated with the loss of dopaminergic receptor function in... analysis of eNOS protein in eNOS knockout mice List of tables and figures xvi Figure 3.5 The β-actin and D1 receptor mRNA expression of prefrontal cortex by RTPCR among control, C57BL mice but treated by simvastatin, and eNOS knockout mice but treated by simvastatin Figure 3.6 The β-actin and D2 receptor mRNA expression of prefrontal cortex by RTPCR among control, C57BL mice but treated by simvastatin, . THE EFFECTS OF SIMVASTATIN ON CENTRAL DOPAMINERGIC SYSTEMS WANG QING, DENNIS NATIONAL UNIVERSITY OF SINGAPORE 2005 THE EFFECTS OF SIMVASTATIN. the dopaminergic systems in the prefrontal cortex of SD rats. The up-regulation of dopamine receptors expression with concurrent increase in receptor function may have specific implication. up-regulation of dopamine receptors. These results strongly indicated that up-regulation of the dopamine receptors after simvastatin treatment occurs independently of the up-regulation of eNOS.