HYDROGEN SULFIDE: A NOVEL NEUROPROTECTIVE AGENT TO TREAT PARKINSON’S DISEASE HU LI-FANG (MD, M.Sci, Nanjing Medical University, China) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2010 ACKNOWLEDGEMENT I would like to express my deepest gratitude to my supervisor, Prof. Bian Jin-Song, for giving me the opportunity to work on this research project as a part-time postgraduate student. I would thank my supervisor for his invaluable comments, enlightening ideas and continuous encouragement. Without his great support, I would not have made great progress on my thesis. I would also thank Prof. Gavin S. Dawe for his guidance in the behaviour study. I would express my special thanks to Mr. Lu Ming for his kindly help and collaboration in the animal work. Sincere appreciation to my colleagues, Neo Kay Li, Pan Tingting, Yong Qian Chen, Wu Zhiyuan, Ester Khin Sandar Win, Tan Choon Ping, Liu Yihong, Tiong Chi Xin, Xie Li, and other friends in Prof. Bian‘s lab for their technical support and help in various aspects over the four years. I would also thank all my friends in Prof. Gavin S. Dawe‘s lab for their support on my animal work. I would also extend my deep gratitude to my husband for supporting and inspiring me to reach my full potential. i TABLE OF CONTENT PUBLICATIONS vii ABBREVIATIONS viii SUMMARY x Chapter I Introduction 1.1 General overview . 1.2 H2S 1.2.1 Chemical properties of H2S . 1.2.2 H2S toxicity . 1.2.3 H2S biosynthesis and metabolism in mammals . 1.2.4 Biological roles of H2S 10 1.2.4.1 Roles of H2S in inflammation . 10 1.2.4.2 Role of H2S in CNS and CNS diseases 14 1.2.4.3 Roles of H2S in cardiovascular system . 25 1.2.4.4 Roles of H2S in gastrointestinal tract 28 1.2.4.5 Others . 30 1.3 PD . 31 1.3.1 Epidemiology 32 1.3.2 Risk factors 32 1.3.3 Pathology and pathogenesis 33 1.3.3.1 Pathology 33 1.3.3.2 Pathogenesis . 34 1.3.4 Clinical features and diagnosis 38 1.3.5 Treatment . 38 1.3.6 Experimental models . 39 1.3.6.1 6-OHDA model 40 ii 1.3.6.2 MPTP/MPP+ model 42 1.3.6.3 Rotenone model 45 1.3.6.4 LPS model 46 1.3.6.5 Other models 49 1.4 Research rational and objectives 52 1.4.1 Rational . 52 1.4.2 Objectives 53 Chapter II Anti-inflammatory effects of H2S on LPS-stimulated microglia .55 2.1 Introduction 55 2.2 Materials and methods 56 2.2.1 Chemicals and reagents . 56 2.2.2 Cell culture 56 2.2.2.1 Microglia cell line culture 56 2.2.2.2 Primary cultured rat cortical microglia and astrocytes preparation 57 2.2.3 NO measurement . 58 2.2.4 TNF-α measurement 58 2.2.5 Reverse transcription polymerase chain reactions (RT-PCR) . 59 2.2.6 Transfection of CBS and CSE into BV2 cells . 59 2.2.7 Western blot analysis . 60 2.2.8 Statistical analysis . 61 2.3 Results 61 2.3.1 Exogenous H2S suppresses LPS-stimulated NO production in microglia . 61 2.3.2 The anti-inflammatory effect of H2S involves p38 MAPK . 63 2.3.3 H2S inhibits TNF- secretion in BV2 cells . 65 2.3.4 Endogenous H2S regulates NO production in BV2 cells . 66 2.3.5 Over-expression of H2S synthesis enzyme suppresses NO production in microglia 68 2.3.6 H2S suppresses LPS-stimulated NO generation in astrocyte . 68 iii 2.4 Discussion 69 Chapter III Anti-inflammatory effects of H2S on rotenone-stimulated microglia 73 3.1 Introduction 73 3.2 Materials and methods 74 3.2.1 Chemicals and reagents . 74 3.2.2 Cell culture 74 3.2.3 Immunocytochemistry . 74 3.2.4 Western blot assays . 75 3.2.5 Intracellular ROS assay . 75 3.2.6 Extracellular superoxide measurement 75 3.2.7 Microglia-mediated neurotoxicity assay . 76 3.2.8 NF-κB activation assay 76 3.2.9 Statistical analysis . 77 3.3 Results 77 3.3.1 NaHS inhibits rotenone-stimulated microglia activation 77 3.3.2 NaHS suppresses rotenone-induced intracellular ROS accumulation . 79 3.3.3 NaHS inhibits rotenone-induced superoxide release from microglia 80 3.3.4 NaHS attenuates microglia-mediated neurotoxicity 81 3.3.5 NaHS inhibits rotenone-induced p38 MAPK/NF-κB activation . 82 3.4 Discussion 86 Chapter IV Anti-apoptotic effect of H2S on SH-SY5Y cells .90 4.1 Introduction 90 4.2 Materials and methods 90 4.2.1 Chemicals and reagents . 90 4.2.2 Cell culture and treatment . 92 4.2.3 Total sulfide measurement 93 4.2.4 Cell viability assay 93 iv 4.2.5 Apoptosis quantification 93 4.2.6 Assessment of mitochondrial membrane potential (ΔΨm) loss 94 4.2.7 Western blot analysis . 94 4.2.8 Analysis of cytosolic cytochrome c accumulation 94 4.2.9 Caspase-9 activity assay 95 4.2.10 Statistical analysis . 95 4.3 Results 95 4.3.1 H2S suppresses rotenone-induced cytotoxicity and apoptosis . 95 4.3.2 H2S inhibits rotenone-induced ΔΨm loss and cytochrome c release . 98 4.3.3 H2S regulates Bax/ Bcl-2 proteins in SH-SY5Y cells . 100 4.3.4 H2S suppresses caspase-9/3 activation and PARP cleavage 101 4.3.5 mitoKATP channels contributes to the protective effects of H2S 103 4.3.6 Rotenone induces p38/JNK MAPK activation 105 4.3.7 H2S inhibits rotenone-induced p38/JNK MAPK activation 107 4.4 Discussion 108 Chapter V Therapeutic effect of H2S in rotenone-induced PD model rats 112 5.1 Introduction 112 5.2 Materials and methods 113 5.2.1 Chemicals 113 5.2.2 Animals . 113 5.2.3 Behavioural test . 113 5.2.4 H2S measurement 114 5.2.5 H2S-producing activity assay . 115 5.2.6 Immunohistochemistry staining 115 5.2.7 NO assay 116 5.2.8 TNF-α assay 116 5.2.9 Western blot analysis . 117 v 5.2.10 Statistical analysis . 117 5.3 Results 117 5.3.1 Endogenous H2S is reduced in the SN of rotenone-treated rats 117 5.3.2 NaHS alleviates rotenone-induced parkinsonian symptoms in rats 118 5.3.3 H2S attenuates rotenone-induced DA neuron loss in the SN . 121 5.3.4 NaHS inhibits microglia activation and the subsequent release of inflammatory factors in the rotenone-induced PD model rats 122 5.4 Discussion 123 Chapter VI General discussion and conclusion .127 6.1 General discussion 127 6.2 Conclusion and perspectives 134 Bibliography .137 vi PUBLICATIONS 1. Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS. Neuroprotective effects of hydrogen sulfide in Parkinson‘s disease rat models. Aging Cell. 2009; 9(2):135-46. 2. Hu LF, Lu M, Wu ZY, Wong PT, Bian J. Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. Mol Pharmacol. 2009; 75(1):2734. 3. Hu LF, Wong PT, Moore PK, Bian JS. Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem. 2007; 100(4):1121-8. 4. Hu LF, Pan TT, Neo KL, Yong QC, Bian JS. Cyclooxygenase-2 mediates the delayed cardioprotection induced by hydrogen sulfide preconditioning in isolated rat cardiomyocytes. Pflugers Arch. 2008 Mar; 455(6):971-8. 5. Hu LF, Wong PT, Bian J. Hydrogen sulphide: neurophysiology and neuropathology. Review. Antioxid Redox Signal. 2010 Sep 2. 6. Hu LF, Wong PT, Bian J. Hydrogen sulfide attenuates rotenone-induced neuroinflammatory responses through down-regulation of NADPH oxidase/ROS signaling pathways in microglia (in preparation) 7. Tay AS, Hu LF, Lu M, Wong PT, Bian JS. Hydrogen sulfide protects neurons against hypoxic injury via stimulation of ATP-sensitive potassium channel/protein kinase C/extracellular signal-regulated kinase/heat shock protein90 pathway. Neuroscience. 2010 Feb 8. 8. Lu M, Choo CH, Hu LF, Tan BH, Hu G, Bian JS. Hydrogen sulfide regulates intracellular pH in rat primary cultured glia cells. Neurosci Res. 2010; 66(1):92-8. 9. Lu M, Hu LF, Hu G, Bian JS. Hydrogen sulfide protects astrocytes against H(2)O(2)induced neural injury via enhancing glutamate uptake. Free Radic Biol Med. 2008; 45(12):1705-13. 10. Lee SW, Hu YS, Hu LF, Lu Q, Dawe GS, Moore PK, Wong PT, Bian JS. Hydrogen sulphide regulates calcium homeostasis in microglial cells. Glia. 2006; 54(2):116-24. vii ABBREVIATIONS AC adenylyl cyclase AD Alzheimer‘s disease AIF apoptosis-inducing factor AOAA amino-oxyacetic acid AP1 activator protein Apaf-1 apoptotic protease activating factor-1 BCA β-cyanol-l-alanine CAT cysteine aminotransferase CBS cystathionine-β-synthase CNS central nervous system CSE cystathionine-γ-lyase CO carbon monoxide COX-2 cyclooxygenase-2 DA dopamine ERK extracellular signal-regulated kinase GSH glutathione GABA γ-aminobutyric acid HA hydroxylamine H2S hydrogen sulfide HD Huntington‘s disease IL-1β interleukin 1β iNOS inducible nitric oxide synthase JAK Janus kinase JNK c-Jun N-terminal kinase KATP ATP-sensitive potassium channel LPS lipopolysaccharide LTP long-term potentiation MAO monoamine oxidase viii MAPK mitogen-activated protein kinase 3-MST 3-mercaptopyruvate sulfurtransferase mitoKATP mitochondrial KATP channel MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydroperidine NaHS sodium hydrogen sulfide NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NMDA N-methyl-D-aspartic acid NO nitric oxide Nrf-2 Nuclear factor-like NSAIDs non-steroidal anti-inflammatory drugs 6-OHDA 6-hydroxydopamine PAG DL-propargylglycine PARP poly (ADP-ribose) polymerase PD Parkinson‘s disease PFA paraformaldehyde PGE2 prostaglandin E2 PI3K phosphoinositide 3-kinase PKA protein kinase A PKC protein kinase C PLC phospholipase C PLP pyridoxal-5‘-phosphate PPAR-γ peroxisome proliferator-activated receptor-γ ROS reactive oxygen species SAM S-adenosyl-L-methionine SN substantia nigra SNpc substantia nigra pars compacta STAT signal transducers and activators of transcription TH tyrosine hydroxylase TNF-α tumor necrosis factor-α VMAT vesicular monoamine transporter ix Bibliography 1. 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Parkinsonism Relat Disord 11:131-3. 152 [...]... in regulation of brain functions PD, characterized by the progressive loss of DA neurons in midbrain, is the second most common neurodegenerative disorder among old population In this thesis, the therapeutic effect of H2S on neurodegeneration and the underlying mechanisms were investigated in both in vitro and in vivo studies Neuroinflammation is one of the main pathological causes/features of PD In. .. for maintaining GSH homeostasis in brain, which in turn preserves mitochondrial 7 function (48) CSE is the rate-limiting enzyme in the transsulfuration pathway for the sulfur transfer methionine to Cys, which is a limiting reagent in the synthesis of GSH Moreover, CSE mRNA is localized in brain and found to be predominantly present in neurons by in situ hybridization The CSE activity in mouse brain was... Collectively, these in vivo and in vitro findings consistently indicate the proinflammatory effects of H2S in acute pancreatitis Carregeenan-induced hindpaw edema The possible role of H2S in another inflammatory situation, carrageenan-induced hindpaw oedema was also investigated (14) An increase of H2S synthesis enzyme activity and MPO activity was observed in inflamed hindpaw Pretreatment with PAG dose-dependently... neuroinflammation remains unknown Given that H2S regulates inflammatory processes in various diseases and that H2S exists in brain at relatively high levels, it is hypothesized that H2S may regulate 1 neuroinflammatory process, and thus the pathogenesis of PD Therefore, this thesis was designed to investigate the potential role of H2S in neuroinflammation and DA neuronal injury The therapeutic effect of. .. detected in different brain regions (9, 201) CBS is a cytoplasm PLP-dependent enzyme Human CBS has a complex structure and regulatory mechanisms (134) It contains the N-terminal heme-binding domain, the catalytic domain, and the C-terminal regulatory domain Two other gaseous transmitters, CO and NO, can bind to the heme-binding domain and result in the inhibition of CBS activity (190, 191) Moreover, the. .. suppressed the up-regulation of SP and its receptor neurokinin-1 (NK-1R) as well as the gene expression of preprotachykinin-A, a precursor of SP, in the caerulein-induced acini Furthermore, NaHS resulted in a significant increase of SP and its receptors These data suggest that H2S also exerts a proinflammatory action in acute pancreatitis, possibly mediated by SP-NK-1R related pathway Collectively, these in. .. of the hepatic activity However, in human brain the activity was 100 times more than that in mouse brain Furthermore, an intact transsulfuration pathway in the brain mediated by both CBS and CSE links to GSH homeostasis, which greatly contributes to the redoxbuffering capacity in brain (201) Nevertheless, the general consensus is that CSE is the primarily physiological source of H2S generation in the. .. exploring H2S biology in the CNS Parkinson‘s disease (PD) is a movement disorder characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra (SN) Its etiology remains elusive and the mechanisms for initiating and aggravating neuronal death are yet to be defined, despite years of intensive research An inflammatory process in CNS, often defined as neuroinflammation, is recently... Recently, there is an explosion of papers describing its functions in various systems and conditions 1.2.4.1 Roles of H2S in inflammation To date, both pro- and anti-inflammatory effects of H2S in vitro and in vivo have been reported H2S is herein positioned as a novel regulator of inflammation Pro-inflammation Most evidence indicating a pro-inflammatory effect of H2S comes from various animal models of inflammatory... (5) These two studies consistently demonstrate a regulatory role of H2S in neurogenic inflammation Anti-inflammation A great body of evidence from both in vivo and in vitro studies mentioned above strongly supports the pro-inflammatory actions of H2S However, lots of studies also note an antiinflammatory role of H2S H2S is demonstrated to alleviate the inflammatory hallmarks including swelling and pain . It contains the N-terminal heme-binding domain, the catalytic domain, and the C-terminal regulatory domain. Two other gaseous transmitters, CO and NO, can bind to the heme-binding domain and. neuroinflammatory process, and thus the pathogenesis of PD. Therefore, this thesis was designed to investigate the potential role of H 2 S in neuroinflammation and DA neuronal injury. The therapeutic. and the underlying mechanisms were investigated in both in vitro and in vivo studies. Neuroinflammation is one of the main pathological causes/features of PD. In this thesis, the effect of