PROTECTIVE EFFECTS OF HYDROGEN SULFIDE AGAINST 6-HYDROXYDOPAMINE-INDUCED CELL INJURY -IMPLICATION FOR TREATMENT OF PARKINSON'S DISEASE TIONG CHI XIN (B.Sc (Biomedical Sciences), University Putra Malaysia, Malaysia) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF PHARMACOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2011 i ACKNOWLEDGEMENTS I would like to express my heartfelt gratitude to my supervisor, Prof Bian Jin-Song, for giving me the opportunity to work on this research project I would also like to thank my supervisor for his invaluable supervisions, enlightening ideas, continuous support and guidance throughout the course of this endeavor I am grateful to my seniors, Dr Lu Ming and Dr Hu Li Fang for their encouragement, technical help and critical comments Sincere appreciation also to all the laboratory members, Xie Li, Wu Zhiyuan, Liu Yihong, Koh Yung Hua, Yong Qian Chen, Hua Fei, Bhushan Nagpure, Shoon Mei Leng and other friends in Prof Bian’s lab for their technical support, assistance in various aspects as well as their warm friendship Their presence has made the laboratory an enjoyable place to work in I would also like to thank my family members and friends for their constant support and encouragement ii TABLE OF CONTENT ACKNOWLEDGEMENTS i PUBLICATIONS vi SUMMARY vii LIST OF TABLES ix LIST OF FIGURES x ABBREVIATIONS xii CHAPTER INTRODUCTION 1.1 General Overview 1.2 Parkinson’s disease (PD) 1.2.1 Epidemiology 1.2.2 Risk factors 1.2.3 Pathology and pathogenesis 1.2.3.1 Pathology 1.2.3.2 Pathogenesis 1.2.4 Clinical features and diagnosis 13 1.2.5 Treatment 13 1.2.6 6-hydroxydopamine (6-OHDA) experimental model 17 1.3 Hydrogen sulfide (H S) 20 1.3.1 Physical and chemical properties of H S 20 1.3.2 Toxicology of H S 21 1.3.3 Endogenous generation and metabolism of H S in mammals 23 iii 1.3.4 Neuropathology of H S 28 1.3.5 Neurophysiological roles of H S 30 1.3.5.1 H S as a neuromodulator 30 1.3.5.2 H S as a neuroprotectant 32 1.3.6 H S and endoplasmic reticulum (ER) stress 35 1.4 SH-SY5Y cells 37 1.5 Research rational and objectives 38 CHAPTER H S PROTECTS AGAINST 6-OHDA-INDUCED CELL INJURY …………………………………………………………………………….40 2.1 Introduction 40 2.2 Materials and methods 41 2.2.2 Cell culture 42 2.2.3 Cell treatment 42 2.2.4 Cell viability assay 42 2.2.5 Cell fractionation for determining PKC isoform translocation 43 2.2.6 Preparation of cell lysates for the detection of TH and phosphorylated Akt ……………………………………………………………………………… 43 2.2.7 Western blot assays 44 2.2.8 Cell transfection and apoptotic detection 44 2.2.9 H S measurement 45 2.2.10 Statistical analysis 46 2.3 Results 47 2.3.1 H S protects against 6-OHDA-induced cell injury 47 iv 2.3.2 H S reverses 6-OHDA-induced loss of TH 49 2.3.3 H S regulates translocation of PKC isoforms in 6-OHDA-treated SH-SY5Y cells 50 2.3.4 Effect of NaHS on cell viability in 6-OHDA-treated SH-SY5Y cells in the presence and absence of inhibitors of PKC isoforms 50 2.3.5 H S-induced neuroprotection involves PI3K/Akt activation 54 2.3.6 Correlation between PKC and Akt 54 2.3.7 CBS overexpression attenuates 6-OHDA-induced apoptosis in SH-SY5Y cells 58 2.4 Discussion 61 CHAPTER H2S PROTECTS AGAINST 6-OHDA-INDUCED ENDOPLASMIC RETICULUM (ER) STRESS 65 3.1 Introduction 65 3.2 Materials and methods 66 3.2.1 Chemicals and reagents 66 3.2.2 Cell culture 67 3.2.3 Cell treatment 67 3.2.4 Cell viability assay 68 3.2.5 Western blot assays 68 3.2.6 Reverse transcription-PCR 69 3.2.7 Statistical analysis 70 3.3 Results 72 3.3.1 H S protects SH-SY5Y cells against 6-OHDA-induced cell death 72 v 3.3.2 H S decreases p-eIF2α expression induced by 6-OHDA 74 3.3.3 H S decreases BiP mRNA expression induced by 6-OHDA 76 3.3.4 H S decreases CHOP expression induced by 6-OHDA 78 3.3.5 Akt activity, but not ERK1/2, mediates the protective effect of H2S on 6OHDA-induced ER stress in SH-SY5Y cells 78 3.3.6 Hsp90 mediates the protective effects of H S on 6-OHDA-induced ER stress in SH-SY5Y cells 81 3.3.7 Interaction between Akt kinase and Hsp90 molecular chaperone 83 3.4 Discussion 84 CHAPTER GENERAL DISCUSSION AND CONCLUSION 88 4.1 General discussion 88 4.2 Conclusion 92 REFERENCES 93 vi PUBLICATIONS Tiong CX, Lu M, Bian JS Protective effect of hydrogen sulphide against 6-OHDAinduced cell injury in SH-SY5Y cells involves PKC/PI3K/Akt pathway Br J Pharmacol 2010, 161:467-480 Xie L*, Tiong CX*, Bian JS Hydrogen sulfide protects SH-SY5Y cells against 6hydroxydopamine-induced endoplasmic reticulum (ER) stress Am J Physiol - Cell Physiol (In Press) Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models Aging Cell 2010, 9:135-146 Lu M, Liu YH, Ho CY, Tiong CX, Bian JS Hydrogen sulfide regulates cAMP homeostasis and renin degranulation in As4.1 and rat renin-rich kidney cells Am J Physiol- Cell Physiol 2012, 302(1):C59-66 Xie L, Hu LF, Tiong CX, Sparatore A, Del Soldato P, Dawe GS, Bian JS Therapeutic effect of ACS84 on 6-OHDA-induced Parkinson’s disease rat model (Ready for submission) * These authors contributed equally to this work vii SUMMARY Parkinson's disease (PD), the second most common neurodegenerative disease, is caused by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by an alteration in the dopamine concentration in the striatum Hydrogen sulfide (H S), the newest member of the gasotransmitter family, serves as an important neuromodulator in regulation of the brain functions The present study aimed to investigate the protective effect of H S against cell injury induced by 6hydroxydopamine (6-OHDA), a selective dopaminergic neurotoxin often used to establish a model of PD The effect of H S on neurotoxin, 6-OHDA was first examined It was found that the exposure to 6-OHDA at 50-200 µM for 12 h decreased cell viability of SHSY5Y cells Exogenous application of NaHS (an H S donor) at 100-1000 µM or overexpression of cystathionine β-synthase (a predominant enzyme to produce endogenous H S in SH-SY5Y cells) protected cells against 6-OHDA-induced cell apoptosis and death NaHS (100 µM) also reversed the up-regulation of cleaved poly (ADP-ribose) polymerase (PARP) in 6-OHDA (50 µM)-treated cells Furthermore, NaHS reversed 6-OHDA-induced loss of tyrosine hydroxylase, the rate-limiting enzyme for dopamine production The underlying signaling mechanisms for H S protection are associated with the activation of PKCα,ε and PI3K/Akt pathway In addition, blockade of PKCα and ε with their specific inhibitors significantly attenuated NaHS-induced Akt phosphorylation, suggesting that activation of Akt by NaHS is PKCα, ε-dependent viii As endoplasmic reticulum (ER) stress has been indicated as a potential mediator of PD, the effect of H S on 6-OHDA-induced ER stress was also examined in this study Consistent with its cytoprotection, NaHS markedly reduced 6-OHDAinduced ER stress responses, including up-regulation of phospho-eIF2α, BiP mRNA level and CHOP protein expression level The protective effect of NaHS against ER stress was mediated by Akt and Hsp90 Interestingly, a decrease in the levels of Hsp90 upon inhibition of Akt activity was observed, suggesting that activation of Akt by NaHS may stimulate Hsp90 protein expression In conclusion, the present study demonstrate for the first time that H S may protect against cell injury and ER stress induced by 6-OHDA neurotoxin via multiple signaling mechanisms and therefore has the potential therapeutic value for PD treatment ix LIST OF TABLES Table 1.1 Various treatments for Parkinson’s disease………………………………17 Table 1.2 Human health effects at various H S concentrations…………………… 21 Table 1.3 Neuropathological roles of H S………………………………………… 27 Table 3.1 Primers for PCR reactions……………………………………………… 69 94 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 CH1 and CH3/HAT domains and cooperate in regulation of transcription and histone acetylation J Virol, 2002 76(10): p 4699-708 Tian, L.L., et al., Protective effect of (+/-) isoborneol against 6-OHDAinduced apoptosis in SH-SY5Y cells Cell Physiol Biochem, 2007 20(6): p 1019-32 Niccoli, G., W.P Orr, and A.P Banning, Extensive right coronary artery dissection following cutting balloon treatment of in-stent restenosis J Invasive Cardiol, 2002 14(4): p 209-11 Imai, Y., et al., An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin Cell, 2001 105(7): p 891-902 Venditti, M., et al., C-myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells Int J Cancer, 2002 99(1): p 35-42 Nagatsua, T and M Sawadab, L-dopa therapy for Parkinson's disease: past, present, and future Parkinsonism Relat Disord, 2009 15 Suppl 1: p S3-8 Weiner, W.J., Levodopa toxic or neuroprotective? 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JS Protective effect of hydrogen sulphide against 6- OHDAinduced cell injury in SH-SY5Y cells involves PKC/PI3K/Akt pathway Br J Pharmacol 2010, 161 : 467 -480 Xie L*, Tiong CX*, Bian JS Hydrogen sulfide. .. protective effect of H S against cell injury induced by 6hydroxydopamine (6- OHDA), a selective dopaminergic neurotoxin often used to establish a model of PD The effect of H S on neurotoxin, 6- OHDA... PKC isoforms in 6- OHDA-treated SH-SY5Y cells 50 2.3.4 Effect of NaHS on cell viability in 6- OHDA-treated SH-SY5Y cells in the presence and absence of inhibitors of PKC isoforms