Pathogenic mechanism induced by S100A8 and S100A9, and neuroprotective effect of a novel herbmedicine, Hepad in Parkinson's disease : 파킨슨 질환에서 S100A8과 S100A9에 의한 병인기전과 Hepad의 신경보호효과

다국어 초록 (Multilingual Abstract)

S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are secreted and exert extracellular paracrine and autocrine functions. S100A8 and S100A9 affect cell death in 1-methyl-4-phenylpyridinium (MPP+) - treated dopaminergic neuronal cells. S100A8 and S100A9 induce cell death via activation of MAPK such as p38 MAPK, JNK and expression of pro-apoptotic proteins, and activation of caspase 9 and caspsase 3 in SH-SY5Y cells. S100A8 and S100A9 also trigger cell death through the Receptor for Advanced Gycation End products (RAGE) and Toll-like receptor 4 (TLR4). Injection of the 6-hydroxydopamine (6-OHDA) plus S100A8 or S100A9 causes more significant loss of tyrosine hydroxylase (TH) immunopositive cell bodies from the substantia and microgliosis than injection group of 6-OHDA in a rat model of Parkinson’s disease. These results indicate that S100A8 and S100A9 may induce neurodegenerative effect. Neuroprotective effects of a novel herb formula, Hepad was investigated on Parkinson’s disease. Dose-dependent treatment with MPP+ decreased the viability of SH-SY5Y cells, and Hepad inhibited the toxic effect of MPP+ and MPP+ plus S100A8 or S100A9. Hepad blocked the production of reactive oxygen species (ROS) induced by MPP+ in SH-SY5Y cells, and suppressed the activation of caspase 9 and caspase 3 due to MPP+. A rat model of Parkinson’s disease was generated by 6-OHDA injection into the left medial forebrain bundle (MFB) of SD rats. In amphetamine sulfate-induced rotational behavioral tests, Hepad administration attenuated circling behavior relative to the 6-OHDA-treated disease group. In addition, Hepad treatment significantly increased the TH- positive cells in the substantia nigra pars compacta (SNpc) that had decreased in response to 6-OHDA treatment. OX-6 expression, which indicates the presence of microglial cells, significantly decreased after treatment of Hepad in contrast to the 6-OHDA-treated disease group. These results indicate that Hepad may be a useful neuroprotective material for the treatment of neurodegenerative disorders such as Parkinson’s disease.

목차 (Table of Contents)

• ABSTRACT = ⅰ
• TABLE OF CONTENTS = ⅲ
• LIST OF FIGURES = ⅴ
• PART ⅠEffect of S100A8 and S100A9 on human SH-SY5Y neuroblastoma cells and a rat model of Parkinson’s disease = 1
• Ⅰ. INTRODUCTION = 1
• Ⅱ. MATERIAL AND METHODS = 4
• Ⅲ. RESULTS = 10
• Ⅳ. DISCUSSION = 35
• PART Ⅱ Neuroprotective effect of a novel herbmedicine, Hepad, on apoptosis of SH-SY5Y cells and a rat model of Parkinson's disease = 44
• Ⅰ. INTRODUCTION = 44
• Ⅱ. MATERIAL AND METHODS = 46
• Ⅲ. RESULTS = 52
• Ⅳ. DISCUSSION = 68
• REFERENCES = 71
• 국문요지 = 75