Suppression of NLRP3 inflammasome and inflammation by MK145 in a hemorrhagic stroke model

다국어 초록 (Multilingual Abstract)

Intracerebral hemorrhage (ICH) is a severe condition affecting around 2 million people annually, caused by vascular damage from hypertension or trauma, leading to brain injury. While current treatments can surgically address the primary damage, they fail to prevent secondary damage from inflammation and toxic responses, leaving no definitive cure. MK145, identified through blood screening of cerebral palsy patients, has shown behavioral improvements in stroke models, prompting its evaluation in an ICH model. In this study, MK145-treated ICH rats exhibited significant neurological and functional recovery. MK145 also reduced inflammation related to toll-like receptor (TLR4) and the NOD-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome, and decreased microglial activation, alleviating inflammatory responses. Unlike stem cell therapies, which face challenges like side effects and high costs, MK145, as a peptide drug, presents a promising alternative with reduced risks. Keywords: Intracerebral Hemorrhage, Toll-like receptor 4 (TLR4), NOD- like receptor, pyrin domain-containing 3 (NLRP3) Inflammasome, Therapeutics effect

목차 (Table of Contents)

• TABLE OF CONTENTS ⅰ
• LIST OF TABLES ⅳ
• LIST OF FIGURES v
• ABSTRACT ⅷ
• Ⅰ. INTRODUCTION 1
• Ⅱ. MATERIALS AND METHODS 7
• 1. Cell culture and treatment 7
• 2. Primary microglia cells culture and treatment 7
• 3. Animals 8
• 4. Intracerebral hemorrhage (ICH) rat model 9
• 5. Drug administration 10
• 6. Behavior Evaluation 12
• 7. Hematoma volume measurement 14
• 8. RNA isolation and quantitative real-time PCR (qRT-PCR) · 14
• 9. Western blot analysis 17
• 10. Immunofluorescence staining 19
• 11. Measurement of NO assay 20
• 12. Statical analysis 21
• Ⅲ. RESULTS 22
• 1. Temporal Dynamics of TLR4/MyD88 and NLRP3 Inflammasome
• Activation Following ICH 22
• 2. MK145 Treatment Improves Survival and Functional Recovery
• in the ICH Model 29
• 3. MK145 Reduces Secondary Brain Damage by Attenuating
• TLR4-Related Inflammation and NLRP3 Inflammasome Activation
• in ICH 38
• 4. Time-Dependent Inflammatory Response and NO Production in
• LPS-Stimulated BV2 Microglia 50
• 5. Evaluation of MK145's Effect on Inflammation and Toxicity in
• BV2 Cells 56
• 6. MK145 Suppresses LPS-Induced Inflammation in BV2 and
• Primary Microglia Cells 58
• Ⅳ. DISCUSSION 67
• Ⅴ. REFERENCE 73
• ABSTRACT IN KOREAN 80