Identification of Novel Peripheral CB1R Antagonists to Suppress Psoriatic Skin Inflammation
- 주제(키워드) Cannabinoid receptor 1 , peripheral , dendritic cell , psoriasis , inflammatory response
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 Wook Kim
- 발행년도 2025
- 학위수여년월 2025. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000034557
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Psoriasis is a chronic autoimmune skin disorder driven by an overactive immune system, resulting in persistent inflammation. Current therapeutic strategies predominantly target cytokines, providing symptomatic relief but are limited by high recurrence rates and an inability to address the underlying immune dysregulation. Cannabinoid receptor 1 (CB1R) has emerged as a pivotal regulator in chronic inflammatory diseases. While existing CB1R antagonists have demonstrated therapeutic efficacy in inflammation management, concerns regarding central nervous system side effects have underscored the need for peripherally selective CB1R antagonists. In this study, psoriasis was employed as a disease model to investigate the potential of CB1R antagonist in modulating inflammation. A novel peripherally selective CB1R antagonist was developed, characterized by high affinity and selectivity for CB1R, alongside a significantly reduced predicted blood-brain barrier (BBB) permeability compared to existing compounds. This design minimizes central nervous system-related side effects through restricted BBB penetration and a low brain-to-plasma ratio. Preclinical evaluations in vitro and in an imiquimod-induced psoriasis-like dermatitis model demonstrated that the compound effectively ameliorated psoriatic inflammation by reducing epidermal hyperplasia and suppressing the production of pro-inflammatory cytokines. Investigations using bone marrow-derived dendritic cells (BMDCs) further revealed that CB1R inhibition suppresses immune activation and attenuates the secretion of inflammatory mediators at the cellular level, offering a fundamental advantage over traditional cytokine-targeted therapies. These findings establish CB1R in dendritic cells as a novel therapeutic target for psoriasis, providing a robust strategy for disease modulation. Furthermore, the compound exhibits potential therapeutic utility across a spectrum of CB1R-mediated disorders, including obesity and contact dermatitis. This study presents a novel peripherally selective CB1R antagonist with significant anti-inflammatory efficacy in psoriasis, highlighting its potential for broader therapeutic applications in CB1R-mediated chronic inflammatory conditions.
more목차
Ⅰ. INTRODUCTION 1
Ⅱ. EXPERIMENTAL 3
1. Materials. 3
2. Preparation and characterization of CB1R antagonist 4
3. Mice 5
4. IMQ-induced psoriasis mice model 6
5. Tango GPCR assay 6
6. Hyperthermia test 7
7. Catalepsy test 7
8. Perfusion 8
9. Immunohistochemistry staining 9
10. Cell culture and treatment 10
11. Cell viability test 11
12. Immunofluorescence staining 12
13. Real-Time quantitative PCR 13
14. Flow cytometry 14
15. Statistical analysis 14
Ⅲ. RESULTS 16
1. CB1R Aggravates the Pathogenesis of Psoriasis. 16
2. Design and Affinity Analysis of Novel Peripheral CB1R Antagonists. 18
3. Behavioral Assessment of Blood-Brain Barrier Permeability of CB1R Antagonists 23
4. Brain-to-Plasma (B/P) Ratio and Tissue Distribution of Compounds Using Perfusion Assay 26
5. In vivo Therapeutic Effects of CB1R Antagonists. 28
6. Histological Analysis of Psoriatic Skin. 31
7. Increased CD11c⁺ Dendritic Cells and CB1R Expression in Psoriatic Skin 33
8. Impact of CB1R Antagonists on Dendritic Cell Differentiation and Activation 35
9. Effect of CB1R Antagonists on Inflammatory Cytokine Expression in IMQ- Stimulated BMDCs 37
Ⅳ. DISCUSSION 39
Ⅴ. REFFRENCE 41
Ⅵ. ABSTRACT IN KOREAN (국문 초록) 44
