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Effects of a highly selective plasma kallikrein inhibitor on collagen-induced arthritis in mice
Y Fujimori1, T Nakamura, K Shimizu
1Department of Orthopaedic Surgery, Faculty of Medicine, Kyoto University, Japan.
Abstract:
A study was conducted to evaluate the effects of a new, highly selective plasma kallikrein inhibitor, PKSI-527, on collagen-induced arthritis (CIA) in mice. PKSI-527 or indomethacin was administered daily intraperitoneally from day 20 postimmunization. Clinical evaluation was performed, and two of the components of the kallikrein-kinin system, high-molecular-weight (HMW) kininogen and plasma prekallikrein, were assayed. PKSI-527, as well as indomethacin, reduced the severity of arthritis significantly. PKSI-527, but not indomethacin, restored consumed components of the kallikrein-kinin system. These results suggest that PKSI-527 suppresses CIA by modifying the kallikrein-kinin system and PKSI-527 as a synthetic plasma kallikrein inhibitor would be a valuable tool to study the mechanism of inflammation of arthritic diseases.
Insights
A novel plasma kallikrein inhibitor, PKSI-527, effectively reduced collagen-induced arthritis (CIA) severity in mice. PKSI-527 also positively impacted the kallikrein-kinin system, unlike indomethacin.
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- Collagen-induced arthritis (CIA) is a mouse model for rheumatoid arthritis.
- The kallikrein-kinin system plays a role in inflammatory processes.
- Selective plasma kallikrein inhibitors are being investigated for therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy of PKSI-527, a selective plasma kallikrein inhibitor, in a mouse model of arthritis.
- To investigate the impact of PKSI-527 on the kallikrein-kinin system during arthritis.
- To compare PKSI-527 with indomethacin, a non-steroidal anti-inflammatory drug.
Main Methods:
- Administration of PKSI-527 or indomethacin intraperitoneally in mice with CIA.
- Clinical assessment of arthritis severity.
- Assay of high-molecular-weight (HMW) kininogen and plasma prekallikrein levels.
Main Results:
- Both PKSI-527 and indomethacin significantly reduced arthritis severity.
- PKSI-527 treatment restored depleted kallikrein-kinin system components.
- Indomethacin did not restore these components.
Conclusions:
- PKSI-527 demonstrates therapeutic potential for arthritic diseases by modulating the kallikrein-kinin system.
- PKSI-527 is a valuable tool for studying inflammatory mechanisms in arthritis.
- Selective plasma kallikrein inhibition offers a promising therapeutic strategy.