A store-operated calcium channel inhibitor attenuates collagen-induced arthritis
1Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
Background And Purpose:
Store-operated calcium (SOC) channels are thought to play a critical role in immune responses, inflammatory diseases and chronic pain. The aim of this study was to explore the potential role and mechanisms of SOC channels in collagen-induced arthritis (CIA).
Experimental Approach:
The CIA mouse model was used to examine the effects of the SOC channel inhibitor YM-58483 on CIA and arthritic pain. Hargreaves' and von Frey hair tests were conducted to measure thermal and mechanical sensitivities of hind paws. elisa was performed to measure cytokine production, and haematoxylin and eosin staining was used to assess knee histological changes. Western blot analysis was performed to examine protein levels.
Key Results:
Pretreatment with 5 or 10 mg · kg(-1) of YM-58483 reduced the incidence of CIA, prevented the development of inflammation and pain hypersensitivity and other signs and features of arthritis disease. Similarly, treatment with YM-58483 after the onset of CIA: (i) reversed the clinical scores; (ii) reduced paw oedema; (iii) attenuated mechanical and thermal hypersensitivity; (iv) improved spontaneous motor activity; (v) decreased periphery production of IL-1β, IL-6 and TNF-α; and (vi) reduced spinal activation of ERK and calmodulin-dependent PKII (CaMKIIα).
Conclusions And Implications:
This study provides the first evidence that inhibition of SOC entry prevents and relieves rheumatoid arthritis (RA) and arthritic pain. These effects are probably mediated by a reduction in cytokine levels in the periphery and activation of ERK and CaMKIIα in the spinal cord. These results suggest that SOC channels are potential drug targets for the treatment of RA.
Insights
Inhibiting store-operated calcium (SOC) channels with YM-58483 effectively prevents and treats collagen-induced arthritis (CIA) and associated pain. This suggests SOC channels are promising drug targets for rheumatoid arthritis (RA) treatment.
Area of Science:
- Immunology
- Pharmacology
- Neuroscience
Background:
- Store-operated calcium (SOC) channels are implicated in immune responses, inflammation, and chronic pain.
- Understanding the role of SOC channels in collagen-induced arthritis (CIA) is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role and mechanisms of SOC channels in CIA.
- To evaluate the therapeutic potential of the SOC channel inhibitor YM-58483 in CIA and associated pain.
Main Methods:
- Utilized the CIA mouse model to assess the effects of YM-58483.
- Measured pain sensitivity using Hargreaves' and von Frey hair tests.
- Analyzed cytokine production (ELISA), histological changes (H&E staining), and protein levels (Western blot).
Main Results:
- YM-58483 pretreatment reduced CIA incidence, inflammation, and pain hypersensitivity.
- Post-onset YM-58483 treatment reversed clinical scores, reduced paw edema, and attenuated hypersensitivity.
- YM-58483 decreased peripheral IL-1β, IL-6, TNF-α production and reduced spinal ERK and CaMKIIα activation.
Conclusions:
- Inhibition of SOC channels prevents and alleviates rheumatoid arthritis (RA) and arthritic pain.
- Therapeutic effects are likely mediated by reduced peripheral cytokine levels and spinal ERK/CaMKIIα activation.
- SOC channels represent potential therapeutic targets for RA treatment.
