A store-operated calcium channel inhibitor attenuates collagen-induced arthritis

作者：Gao, X. H.; Gao, R.; Tian, Y. Z.; McGonigle, P.; Barrett, J. E.; Dai, Y.; Hu, H.^*

来源：British Journal of Pharmacology, 2015, 172(12): 2991-3002.

DOI：10.1111/bph.13104

• ACTIVATED CA2+ CHANNELS
• KINASE-II CONTRIBUTES
• NECROSIS-FACTOR-ALPHA
• RHEUMATOID-ARTHRITIS
• CENTRAL SENSITIZATION
• CYTOKINE PRODUCTION
• CELL-ACTIVATION
• PERSISTENT PAIN
• PROTEIN-KINASE
• ENTRY BLOCKER

Background and PurposeStore-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 ApproachThe 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 ResultsPretreatment with 5 or 10mgkg(-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-1, IL-6 and TNF-; and (vi) reduced spinal activation of ERK and calmodulin-dependent PKII (CaMKII).
Conclusions and ImplicationsThis 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 CaMKII in the spinal cord. These results suggest that SOC channels are potential drug targets for the treatment of RA.

• 出版日期2015-6
• 单位中国药科大学