title: A store-operated calcium channel inhibitor attenuates collagen-induced arthritis.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.|Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors: X H
authors: XH
authors: Gao
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: R
authors: R
authors: Gao
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: Y Z
authors: YZ
authors: Tian
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: P
authors: P
authors: McGonigle
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: J E
authors: JE
authors: Barrett
authors: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
authors: Y
authors: Y
authors: Dai
authors: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: H
authors: H
authors: Hu
mesh_terms: D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D003094:Collagen / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D013830:Thiadiazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D002121:Calcium Channel Blockers; D016207:Cytokines; D013830:Thiadiazoles; D003094:Collagen
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