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Intra-articular AMPA/kainate glutamate receptor antagonists alleviate inflammation, pain and pathology in rat antigen induced arthritis [Abstract]

Bonnet, C. S., Williams, Anwen Sian, Moideen, A. N., Nowell, Mari Ann and Mason, Deborah Jane 2011. Intra-articular AMPA/kainate glutamate receptor antagonists alleviate inflammation, pain and pathology in rat antigen induced arthritis [Abstract]. International Journal of Experimental Pathology 92 (6) , A14-A14. 10.1111/j.1365-2613.2011.00780.x

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Introduction: Concentrations of the neurotransmitter glutamate are greatly increased in synovial fluids of RA and OA patients, where they correlate with cytokine concentrations. Previously, we demonstrated that human synoviocytes express functional glutamate receptors (GluRs) and that activation of NMDA GluRs decreases proMMP2 expression, whilst activation of kainate GluRs increases IL-6 release (Flood et al. 2007). High glutamate concentrations in the joint cause arthritic pain which is alleviated by intra-articular injection of GluR antagonists. However, the effects of such inhibitors on arthritis progression via GluRs on other joint tissues have not been considered. We are investigating the hypothesis that specific GluR subunits in the arthritic synovium mediate proinflammatory, degradative and proliferative responses, and may be therapeutically targeted to reduce disease rogression and pain. Materials and Methods: Using the mono-articular antigen induced arthritis (AIA) rat model, we used intra-articular injection of NBQX to inhibit AMPA/kainate receptors at the time of arthritis induction, prior to peak IL-6 levels. Over a 21 day period, we measured knee swelling and gait patterns from AIA, AIA + NBQX and normal rats (n = 6 per group). A combination of motion analysis, using Qualisys Pro-Reflex MCU-1000 cameras, and footprint characteristics revealed limping and abnormal movements as an indirect measure of pain. On day 21, joint tissues were taken for reverse transcription PCR, x-ray, immunohistochemistry and histology to examine GluR expression and joint destruction. Results: Less knee swelling (ANOVA with Fisher’s post hoc test, P < 0.0006) was found in NBQX treated rats compared to AIA rats. Using footprints to indicate abnormal loading and movements, NBQX treated rats displayed less pain related behaviour during the initial flare of arthritis compared to AIA rats (Mann–Whitney test, P = 0.0002). Radiological pathology appeared reduced in NBQX rats compared to AIA rats (8.33 and 12, mean x-ray erosion/osteophyte score respectively). Ionotropic and metabotropic GluRs mRNA was differentially expressed in cartilage, synovium, meniscus,fat pad, patella, femoral head and shaft of rat knees. Discussion: We have shown that intra-articular NBQX treatment alleviates inflammation, pain and pathology in arthritis in vivo and that GluRs are differentially expressed in knee joint tissues. This supports our hypothesis that kainate GluRs may be specifically targeted to ease pain, inflammation and pathology in arthritis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RB Pathology
Publisher: Wiley-Blackwell
ISSN: 0959-9673
Last Modified: 13 Aug 2018 20:32

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