ATTENUATION OF PAIN AND INFLAMMATION IN ADJUVANT-INDUCED ARTHRITIS BY SELECTIVE INHIBITION OF PROTEASOME

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology. In RA, inflammation and pain are initial symptoms followed by bone and cartilage destruction. Proinflammatory cytokines play a significant role in the initiation and progress of inflammation and tissue destruction. Sensory neuropeptide substance P (SP) participates not only in nociception but also in pro-inflammatory processes by enhancing vasodilatation and recruitment of inflammatory cells. Ubiquitin proteasome system (UPS) activates a transcription factor, NF-κB which regulates the synthesis of proinflammatory mediators like cytokines; however its role in regulating pro inflammatory sensory neuropeptides is unknown. A number of proteasome inhibitors have been shown to down regulate the activity of NF-κB and hence reduce inflammation. In the present study, the effect of proteasome inhibitor (MG 132) on the severity of arthritis and pain was observed along with the expression of SP-positive nerve fibres in the ankle joint in a chronic inflammatory model of rat adjuvant arthritis.

Histology and mechanical pain tests showed a significant reduction in inflammation and pain in ankle joint by daily administration of proteasome inhibitor MG132 at the dose of 1mg/kg body weight compared to untreated groups. Radiographic analysis of ankle joints indicated a reduction in soft tissue swelling and joint destruction in the treatment group. A marked reduction in the NF-κB activity was observed by EMSA. Furthermore, proteasome inhibition resulted in the normalization of up regulated neuronal response occurred during inflammation by significantly reducing the expression of SP-positive fibres in the ankle joint as demonstrated by immunohistochemistry.

Our data provide the evidence that proteasome inhibitor MG132 can reduce severity of arthritis and reverse inflammatory pain behaviour by influencing the peripheral sensory nervous system. The drugs targeting UPS can be developed for treatment of chronic inflammatory joint disorders.