Abstract
Rheumatoid arthritis (RA) is a painful chronic autoimmune disease affecting the joints. Its first-line therapy, Methotrexate (MTX), although effective in ameliorating the progress of the disease, induces hepatotoxicity over long-term usage. Thus, seeking natural compounds with fewer side effects could be an alternative therapeutic approach. This study aimed to investigate the anti-inflammatory, antiarthritic, and antioxidative effects of synthetic trans-Δ9-tetrahydrocannabinol (Δ9-THC) dissolved in sesame oil (Dronabinol) against MTX in adjuvant-induced arthritis (AIA) rat model. Daily oral administration of Δ9-THC/sesame oil, over a period of 21 days, was well tolerated in arthritic rats with no particular psychoactive side effects. It markedly attenuated the severity of clinical manifestations, recovered the histopathological changes in tibiotarsal joints, and repressed the splenomegaly in arthritic rats. Δ9-THC/sesame oil therapy showed similar effects to MTX in neutralizing the inflammatory process of AIA, through attenuating erythrocyte sedimentation rate (ESR) scores and proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and interleukin-6 (IL-6) levels, to normal values. As opposed to MTX, this natural combination markedly protected the liver of arthritic rats and downregulated the induced oxidative stress by increasing the antioxidant defense system such as activities of catalase and superoxide dismutase (SOD) and levels of glutathione (GSH). These results suggest promising effects for the clinical use of Δ9-THC/sesame oil therapy in alleviating arthritic clinical signs as well as arthritis-induced liver injury.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that attacks the synovial lining of diarthrodial joints and causes formation of pannus tissue
Two days following complete Freund's adjuvant (CFA) challenge, rats were randomly assigned into four adjuvant-induced arthritis (AIA) groups where each group consisted of eight rats (n=8): untreated control AIA group; AIA group treated with MTX (0.75mg/kg/week) for 21 days, intraperitoneally (Sigma-Aldrich Co, USA) [30]; AIA group treated with Dronabinol (Δ9-THC/sesame oil, 2.5mg/kg/daily) for 21 days, by diet (Dronabinol, Watson Laboratories, USA); and AIA group treated with equivalent volumes of sesame oil for 21 days, by diet
superoxide dismutase (SOD) activity in Δ9-THC/sesame oil-treated group were found to be significantly higher than those in sesame oil-treated AIA group, suggesting a better antioxidative activity of Δ9-THC on liver tissue (Figure 6(c)). This is the first study to present a potential therapeutic value of Dronabinol (Δ9-THC/sesame oil) on RA by demonstrating its anti-inflammatory and antiarthritic effects on AIA rat model and its protective impact on the oxidative stress produced by the disease itself
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that attacks the synovial lining of diarthrodial joints and causes formation of pannus tissue. This tissue is known to expand and invade the cartilage and bone, eventually damaging them and leading to physical disabilities such as the loss of articular function [1, 2]. Besides having local effects on the synovial microenvironment where they are released, these cytokines can reach systemic circulation and mediate inflammatory responses in other organs They stimulate phagocytic cells to produce reactive oxygen species (ROS), which mediate tissue injury in RA. Excessive production of free radicals in arthritic animals and RA patients is associated with a stimulated prooxidant system and a deficient antioxidative defense system, leading to oxidative stress and lipid peroxidation that damage the synovium, and other organs such as the liver [5,6,7,8,9,10,11]
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