Anti-arthritic efficacy of geraniol and methotrexate via miRNA-driven NLRP3 inflammasome suppression in rat adjuvant-induced arthritis

Abstract

OBJECTIVE: Geraniol (GO), a traditional plant-derived medicine, has demonstrated anti-osteoclastogenic properties that preserve bone integrity and inhibit bone resorption. This study aimed to evaluate the effect of GO in the adjuvant arthritis rat model, alone and combined with methotrexate (MX), with emphasis on miR-124 and miR-30a effect on the inflammasome (NLRP3)-related disease progression pathways. METHODS: Fourteen days post-adjuvant injection, male Sprague-Dawley rats were treated with methotrexate (MX, 1 mg/kg/week), low-dose GO (100 mg/kg/day), high-dose GO (200 mg/kg/day), or a combination of MX and high-dose GO for 14 days. Arthritis progression was assessed using the arthrogram score and hind paw swelling. Tibiotarsal joint tissue was analyzed for inflammatory and autophagy markers, angiogenic factors, miR-124, and miR-30a. Radiological and histopathological examination of the ankle joint was performed, as well as immunohistochemistry for NLRP3. RESULTS: Increased hind paw swelling and changes in radiological and histopathological characteristics confirmed the development of AA. Biochemical analysis of synovial tissue revealed decreased expression of miR-124 and miR-30a, accompanied by increased NLRP3 expression, as well as enhanced autophagy, angiogenesis, and inflammatory markers. Geraniol, in a dose-dependent manner, could reverse inflammatory parameters without any significant toxicological signs. CONCLUSION: These findings suggest that GO modulates the NLRP3 pathway through miRNA regulation. The synergistic effect of the GO and MX combination uncovers a novel therapeutic strategy in RA.