Eucalyptol Ameliorates Neuroendocrine Stress-Aggravated Rheumatoid Arthritis Through Anti-inflammatory, Antioxidant,...

Rheumatoid arthritis (RA) is a lingering autoimmune disorder typified by synovial inflammation, oxidative imbalance, and advanced articular damage. Psychological and physical stress are known to exacerbate disease progression by enhancing inflammatory signaling and disrupting redox homeostasis. Although methotrexate remains a first-line therapy, its long-term use is accompanied by adverse effects, necessitating safer adjunctive strategies. Eucalyptol (1,8-cineole), a naturally occurring monoterpene, has demonstrated anti-inflammatory and antioxidant potential; however, its role in stress-aggravated RA remains inadequately explored.

To evaluate the protective effects of eucalyptol in restraint stress-augmented Complete Freund's Adjuvant (CFA)-induced arthritis and to investigate its underlying mechanisms, both as monotherapy and in combination with methotrexate.

Experimental arthritis was induced in Wistar rats using CFA, followed by chronic restraint stress for 28 days. Animals were treated with eucalyptol (50, 100, or 200 mg/kg), methotrexate (1 mg/kg), or their combination. Disease progression was assessed using clinical scoring, functional parameters, biochemical assays, cytokine profiling, nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathway analysis, gene expression studies, and histopathological evaluation.

Restraint stress significantly aggravated arthritic severity, resulting in increased oxidative and nitrosative stress, elevated pro-inflammatory cytokines, activation of NF-κB/MAPK signaling, and enhanced joint damage. Eucalyptol treatment produced significant dose-dependent improvements across these parameters. Notably, it reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels while restoring antioxidant defenses. Combination therapy demonstrated the most pronounced therapeutic effect, with near normalization of multiple disease indicators.

Eucalyptol attenuates stress-exacerbated RA through integrated anti-inflammatory and antioxidant mechanisms. Its enhanced efficacy in combination with methotrexate highlights its potential as a complementary therapeutic strategy in RA management. Serum NF-κB and MAPK levels were used as surrogate markers of pathway involvement.