Theobromine as a multi-target therapeutic agent: Analgesic, anti-inflammatory, and anti-arthritic potential with network pharmacology insights.

Abstract

Objective: Inflammatory disorders, including rheumatoid arthritis (RA) and osteoarthritis, contribute significantly to global health burdens. Theobromine, a xanthine alkaloid present in cocoa, has pharmacological properties with potential therapeutic benefits in inflammatory conditions. Nonetheless, its analgesic and anti-inflammatory attributes remained underexplored.

Materials and methods: Analgesic, anti-arthritic and anti-inflammatory efficacy of theobromine was evaluated via experimental models, alongside network pharmacology to understand its molecular mechanisms. Theobromine's effects were assessed in multiple models: acetic acid-induced writhing, tail immersion, and formalin tests to evaluate analgesia; carrageenan- and egg albumin-induced paw edema models for anti-inflammatory activity; and protein denaturation and human red blood cell (HRBC) membrane stabilization for anti-arthritic effects. Network pharmacology was utilized to identify molecular targets and pathways, including KEGG pathway enrichment analysis.

Results: Theobromine exhibited significant analgesic effects, reducing writhing behavior by 42.71% at 200mg/kg, and increasing tail-flick latency. Theobromine significantly lowered pain during both early as well as late phase of formalin test. Inflammation was notably reduced in both egg albumin and carrageenan inflammatory models. Theobromine also demonstrated anti-arthritic properties, inhibiting protein denaturation and stabilizing HRBC membranes. Network pharmacology revealed key targets such as COX-2, TNF-α, and NF-kB, implicated in inflammation and immune responses.

Conclusion: Theobromine exhibits significant analgesic, anti-inflammatory, and anti-arthritic effects. Network pharmacology provides insights into its molecular mechanisms, suggesting its promise as a therapeutic modality for inflammatory disorders.