COX-2: Cyclooxygenase-2

COX-2 (Cyclooxygenase-2) is an inducible enzyme (vs constitutive COX-1) that catalyzes the conversion of arachidonic acid into pro-inflammatory prostaglandins (PGE2, PGI2). It is a target of selective NSAIDs (celecoxib, etoricoxib) and numerous natural inhibitors such as [6]-gingerol and curcumin.

Characteristics

• Inducible by TNF-α, IL-1β, LPS, NF-kB
• Lowly expressed at rest, highly expressed during inflammation
• Target of Coxibs (selective anti-inflammatory drugs)
• Localization: epithelial cells, fibroblasts, macrophages, neurons

Prostaglandin cascade

1. Phospholipase A2 releases arachidonic acid from membrane phospholipids
2. COX-2 converts AA into PGG2 then PGH2
3. PGH2 is then transformed into PGE2 (pain, fever, inflammation), PGI2 (vasodilation), TXA2 (platelet aggregation)

Pathologies involving hyperactivated COX-2

• Osteoarthritis and rheumatoid arthritis
• Chronic tendinopathies
• Chronic migraines
• Endometriosis (PGE2 in pelvic pain)
• Colorectal cancer (promoting role)

Natural inhibitors

• [6]-gingerol: documented COX-2 inhibition — partial equivalent of NSAIDs without major gastric toxicity
• Curcumin: potent COX-2 inhibition
• Boswellia serrata (frankincense)
• Omega-3 EPA: substrate competition with arachidonic acid

Advantage of ginger vs NSAIDs

Classic NSAIDs (ibuprofen, diclofenac) inhibit both COX-1 AND COX-2 → gastric toxicity. Coxibs are COX-2 selective but have cardiovascular toxicity (rofecoxib withdrawn from the market). Gingerol inhibits COX-2 with a better tolerance profile.

COX-2 and INTI

Inhibition of COX-2 is one of INTI's pain-relieving mechanisms, without the gastric risk of NSAIDs. Documented effect equivalent to 200mg of ibuprofen for osteoarthritis pain in some studies.