Stabilization of delphinidin in a complex with sulfobutylether-β-cyclodextrin allows for antinociception in inflammatory pain.

Delphinidin (DEL) is a plant-derived antioxidant with clinical potential to treat inflammatory pain but suffers from poor solubility and low bioavailability. AIMS To develop a well-tolerated CD-DEL complex with enhanced bioavailability and to investigate the mechanisms behind its an-tinociceptive effects in a preclinical model of inflammatory pain. RESULTS CD-DEL was highly soluble and stable in aqueous solution and was nontoxic. Systemic administration of CD-DEL reversed mechanical and heat hyperalgesia while its local application into the CFA-induced inflamed paw dose-dependently reduced mechanical hyperalgesia, paw volume, formation of the lipid peroxidation product 4-HNE, and tissue migration of CD68+ macrophages. CD-DEL also directly prevented 4-HNE-induced mechanical hyperalgesia, cold allodynia and an in-crease in the intracellular calcium concentration into TRPA1 expressing cells. Both, 4-HNE- and CFA-induced ROS levels were sensitive to CD-DEL, while its capacity to scavenge su-peroxide anion radicals (IC50: 70 ± 5 µM) was higher than for hydroxyl radicals (IC50: 600 ± 50 µM). Finally, CD-DEL upregulated HO-1 that was prevented by HMOX-1 siRNA in vitro. INNOVATION In vivo application of DEL to treat inflammatory pain is facilitated by complexation with CD. Apart from its antioxidant effects, the CD-DEL has a unique second antioxidative mechanism involving capturing of 4-HNE into the CD cavity followed by displacement and release of the ROS scavenger DEL. CONCLUSION CD-DEL has antinociceptive, antioxidative and anti-inflammatory effects making it a promising formulation for the local treatment of in-flammatory pain.