Stabilization of Delphinidin in Complex with Sulfobutylether-β-Cyclodextrin Allows for Antinociception in Inflammatory Pain

Antioxid Redox Signal. 2021 Jun 1;34(16):1260-1279. doi: 10.1089/ars.2019.7957. Epub 2020 Nov 9.


Aims: Delphinidin (DEL) is a plant-derived antioxidant with clinical potential to treat inflammatory pain but suffers from poor solubility and low bioavailability. The aim of the study was to develop a well-tolerated cyclodextrin (CD)-DEL complex with enhanced bioavailability and to investigate the mechanisms behind its antinociceptive 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 complete Freund's adjuvant (CFA)-induced inflamed paw dose-dependently reduced mechanical hyperalgesia, paw volume, formation of the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE), and tissue migration of CD68+ macrophages. CD-DEL also directly prevented 4-HNE-induced mechanical hyperalgesia, cold allodynia, and an increase in the intracellular calcium concentration into transient receptor potential ankyrin 1 expressing cells. Both 4-HNE- and CFA-induced reactive oxygen species (ROS) levels were sensitive to CD-DEL, while its capacity to scavenge superoxide anion radicals (inhibitory concentration 50 [IC50]: 70 ± 5 μM) was higher than that observed for hydroxyl radicals (IC50: 600 ± 50 μM). Finally, CD-DEL upregulated heme oxygenase 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 inflammatory pain.

Keywords: 4-HNE; ROS; antinociception; cyclodextrins; delphinidin; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism
  • Animals
  • Anthocyanins / administration & dosage*
  • Anthocyanins / chemistry
  • Anthocyanins / pharmacology
  • Anti-Inflammatory Agents / administration & dosage*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Calcium / metabolism
  • Disease Models, Animal
  • Drug Stability
  • Freund's Adjuvant / adverse effects
  • HEK293 Cells
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / metabolism
  • Male
  • Rats
  • TRPA1 Cation Channel / genetics
  • TRPA1 Cation Channel / metabolism
  • beta-Cyclodextrins / chemistry*


  • Aldehydes
  • Anthocyanins
  • Anti-Inflammatory Agents
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • beta-Cyclodextrins
  • SBE4-beta-cyclodextrin
  • Freund's Adjuvant
  • delphinidin
  • 4-hydroxy-2-nonenal
  • Calcium