Topical Fluoxetine as a Novel Therapeutic That Improves Wound Healing in Diabetic Mice

Diabetes. 2019 Jul;68(7):1499-1507. doi: 10.2337/db18-1146. Epub 2019 May 2.


Diabetic foot ulcers represent a significant source of morbidity in the U.S., with rapidly escalating costs to the health care system. Multiple pathophysiological disturbances converge to result in delayed epithelialization and persistent inflammation. Serotonin (5-hydroxytryptamine [5-HT]) and the selective serotonin reuptake inhibitor fluoxetine (FLX) have both been shown to have immunomodulatory effects. Here we extend their utility as a therapeutic alternative for nonhealing diabetic wounds by demonstrating their ability to interact with multiple pathways involved in wound healing. We show that topically applied FLX improves cutaneous wound healing in vivo. Mechanistically, we demonstrate that FLX not only increases keratinocyte migration but also shifts the local immune milieu toward a less inflammatory phenotype in vivo without altering behavior. By targeting the serotonin pathway in wound healing, we demonstrate the potential of repurposing FLX as a safe topical for the challenging clinical problem of diabetic wounds.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Foot / drug therapy
  • Diabetic Foot / metabolism
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Fluoxetine / therapeutic use*
  • Humans
  • Male
  • Mice
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / drug effects
  • Skin / metabolism
  • Wound Healing / drug effects


  • Fluoxetine