Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors

Pharmacol Res. 2015 Dec;102:286-97. doi: 10.1016/j.phrs.2015.10.007. Epub 2015 Oct 28.


Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets.

Keywords: Antinociceptive effect; Antioxidant; Diabetes; Fisetin; GABA(A).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Antioxidants / metabolism*
  • Bicuculline / pharmacology
  • Cyclic N-Oxides / pharmacology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Neuropathies / metabolism*
  • Disease Models, Animal
  • Flavonoids / pharmacology*
  • Flavonols
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / drug therapy*
  • Neuralgia / metabolism
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Receptors, GABA-A / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Streptozocin / pharmacology


  • Analgesics
  • Antioxidants
  • Cyclic N-Oxides
  • Flavonoids
  • Flavonols
  • Reactive Oxygen Species
  • Receptors, GABA-A
  • phenyl-N-tert-butylnitrone
  • Streptozocin
  • fisetin
  • Bicuculline