1. Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.
- Author
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Zhao X, Li XL, Liu X, Wang C, Zhou DS, Ma Q, Zhou WH, and Hu ZY
- Subjects
- Animals, Bicuculline pharmacology, Cyclic N-Oxides pharmacology, Diabetes Mellitus, Experimental metabolism, Disease Models, Animal, Flavonols, Ganglia, Spinal drug effects, Ganglia, Spinal metabolism, Hyperalgesia drug therapy, Hyperalgesia metabolism, Male, Mice, Mice, Inbred C57BL, Neuralgia metabolism, Oxidative Stress drug effects, Reactive Oxygen Species metabolism, Spinal Cord drug effects, Spinal Cord metabolism, Streptozocin pharmacology, Analgesics pharmacology, Antioxidants metabolism, Diabetic Neuropathies metabolism, Flavonoids pharmacology, Neuralgia drug therapy, Receptors, GABA-A metabolism
- Abstract
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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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