Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy

Diabetes Metab Res Rev. 2014 Nov;30(8):669-78. doi: 10.1002/dmrr.2549.


Background: Peroxynitrite, a product of the reaction of superoxide with nitric oxide, causes oxidative stress with concomitant inactivation of enzymes, poly(ADP-ribosylation), mitochondrial dysfunction and impaired stress signalling, as well as protein nitration. In this study, we sought to determine the effect of preventing protein nitration or increasing peroxynitrite decomposition on diabetic neuropathy in mice after an extended period of untreated diabetes.

Methods: C57Bl6/J male control and diabetic mice were treated with the peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS, 10 mg/kg/day) or protein nitration inhibitor (-)-epicatechin gallate (20 mg/kg/day) for 4 weeks, after an initial 28 weeks of hyperglycaemia.

Results: Untreated diabetic mice developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and loss of intraepidermal nerve fibres. Both FeTMPS and epicatechin gallate partially corrected sensory nerve conduction slowing and small sensory nerve fibre dysfunction without alleviation of hyperglycaemia. Correction of motor nerve conduction deficit and increase in intraepidermal nerve fibre density were found with FeTMPS treatment only.

Conclusions: Peroxynitrite injury and protein nitration are implicated in the development of diabetic peripheral neuropathy. The findings indicate that both structural and functional changes of chronic diabetic peripheral neuropathy can be reversed and provide rationale for the development of a new generation of antioxidants and peroxynitrite decomposition catalysts for treatment of diabetic peripheral neuropathy.

Keywords: antioxidants; diabetic neuropathy; nitrosative stress; oxidative stress; peroxynitrite; superoxide.

Publication types

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

MeSH terms

  • Animals
  • Antioxidants / adverse effects
  • Antioxidants / therapeutic use
  • Behavior, Animal / drug effects
  • Catechin / adverse effects
  • Catechin / analogs & derivatives
  • Catechin / therapeutic use
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetic Neuropathies / metabolism*
  • Diabetic Neuropathies / pathology
  • Diabetic Neuropathies / physiopathology
  • Diabetic Neuropathies / prevention & control
  • Epidermis / drug effects
  • Epidermis / innervation*
  • Epidermis / metabolism
  • Epidermis / pathology
  • Ferric Compounds / adverse effects
  • Ferric Compounds / therapeutic use
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Male
  • Metalloporphyrins / adverse effects
  • Metalloporphyrins / therapeutic use
  • Mice, Inbred C57BL
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Nerve Tissue Proteins / metabolism*
  • Neural Conduction / drug effects
  • Oxidative Stress / drug effects
  • Peripheral Nervous System / drug effects
  • Peripheral Nervous System / metabolism*
  • Peripheral Nervous System / pathology
  • Peripheral Nervous System / physiopathology
  • Peroxynitrous Acid / antagonists & inhibitors
  • Peroxynitrous Acid / metabolism*
  • Reaction Time / drug effects
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Sensory Receptor Cells / pathology


  • 5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III)
  • Antioxidants
  • Ferric Compounds
  • Metalloporphyrins
  • Nerve Tissue Proteins
  • Peroxynitrous Acid
  • Catechin
  • epicatechin gallate