Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes.

Abstract

Whereas the important role of free radicals in diabetes-associated complications is well established, the contributions of the highly reactive oxidant peroxynitrite have not been properly explored. The present study used a pharmacological approach to evaluate the role of peroxynitrite in peripheral diabetic neuropathy. Control and STZ-diabetic mice were maintained with or without treatment with the potent peroxynitrite decomposition catalyst Fe(III) tetramesitylporphyrin octasulfonate (FeTMPS), at doses of 5 or 10 mg/kg/day in the drinking water for 3 weeks after an initial 3 weeks without treatment. Mice with a 6-week duration of diabetes developed clearly manifest motor (MNCV) and sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall-Sellito test), tactile allodynia (flexible von Frey filament test), and approximately 44% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, grey matter of the spinal cord, and dorsal root ganglion neurons. FeTMPS treatment alleviated or essentially corrected (at a dose of 10 mg/kg/day) MNCV and SNCV deficits, and was associated with less severe small sensory nerve fiber dysfunction and degeneration. Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons in peroxynitrite decomposition catalyst-treated diabetic mice was markedly reduced. In conclusion, peroxynitrite contributes to large motor, large sensory, and small sensory fiber neuropathy in streptozotocin-diabetic mice. The findings provide rationale for development of potent peroxynitrite decomposition catalysts for the treatment of diabetic neuropathy.

• Authors: Viktor R Drel, Pal Pacher, Igor Vareniuk, Ivan A Pavlov, Olga Ilnytska, Valeriy V Lyzogubov, Seth R Bell, John T Groves, Irina G Obrosova
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 20 Issue 6 Pg. 783-92 (Dec 2007) ISSN: 1107-3756 [Print] Greece
• PMID: 17982684 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• 5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III)
• Ferric Compounds
• Metalloporphyrins
• Peroxynitrous Acid
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Behavior, Animal (physiology)
• Diabetes Mellitus, Experimental (metabolism)
• Diabetes Mellitus, Type 1 (complications, metabolism)
• Diabetic Neuropathies (etiology, metabolism)
• Disease Models, Animal
• Ferric Compounds (chemistry, metabolism)
• Humans
• Metalloporphyrins (chemistry, metabolism)
• Mice
• Mice, Inbred C57BL
• Neural Conduction
• Oxidative Stress
• Peroxynitrous Acid (chemistry, metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Sciatic Nerve (metabolism)