Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes.
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.
Drel
Viktor R
VR
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
Pacher
Pal
P
Vareniuk
Igor
I
Pavlov
Ivan A
IA
Ilnytska
Olga
O
Lyzogubov
Valeriy V
VV
Bell
Seth R
SR
Groves
John T
JT
Obrosova
Irina G
IG
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000737:chemistry / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism
C112917:5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III); D005290:Ferric Compounds; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D011065:Poly(ADP-ribose) Polymerases