A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice.
Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type 1 diabetes. In this study the role of nitrosative stress in diabetic sensory neuropathy is evaluated. The peroxynitrite decomposition catalyst Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin (FP15) was administered to control and streptozotocin (STZ)-diabetic mice at the dose of 5 mg kg(-1) day(-1) (FP15), for 3 weeks after initial 3 weeks without treatment. Mice with 6-week duration of diabetes developed clearly manifest 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 38% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, grey matter of spinal cord, and dorsal root ganglion neurons. FP15 treatment was associated with alleviation of thermal and mechanical hypoalgesia. Tactile response threshold tended to increase in response to peroxynitrite decomposition catalyst treatment, but still remained approximately 59% lower compared with non-diabetic controls. Intraepidermal nerve fiber density was 25% higher in FP15-treated than in untreated diabetic rats, but the difference between two groups did not achieve statistical significance (p=0.054). Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons of peroxynitrite decomposition catalyst-treated diabetic mice were markedly reduced. In conclusion, nitrosative stress plays an important role in sensory neuropathy associated with Type 1 diabetes. The findings provide rationale for further studies of peroxynitrite decomposition catalysts in a long-term diabetic model.
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
I
Ilnytska
Olga
O
Lyzogubov
Valeriy V
VV
Tibrewala
Jyoti
J
Groves
John T
JT
Obrosova
Irina G
IG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005455:Fluorescent Antibody Technique; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D008665:Metalloporphyrins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; D013311:Streptozocin