A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

• Published in: European journal of pharmacology Vol. 569; no. 1; pp. 48 - 58
• Main Authors: Drel, Viktor R., Pacher, Pal, Vareniuk, Igor, Pavlov, Ivan, Ilnytska, Olga, Lyzogubov, Valeriy V., Tibrewala, Jyoti, Groves, John T., Obrosova, Irina G.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 13-08-2007; Elsevier
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Body Weight - drug effects; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - etiology; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - prevention & control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fluorescent Antibody Technique; Hot Temperature; Hyperalgesia - etiology; Hyperalgesia - prevention & control; Immunohistochemistry; Intraepidermal nerve fiber loss; Male; Medical sciences; Metalloporphyrins - metabolism; Metalloporphyrins - pharmacology; Metalloporphyrins - therapeutic use; Mice; Mice, Inbred C57BL; Nerve Fibers - drug effects; Nerve Fibers - metabolism; Nerve Fibers - pathology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Nitrosative stress; Pain Threshold - drug effects; Peroxynitrite decomposition catalyst; Peroxynitrous Acid - metabolism; Pharmacology. Drug treatments; Poly Adenosine Diphosphate Ribose - metabolism; Poly(ADP-ribose) polymerase; Reaction Time - drug effects; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; Sciatic Nerve - pathology; Spinal Nerve Roots - drug effects; Spinal Nerve Roots - metabolism; Spinal Nerve Roots - pathology; Streptozocin; Tactile allodynia; Thermal hypoalgesia; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Poly(ADP-ribose) polymerase; Tactile allodynia; Thermal hypoalgesia; Peroxynitrite decomposition catalyst; Intraepidermal nerve fiber loss; Nitrosative stress; Endocrinopathy; Antineoplastic agent; Glycosyltransferases; Neuropathy; ADP-ribosyltransferase; Nerve fiber; Streptozotocin; Allodynia; Nervous system diseases; Enzyme; Transferases; Diabetes mellitus; Rodentia; Stress; NAD; Vertebrata; Antibiotic; Mammalia; Mouse; Animal; Pentosyltransferases
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.05.055

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 ∼
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 ∼
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.