Role for nitrosative stress in diabetic neuropathy: evidence from studies with a peroxynitrite decomposition catalyst.
Nitrosative stress, that is, enhanced peroxynitrite formation, has been documented in both experimental and clinical diabetic neuropathy (DN), but its pathogenetic role remains unexplored. This study evaluated the role for nitrosative stress in two animal models of type 1 diabetes: streptozotocin-diabetic mice and diabetic NOD mice. Control (C) and streptozotocin-diabetic (D) mice were treated with and without the potent peroxynitrite decomposition catalyst FP15 (5 mg kg(-1) d(-1)) for 1 wk after 8 wk without treatment. Sciatic nerve nitrotyrosine (a marker of peroxynitrite-induced injury) and poly(ADP-ribose) immunoreactivities were present in D and absent in C and D+FP15. FP15 treatment corrected sciatic motor and hind-limb digital sensory nerve conduction deficits and sciatic nerve energy state in D, without affecting those variables in C. Nerve glucose and sorbitol pathway intermediate concentrations were similarly elevated in D and D+FP15 vs C. In diabetic NOD mice, a 7-day treatment with either 1 or 3 mg kg(-1) d(-1) FP15 reversed increased tail-flick latency (a sign of reduced pain sensitivity); the effect of the higher dose was significant as early as 3 days after beginning of the treatment. In conclusion, nitrosative stress plays a major role in DN in, at least, type 1 diabetes. This provides the rationale for development of agents counteracting peroxynitrite formation and promoting peroxynitrite decomposition, and their evaluation in DN.
Obrosova
Irina G
IG
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. obrosoig@pbrc.edu
Mabley
Jon G
JG
Zsengellér
Zsuzsanna
Z
Charniauskaya
Tamara
T
Abatan
Omorodola I
OI
Groves
John T
JT
Szabó
Csaba
C
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003401:Creatine / Q000032:analysis; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000209:etiology / Q000503:physiopathology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010725:Phosphocreatine / Q000032:analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D026361:Reactive Nitrogen Species / Q000502:physiology*; D012584:Sciatic Nerve / Q000737:chemistry / Q000503:physiopathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; D026361:Reactive Nitrogen Species; D010725:Phosphocreatine; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D003401:Creatine