Role for nitrosative stress in diabetic neuropathy: evidence from studies with a peroxynitrite decomposition catalyst

Abstract

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.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Reports on both toxic and protective effects of Fe porphyrins have been published (30,231,238,313). Although the corresponding Fe and Mn porphyrins have very similar rate constants for O 2 ·À dismutation, all Fe porphyrins studied by us thus far were toxic to Escherichia coli; no aerobic growth was detected in SOD-negative mutants with Fe porphyrins at levels at which analogous Mn porphyrins were fully protective (30).…”

“…We and several other groups worked extensively on in vitro and in vivo studies of Fe porphyrins as SOD mimics and ONOO -À scavengers (17,30,45,76,91,126,169,170,184,185,197,211,229,231,232,238,239,309,310,313). The k cat for O 2 ·À dismutation, as well as for ONOO À reduction, is very similar for Fe and Mn analogues (184,185,310) (Table 1).…”

“…Ortho isomers of Fe(III) substituted pyridylporphyrins. Groves et al (45,126,197,211,231,232,238,313) synthesized and used in different animal models Fe analogues of ortho quaternized N-pyridylporphyrins as ONOO À scavengers. Two of those have frequently been studied: the triethyleneglycolated FP-15 and the WW-85 that bears pyridyl benzoate substituents (-CH 2 -C 6 H 4 COO À ).…”

Nitrative stress and poly(ADP-ribose) polymerase activation in healthy and gestational diabetic pregnancies

“…Systemic hyperglycaemia triggers the generation of various reactive oxygen and nitrogen species, such as peroxynitrite, which is formed by the reaction of superoxide and nitric oxide [14,15]. Nitration of protein tyrosine residues is one of the typical biochemical reactions induced by peroxynitrite.…”

“…However, its overactivation leads to cellular dysfunction and necrotic cell death [14,[16][17][18]. In addition, PARP activation also leads to the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus, inducing apoptotic pathways [15]. Since oxidative stress is already increased during pregnancy, its contribution to GDM-derived cardiovascular complications is difficult to determine.…”