Evaluation of the peroxynitrite decomposition catalyst Fe(III) tetra-mesitylporphyrin octasulfonate on peripheral neuropathy in a mouse model of type 1 diabetes

Abstract

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) tetra-mesitylporphyrin 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 ~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.

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

“…Evidence for the important role of the potent oxidant peroxynitrite, a product of superoxide anion radicals and nitric oxide (6,43), in diabetic complications including endothelial dysfunction (44), peripheral (45)(46)(47)(48) and autonomic (49) neuropathy, and retinopathy (50) is emerging. Peroxynitrite causes multiple cytotoxic effects including lipid peroxidation, protein nitration and nitrosylation, DNA breakage and base modification, impairment of cell signaling, depolarization of mitochondrial membrane, PARP and metalloproteinase activation, and, in extreme cases, necrosis and premature apoptosis (6,43).…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…32 Thermal hypoalgesia is present in a large proportion of patients with advanced PDN. This condition has been described in STZ-diabetic rats with longer-term (Ն12 weeks) diabetes, 19,44 and in a number of diabetic mouse models, including SVEV129ϫC57BL/6, 45 C57Bl/ 6J, 13,14,46,47 Swiss Webster, 48 -50 129S1/SvImJ, 44 and CD1 51 mice made diabetic with STZ, as well as nonobese diabetic (NOD) mice, 52 leptin-deficient (ob/ob) mice, 53,54 and diabetic Akita mice (V.R. Drel and I.G.…”

“…Surprisingly, a number of mechanisms contributing to increased thermal sensitivity in the rat models with relatively short-term duration of diabetes were also implicated in development of thermal hypoalgesia in rats with diabetes of longer duration or diabetic mice. Those include increased AR activity, 19 activation of the AGE/ RAGE axis, 25,45,48 and oxidative-nitrosative stress, 13,14,47,53 as well as activation of ACE 22,61 and PARP. 12,44 Several studies, including one identifying an important role of insulin signaling, 51 implicate neurotrophic factor deficiency in diabetes-induced thermal sensory loss.…”

“…The tail-flick and hotplate tests are less sensitive in detecting thermal hyperor hypoalgesia and effects of experimental therapies in diabetic rats and mice. [12][13][14] In general, the hot-plate test is seldom used in diabetic rat studies, although it has been sensitive enough to demonstrate thermal hyperalgesia in several studies. 15,16 Thermal hyperalgesia has been registered in some patients with mild PDN, whereas advanced-stage disease is typically characterized by elevated thermal perception thresholds (hypoalgesia) that progress to sensory loss, occurring in conjunction with unmyelinated peripheral nerve fiber degeneration.…”

“…Thermal hypoalgesia in STZ-diabetic rats and ob/ob mice was prevented or alleviated by AR inhibitors. 19,53 A number of pharmacological agents increased or normalized thermal response latencies in STZ-diabetic rats and mice: peroxynitrite decomposition catalysts, 13,46 the PARP inhibitor…”