Part I: Pathogenetic Role of Peroxynitrite in the Development of Diabetes and Diabetic Vascular Complications: Studies With FP15, A Novel Potent Peroxynitrite Decomposition Catalyst

Abstract

Background: Peroxynitrite is a cytotoxic oxidant formed from nitric oxide (NO) and superoxide. Tyrosine nitration, a footprint of peroxynitrite, has been demonstrated in the pancreatic islets as well as in the cardiovascular system of diabetic subjects. Delineation of the pathogenetic role of peroxynitrite in disease conditions requires the use of potent, in vivo active peroxynitrite decomposition catalysts. The aim of the current work was to produce a potent peroxynitrite decomposition catalyst and to test its effects in rodent models of diabetes and its complications. Methods: FP15 was synthesized and analyzed using standard chemical methods. Diabetes was triggered by the administration of streptozotocin. Tyrosine nitration was measured immunohistochemically. Cardiovascular and vascular measurements were conducted according to standard physiologic methods. Results: FP15, a potent porphyrinic peroxynitrite decomposition catalyst, potently

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 ).…”

“…introducing triethyleneglycol moieties was to increase the blood-circulation lifetime (36,313). Yet bulkiness may limit to some extent their access to cells and in turn their efficacy, as observed with protection of SOD-deficient E. coli (36,38,241).…”

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

“…Furthermore, recent findings [27,29] indicate increased formation of peroxynitrite, a product of the reaction between superoxide anion radicals and nitric oxide, in experimental models and human subjects with PDN. Studies with the potent peroxynitrite decomposition catalyst FP15 [30,31] suggest that peroxynitrite is primarily responsible for enhanced poly(ADP-ribosyl)ation in a number of pathological conditions associated with oxidative stress. We have recently found that FP15 administered at the very low dose of 5 mg/kg for one week after two months of untreated STZ-diabetes completely reverses peripheral nerve nitrotyrosine and poly(ADP-ribose) accumulation, as well as MNCV and SNCV deficits of early PDN in the mouse model (I. G. Obrosova and C. Szabó, unpublished).…”