Michael K. Stern

Evidence of peroxynitrite involvement in the carrageenan-induced rat paw edema

The role of peroxynitrite generated from nitric oxide and superoxide anion was investigated in a model of acute inflammation induced by the injection of carrageenan into the rat hind paw. Paw edema was inhibited 8 h following the administration of carrageenan by N-iminoethyl-L-lysine (3-30 mg/kg, n = 6) or aminoguanidine (30-300 mg/kg, n = 6), two selective inhibitors of inducible nitric oxide synthase and by recombinant human Cu/Zn superoxide dismutase coupled to polyethyleneglycol (12 x 10(3) U/kg, n = 6, P < 0.001). Moreover, at the same time point following carrageenan administration, intense immunoreactive staining for nitrotyrosine (a marker of peroxynitrite formation) was detected. Our results suggest that the generation of nitric oxide, superoxide anion and peroxynitrite contributes to the edema observed in this acute model of inflammation.

Evidence for the production of peroxynitrite in inflammatory CNS demyelination

Peroxynitrite, which is generated by the reaction of nitric oxide (NO) with superoxide, is a strong oxidant that can damage subcellular organelles, membranes and enzymes through its actions on proteins, lipids, and DNA, including the nitration of tyrosine residues of proteins. Detection of nitrotyrosine (NT) serves as a biochemical marker of peroxynitrite-induced damage. In the present studies, NT was detected by immunohistochemistry in CNS tissues from mice with acute experimental autoimmune encephalomyelitis (EAE). NT immunoreactivity was displayed by many mononuclear inflammatory cells, including CD4+ cells. It was also observed in astrocytes near EAE lesions. Immunostaining for the inducible isoform of NO synthase (iNOS) was also observed, particularly during acute EAE. These data strongly suggest that peroxynitrite formation is a major consequence of NO produced via iNOS, and implicate this powerful oxidant in the pathogenesis of EAE.

A catalyst of peroxynitrite decomposition inhibits murine experimental autoimmune encephalomyelitis

Peroxynitrite (PN), the product of nitric oxide (NO) reacted with superoxide, is generated at sites of inflammation. Nitrotyrosine (NT), a marker of PN formation, is abundant in lesions of acute experimental autoimmune encephalomyelitis (EAE), and in active multiple sclerosis (MS) plaques. To determine whether PN plays a role in EAE pathogenesis, mice induced to develop EAE were treated with a catalyst specific for the decomposition of PN. Because this catalyst has no effect upon NO, using it allowed differentiation of PN-mediated effects from NO-mediated effects. Mice receiving the PN decomposition catalyst displayed less severe clinical disease, and less inflammation and demyelination than control mice. Encephalitogenic T cells could be recovered from catalyst-treated mice, indicating that the PN decomposition catalyst blocked the pathogenic action of PN at the effector stage of EAE, but was not directly toxic to encephalitogenic T cells. PN plays an important role distinct from that of NO in the pathogenesis of EAE, a major model for MS.

Industrial Perspectives on the use of Dioxygen: New Technology to Solve Old Problems

The selective catalytic oxidation of organic molecules continues as a very important reaction pathway for the synthesis of primary and specialty chemicals in the chemical industry worldwide. Catalytic utilization of molecular oxygen using both soluble metal compounds in liquid reaction media (homogeneous catalysis) and the surfaces of metals or metal oxide compounds in gas or liquid reaction media (heterogeneous catalysis) is very important today, and will become even more important in the future as worldwide environmental policies become more stringent. This will necessitate the development of new “no-waste” technologies which will provide economically viable syntheses of molecules of commercial importance. Clearly, selective catalytic oxidation with O2 represents critical technology and will be an area in which continued research and technical breakthroughs will be required.

The Synthesis and Chemistry of Formylphosphonate

New methods of synthesis and reactions of formylphosphonate have been investigated. Attempts to deprotect the corresponding diethyl acetal with TiIV halides led instead to the formation of halo(ethoxy)methylphosphonates which undergo substitution reactions with a wide range of nucleophiles. The products of reactions of formylphosphonate with bifunctional nucleophiles are determined in most cases by Baldwins Rules, while the imines derived from formylphosphonate undergo Diels-Alder reactions only in those cases which carry a strongly electron-withdrawing N-substitutent.