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D P Riley

Publications and source records attributed to D P Riley.

At least 19 recordsLinked to original sources
PubMed2001

Protective effects of M40403, a superoxide dismutase mimetic, in a rodent model of colitis.

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of the present study was to examine the effects of M40403, a superoxide dismutase mimetic, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). Rats experienced bloody diarrhoea and significant loss of body weight. At 4 days after TNBS administration, the colon damage was characterised by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and expression of P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase showed an intense staining in the inflamed colon. Treatment with M40403 (5 mg/kg daily i.p.) significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture as well as a significant reduction of colonic myeloperoxidase activity and malondialdehyde levels. M40403 also reduced the appearance of nitrotyrosine and poly (ADP-ribose) synthetase immunoreactivity in the colon as well as reduced the up-regulation of ICAM-1 and the expression of P-selectin. The results of this study suggested that administration of a superoxide dismutase mimetic may be beneficial for treatment of inflammatory bowel disease.

Animals↗
PubMed2001

Computer-aided design (CAD) of Mn(II) complexes: superoxide dismutase mimetics with catalytic activity exceeding the native enzyme.

New Mn(II) macrocyclic pentaamine complexes derived from the biscyclohexyl-pyridine complex, M40403 ([manganese(II)dichloro[(4R,9R,14R,19R)-3,10,13,20,26-pentaazatetracyclo[20.3.1.0.(4,9)0(14,19)]hexacosa-1(26),-22(23),24-triene]]), are described here. The complex M40403 was previously shown to be a superoxide dismutase (SOD) catalyst with rates for the catalytic dismutation of superoxide to oxygen and hydrogen peroxide at pH = 7.4 of 1.2 x 10(+7) M(-1) s(-1).(1) The use of the computer-aided design paradigm reported previously for this class of Mn(II) complexes(2,3) led to the prediction that the 2S,21S-dimethyl derivative of M40403 should possess superior catalytic SOD activity. The synthesis of this new macrocyclic Mn(II) complex, [manganese(II)dichloro[2S, 21S-dimethyl-(4R,9R,14R,19R)-3,10,13,20,26-pentaazatetracyclo[20.3.1.0.(4,9)0(14,19)]hexacosa-1(26),22(23),24-triene]], 5, was accomplished via a high yield template condensation utilizing the linear tetraamine, N,N'-Bis[(1R,2R)-[2-(amino)]cyclohexyl]-1,2-diaminoethane, 1, 2,6-diacetylpyridine, and MnCl(2) to form the macrocyclic diimine complex, 2, which then is reduced. The two other possible dimethyl diastereomers of 5 (2R,21R-dimethyl,3, and 2R,21S-dimethyl, 6) were also prepared via reduction of the diimine complex 2. Two of these complexes, 3 and 5, were characterized by X-ray structure determination confirming their absolute stereochemistry as 2R,21R-dimethyl and 2S,21S-dimethyl, respectively. The results of the MM calculations which predict that the 2S,21S-dimethyl complex, 5, should be a high activity catalyst and that the 2R,21R-dimethyl complex, 3, should have little or no catalytic activity are presented. The catalytic SOD rates for these complexes are reported for each of these complexes and a correlation with the modeling predictions is established showing that 2R,21R-complex, 3, has no measurable catalytic rate, while the 2R,21S complex, 6, is identical to M40403, and the 2S,21S- complex, 5, possesses a very fast rate at pH = 7.4 of 1.6 x 10(+9) M(-1) s(-1) exceeding that of the native mitochondrial MnSOD enzymes.

Catalysis↗
PubMed2001

Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion.

1. Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of M40401, a new S:,S:-dimethyl substituted biscyclohexylpyridine Mn-based superoxide dismutase mimetic (SODm, k(cat)=1.2x10(+9) M(-1) s(-1) at pH=7.4), in rats subjected to SAO shock. 2. Treatment of rats with M40401 (applied at 0.25, 2.5 or 25 microg kg(-1), 15 min prior to reperfusion), attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. M40401 also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. 3. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SAO-shocked rats which had received M40401. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40401 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue sections from SAO-shocked rats. M40401 treatment significantly improved survival. 4. Additionally, the very high catalytic activity of this new mimetic (comparable to the native human Cu/Zn SOD enzyme and exceeding the activity of the human Mn SOD enzyme) translates into a very low dose ( approximately microg kg(-1)) required to afford protection in this SAO model of ischemia reperfusion injury. 5. Taken together, our results clearly demonstrate that M40401 treatment exerts a protective effect, and part of this effect may be due to inhibition of the expression of adhesion molecules and peroxynitrite-related pathways with subsequent reduction of neutrophil-mediated cellular injury.

Animals↗
PubMed2001

Pharmacological manipulation of the inflammatory cascade by the superoxide dismutase mimetic, M40403.

1. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that removes superoxide anions (*O2-) without interfering with other reactive species known to be involved in inflammatory responses (e.g. nitric oxide, NO and peroxynitrite, ONOO-). 2. As such, M40403 represents an important pharmacological tool to dissect the roles of *O2- in acute and chronic inflammation. For this purpose, the pharmacological profile of M40403 was evaluated in carrageenan-induced pleurisy. 3. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by: fluid accumulation in the pleural cavity which contained a large number of neutrophils (PMNs) as well as an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E2 (PGE2), tumour necrosis factor alpha, (TNFalpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and interleukin-10 (IL-10). 4. All parameters of inflammation were attenuated by M40403 except for NOx, PGE2 and IL-10 which remained unaltered. Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS) as determined by immunohistochemical analysis of lung tissues. 5. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PARS was reduced by M40403. 6. These results clearly indicate that *O2- plays a critical role in the development of the inflammatory response by altering key components of the inflammatory cascade. Therefore, synthetic enzymes of SOD such as M40403, offers a novel therapeutic approach for the management of various inflammatory diseases where these radicals have been postulated to play a role.

Animals↗
PubMed2001

Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury.

A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially superoxide and hydroxyl radical) and high-energy oxidants (such as peroxynitrite) as mediators of inflammation, shock, and ischemia/reperfusion injury. The aim of this review is to describe recent developments in the field of oxidative stress research. The first part of the review focuses on the roles of reactive oxygen species (ROS) in shock, inflammation, and ischemia/reperfusion injury. The second part of the review deals with the novel findings using recently identified pharmacological tools (e.g., peroxynitrite decomposition catalysts and selective superoxide dismutase mimetics (SODm) in shock, ischemia/reperfusion, and inflammation. 1) The role of ROS consists of immunohistochemical and biochemical evidence that demonstrates the production of ROS in shock, inflammation, and ischemia/reperfusion injury. ROS can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane sodium/potassium ATPase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of shock, inflammation, and ischemia/reperfusion. 2) Treatment with either peroxynitrite decomposition catalysts, which selectively inhibit peroxynitrite, or with SODm, which selectively mimic the catalytic activity of the human superoxide dismutase enzymes, have been shown to prevent in vivo the delayed vascular decompensation and the cellular energetic failure associated with shock, inflammation, and ischemia/reperfusion injury. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) are all potential reactants capable of initiating DNA single-strand breakage, with subsequent activation of the nuclear enzyme poly(ADP-ribose) synthetase, leading to eventual severe energy depletion of the cells and necrotic-type cell death. Antioxidant treatment inhibits the activation of poly(ADP-ribose) synthetase and prevents the organ injury associated with shock, inflammation, and ischemia/reperfusion.

Animals↗
PubMed2000

Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock.

A major feature of septic shock is the development of a vascular crisis characterized by nonresponsiveness to sympathetic vasoconstrictor agents and the subsequent irreversible fall in blood pressure. In addition, sepsis, like other inflammatory conditions, results in a large increase in the production of free radicals, including superoxide anions (O(2)) within the body. Here we show that O(2) reacts with catecholamines deactivating them in vitro. Moreover, this deactivation would appear to account for the hyporeactivity to exogenous catecholamines observed in sepsis, because administration of a superoxide dismutase (SOD) mimetic to a rat model of septic shock to remove excess O(2) restored the vasopressor responses to norepinephrine. This treatment with the SOD mimetic also reversed the hypotension in these animals; suggesting that deactivation of endogenous norepinephrine by O(2) contributes significantly to this aspect of the vascular crisis. Indeed, the plasma concentrations of both norepinephrine and epinephrine in septic rats treated with the SOD mimetic were significantly higher than in untreated rats. Interestingly, the plasma concentrations for norepinephrine and epinephrine were inversely related to the plasma concentrations of adrenochromes, the product of the autoxidation of catecholamines initiated by O(2). We propose, therefore, that the use of a SOD mimetic represents a new paradigm for the treatment of septic shock. By removing O(2), exogenous and endogenous catecholamines are protected from autoxidation. As a result, both hyporeactivity and hypotension are reversed, generation of potentially toxic adrenochromes is reduced, and survival rate is improved.

Adrenochrome↗
PubMed1999

A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats.

Many human diseases are associated with the overproduction of oxygen free radicals that inflict cell damage. A manganese(II) complex with a bis(cyclohexylpyridine)-substituted macrocyclic ligand (M40403) was designed to be a functional mimic of the superoxide dismutase (SOD) enzymes that normally remove these radicals. M40403 had high catalytic SOD activity and was chemically and biologically stable in vivo. Injection of M40403 into rat models of inflammation and ischemia-reperfusion injury protected the animals against tissue damage. Such mimics may result in better clinical therapies for diseases mediated by superoxide radicals.

Animals↗
PubMed1999

Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin-induced intestinal damage.

1. The relative contributions of superoxide anion (O2-) and peroxynitrite (PN) were evaluated in the pathogenesis of intestinal microvascular damage caused by the intravenous injection of E. coli lipopolysaccharide (LPS) in rats. The superoxide dismutase mimetic (SODm) SC-55858 and the active peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-disulphonatophenyl)-por phyrinato iron (III) and 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)-porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were used to assess the roles of O2- and PN respectively. 2. The intravenous injection of LPS elicited an inflammatory response that was characterized by a time-dependent infiltration of neutrophils, lipid peroxidation, microvascular leakage (indicative of microvascular damage), and epithelial cell injury in both the duodenum and jejunum. 3. Administration of the SODm SC-55858, FeTMPS or FeTMPyP at 3 h post LPS reduced the subsequent increase in microvascular leakage, lipid peroxidation and epithelial cell injury. Inactive peroxynitrite decomposition catalysts exhibited no protective effects. Only, SC-55858 inhibited neutrophil infiltration. 4. Our results suggest that O2 and peroxynitrite play a significant role in the pathogenesis of duodenal and intestinal injury during endotoxaemia and that their remoyal by SODm and peroxynitrite decomposition catalysts offers a novel approach to the treatment of septic shock or clinical conditions of gastrointestinal inflammation. Furthermore, the remarkable protection of the intestinal epithelium by these agents suggests their use during chemo- and radiation therapy, cancer treatments characterized by gastrointestinal damage. Potential mechanisms through which these radicals evoke damage are discussed.

Animals↗
PubMed1998

Therapeutic manipulations of peroxynitrite.

Interest in peroxynitrite (PN) chemistry soared after recognition in 1987 of the biological role of nitric oxide, and PN has recently emerged as a possible key mediator of in vivo oxidative stress and disease. The role of PN in disease processes can be dissected both pharmacologically and biochemically, and several laboratories have examined the cellular production of peroxynitrite. In vitro demonstrations of PN-mediated cellular injury have served to strengthen the case for peroxynitrite's proposed role in the pathogenesis of human neurodegenerative disorders as examined in animal models and in diseased human tissue. Among the nervous system disorders in which PN is strongly implicated in pathology are stroke, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. Pathologies driven by the formation of PN are amenable to pharmacological intervention at either the reactant (nitric oxide, superoxide anions) or the product (peroxynitrite). Strategies for blocking the deleterious biochemistry of peroxynitrite must aim to decrease either the flux or the intrinsic lifetime of the peroxynitrite; three particular tactics would accomplish such purposes. A novel class of antiinflammatory agents has recently been identified: PN decomposition catalysts. Identification of these catalysts offers the scientific community the opportunity to elucidate and further our understanding of the roles of peroxynitrite in animal models of diseases, which may lead to a major breakthrough in understanding the physiopathological importance of this molecule.

Journal Article↗
PubMed1996

Manganese-based superoxide dismutase mimetics inhibit neutrophil infiltration in vivo.

In a previous study (Hardy et al. (1994) J. Biol. Chem. 269, 18535-18540), we observed that the manganese-based superoxide dismutase mimetic Mn(II)-dichloro(1,4,7,10,13-pentaazacyclopentadecane) (MnPAM) inhibited neutrophil-mediated cell injury in vitro. We have extended these studies with the low molecular weight superoxide dismutase mimic to evaluate the role of superoxide in neutrophil-mediated tissue injury in vivo. In a dose-dependent manner, MnPAM inhibited colonic tissue injury and neutrophil accumulation into the colonic tissue induced by the intracolonic instillation of dilute aqueous acetic acid in mice. Tissue injury was assessed by visual and histological analysis. Neutrophil infiltration was determined by tissue myeloperoxidase activity and confirmed by histological analysis. Two novel Mn(II) dichloro complexes of the carbon-substituted macrocycles 2-methyl-1,4,7,10,13-pentaazacyclopentadecane (MnMAM) and 2-(2-methylpropyl)-1,4,7,10,13-pentaazacyclopentadecane (MnBAM) effectively catalyzed the dismutation of superoxide with catalytic rate constants (kcat) of 3. 31 x 10(7) M-1 s-1 and 1.91 x 10(7) M-1 s-1, respectively, as determined by stopped-flow kinetic analysis at pH 8.1 and 21 degrees C. The superoxide dismutase mimetics MnMAM and MnBAM also attenuated dilute aqueous acetic acid-induced tissue injury and neutrophil infiltration into colonic tissue; however, two Mn(II) complexes that had little or no detectable SOD activity (kcat </= 0.1 x 10(7) M-1 s-1), specifically the Mn(II) dichloro complexes of 1,4,7,10,13-pentaazacyclohexadecane and 1,4,7,11,14-pentaazacycloheptadecane, failed to inhibit the colonic tissue injury or infiltration of neutrophils in mice treated intracolonically with dilute aqueous acetic acid. These results are consistent with a proinflammatory role for superoxide in the mediation of neutrophil infiltration in vivo.

Animals↗
PubMed1995

Potentiation of nitric oxide-mediated vascular relaxation by SC52608, a superoxide dismutase mimic.

Nitric oxide (NO) produced by the vascular endothelium is an endogenous contributor to the regulation of vascular relaxation and the maintenance of blood pressure. The effective half-life of NO and the relaxation of aortic rings by NO is enhanced by a reduction in the concentration of superoxide radicals with superoxide dismutase (SOD). In the current study, SC52608, a newly synthesized SOD mimic with a manganese core, was tested for its ability to potentiate the activity of NO both in vitro and in vivo. SC52608 relaxation of rat aortic segments was endothelium dependent as well as concentration dependent. The maximum relaxation following KCl contraction was 44% with 300 microM SC52608. Cyclic GMP concentrations in the segments were increased 1.6- and 3.2-fold with 5 and 300 microM SC52608, respectively. N-monomethyl-I-arginine pretreatment of aortic rings abolished the relaxation and cyclic GMP accumulation mediated by SC52608. In a smooth muscle cell reporter system of nitric oxide synthase activity, SC52608 potentiated the increase in cyclic GMP elicited by NO in a concentration-dependent manner with a maximum increase of 5.2-fold at 100 microM. Injection of SC52608 into conscious, restrained rats resulted in a dose-dependent decrease of blood pressure. Therefore, the data suggest that SC52608 potentiates the actions of nitric oxide on vascular tone, cyclic GMP, and blood pressure by enhancing the half-life of NO through a mechanism that mimics the action of SOD.

Animals↗
PubMed1994

Superoxide dismutase mimetics inhibit neutrophil-mediated human aortic endothelial cell injury in vitro.

In this study, we evaluated the ability of low molecular weight manganese-based superoxide dismutase mimetics to attenuate neutrophil-mediated oxygen radical damage to human aortic endothelial cells in vitro. Human neutrophils, when exposed to tumor necrosis factor-alpha and the complement compound C5a, induced endothelial damage assessed by the release of 51Cr into the medium. This damage correlated with the amount of superoxide generated by neutrophils. Three superoxide dismutase mimetics, with catalytic rate constants for superoxide dismutation ranging from 4 to 9 x 10(7) M-1 S-1, inhibited neutrophil- or xanthine oxidase-mediated endothelial cell injury in a concentration-dependent manner. A similar manganese-based compound with no detectable superoxide dismutase activity was ineffective in inhibiting injury. Fluorescent studies of the neutrophil respiratory burst showed that the superoxide dismutase mimetics were protective without interfering with the generation of superoxide by activated neutrophils. Catalase, elastase inhibitors, and desferrioxamine mesylate (an iron chelator and hydroxyl radical scavenger) were not protective against cell injury. This investigation demonstrates that neutrophil-mediated human aortic endothelial cell injury in vitro is mediated by the superoxide anion and that low molecular weight manganese-based superoxide dismutase mimetics are effective in abrogating this damage.

Antioxidants↗
PubMed1994

Protective effects of the SOD-mimetic SC-52608 against ischemia/reperfusion damage in the rabbit isolated heart.

An experimental model of myocardial ischemia/reperfusion injury was used to assess the cardioprotective effects of SC-52608, a low molecular weight superoxide dismutase mimetic. Langendorff perfused rabbit isolated hearts were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Hearts perfused in the presence of 20 microM SC-52608 exhibited a decrease in the release of creatine kinase and intracellular potassium compared to hearts receiving vehicle (control). A progressive increase in left ventricular end-diastolic pressure developed upon reperfusion in all hearts, but was significantly greater in control hearts when compared to hearts treated with SC-52608 (P < 0.05). In addition, results obtained with a radiolabeled monoclonal antibody to the intracellular protein myosin, indicate an increased degree of irreversible damage in vehicle-treated hearts. Myocardial protection was not significant in an additional group of hearts treated with 10 microM SC-52608. The hemodynamic, biochemical, morphological, as well as the antimyosin binding data, demonstrate that pretreatment with SC-52608 protects the myocardium from damage associated with global ischemia and reperfusion. The mechanism by which SC-52608 mediates the observed protective effect is most likely related to its ability to scavenge superoxide.

Animals↗
PubMed1994

External abdominal aortic compression: a study of a resuscitation manoeuvre for postpartum haemorrhage.

External aortic compression is an emergency manoeuvre proposed to reduce postpartum haemorrhage and permit time for resuscitation and control of bleeding. To assess this technique, a prospective study was performed on twenty normal non-bleeding parturients. The abdominal aorta was compressed by firm pressure with a closed fist just above the umbilicus. Leg and arm arterial blood pressures were measured and femoral artery pulsation felt before, during and after compression. Leg blood pressure was completely obliterated in 55% and significantly reduced (P < 0.01) in a further 10% of subjects. All of these subjects with reduced or absent leg blood pressure also had obliteration of the femoral pulse with compression. Systemic arterial blood pressure was not significantly elevated by successful aortic occlusion. Discomfort with the manoeuvre was significantly increased (P < 0.05) in the group of subjects that had successful aortic occlusion. It is recommended that external aortic compression be considered in severe life-threatening postpartum haemorrhage, particularly during stabilisation or transport of the patient. This simple manoeuvre may be used as an adjunct to other measures and could prove of benefit, especially in locations or situations where advanced medical assistance is geographically or temporally removed.

Aorta, Abdominal↗
PubMed1994

Inhibition of in vivo myocardial ischemic and reperfusion injury by a synthetic manganese-based superoxide dismutase mimetic.

We determined whether an organic superoxide dismutase mimetic could reduce myocardial injury resulting from a 90-min occlusion of the left circumflex coronary artery, followed by 18 hr of reperfusion in an anesthetized canine. The superoxide dismutase-mimetic studied (SC-52608) was a synthetic Mn-based macrocyclic compound. SC-52608 or the inactive analog SC-54385 was administered as four doses of 4 mg/kg i.v. Drug, inactive analog or vehicle was administered 30 and 15 min before ischemia and 15 min and immediately before reperfusion. To ensure parity of left circumflex coronary artery occlusion-induced ischemia, only animals with ischemic zone blood flow of less than 0.15 ml/min/g were included in the final analysis. Ischemic zone blood flow was 0.069 +/- 0.016 ml/min/g in control animals (n = 10), 0.072 +/- 0.010 ml/min/g in SC-52608-treated animals (n = 11) and 0.053 +/- 0.011 ml/min/g in SC-54385-treated (n = 9) animals. A transient hypotensive effect was observed upon SC-52608 administration. Hemodynamic parameters were otherwise unaffected by SC-52608 or SC-54385. The areas at risk of infarct were 39.6 +/- 1.9%, 38.7 +/- 1.1% and 39.4 +/- 1.1% in control, SC-52608-treated and SC-54385-treated animals, respectively. Myocardial infarct sizes (% of area at risk of infarct) were 44.2 +/- 5.6%, 25.7 +/- 4.3% and 35.1 +/- 4.9% in control, SC-52608-treated and SC-54385-treated animals, respectively (P < .05 control vs. SC-52608-treated). Therefore, the synthetic superoxide dismutase mimetic protected the regionally ischemic and reperfused myocardium from injury, implicating oxygen-derived radicals in the tissue-injury process.

Animals↗