Biomedical subjects

Declan P Naughton

Publications and source records attributed to Declan P Naughton.

11 recordsLinked to original sources

PubMed2006

Dietary chelators as antioxidant enzyme mimetics: implications for dietary intervention in neurodegenerative diseases.

Following recent reviews on the role of metal ions in oxidative stress and neurodegenerative diseases, this article reports advances in the study of dietary components for the control of these conditions. Poor metal ion homeostasis is credited with pathological roles in the progression of a number of disorders including Alzheimer's disease, Parkinson's disease and multiple sclerosis. Synthetic metal ion chelators continue to show promise as a new therapeutic approach for neurodegenerative disorders. Dietary chelators, unlike most vitamins, are, however, capable of negating or even reversing the roles of metal ions by: (i) decorporation of metal ions, (ii) redox silencing, (iii) dissolution of deposits, and (iv) generation of an antioxidant enzyme mimetic. This review gives a critical evaluation of recent progress in, and potential for, dietary control of neurodegeneration on the basis of the formation of antioxidant enzyme mimetics.

Alzheimer Disease↗

PubMed2005

Lipophilic ionophore complexes as superoxide dismutase mimetics.

A wide range of metal ion complexes exhibit superoxide dismutase like activities as detected by inhibition of nitroblue tetrazolium reduction. Mn(II) and Cu(II) complexes of EDTA, EHPG, and EGTA exhibit SOD like activities commensurate with many of the purpose-built SOD mimics. Here, we report analogous lipophilic chelators that localise metal ions (Cu(II), Mn(II), and Fe(III)) in the lipid membranes and lipoproteins to protect them from superoxide mediated oxidative damage. Spectroscopic titrations and Jobs method confirm that both 1:1 and 2:1 metal ion monensin complexes form. The cupric complexes are the most active exhibiting IC(50) values of 0.09 and 0.18 microM for 2Cu(II)-monensin and Cu(II)-monensin, respectively, for superoxide destruction. In addition, the IC(50) value for Mn(II)-monensin is 0.31 microM. In conclusion, Mn(II) and Cu(II) complexes of the ionophore monensin exhibit considerable superoxide scavenging activities and represent a novel class of catalytic antioxidants for the protection of lipid structures.

Antioxidants↗

PubMed2005

Why nutraceuticals do not prevent or treat Alzheimer's disease.

A great deal of research has pointed to deleterious roles of metal ions in the development of Alzheimer's disease. These include: i) the precipitation and aggregation of amyloid beta (Abeta) peptides to form senile plaques and neurofibrillary tangles, and/or ii) the augmentation of oxidative stress by metal ion mediated production and activation of hydrogen peroxide. The growing trend in nutraceutical intake is in part a result of the belief that they postpone the development of dementias such as Alzheimer's disease. However, pathogenic events centred on metal ions are expected to be aggravated by frequent nutraceutical intake. Novel therapeutic approaches centred on chelators with specificity for copper and iron ions should be fully explored.

Alzheimer Disease↗

PubMed2005

Therapeutic chelators for the twenty first century: new treatments for iron and copper mediated inflammatory and neurological disorders.

Superoxide, hydrogen peroxide, hydroxyl radicals and peroxynitrite are collectively termed reactive oxygen and nitrogen species (RONS). They have been ascribed an important role in oxidative stress contributing to the progression of inflammatory diseases. RONS generating systems include the inflammatory response, enzymatic pathways and as side products of catabolism. Protective enzymes exist for the regulation of RONS such as superoxide dismutase, catalase and glutathione peroxidase. Furthermore, vitamins play a secondary role in deactivating RONS. The redox active metal ions such as ferrous and cuprous ions are released from the storage proteins ferritin and caeruloplasmin by RONS. Redox active metal ions further activate/generate RONS and thus perpetuate their damaging effects. Here we report recent therapies that focus on intervening in the roles of metal ions in oxidative stress. These include: i) chelators which complex labile metal ions to form antioxidant enzyme mimetics, ii) site-specific RONS scavengers, where dual functionality co-localizes the scavenger and chelation centre to direct scavenging, and iii) redox silencing, metal complexation with concomitant stabilization of the metal ion in the oxidized form to prevent further activation of RONS. The rationale for this new therapeutic approach and recent advances will be presented in this review.

Chelating Agents↗

PubMed2004

Differentiating midazolam over-sedation from neurological damage in the intensive care unit.

INTRODUCTION: Midazolam is used routinely to sedate patients in the intensive care unit (ICU). We suspected that midazolam over-sedation was occurring in the ICU of the Guy's and St. Thomas' Trust and that it could be difficult to differentiate this from underlying neurological damage. A sensitive assay for detecting midazolam and 1-hydroxymidazolam glucuronide (1-OHMG) in serum was developed and applied in the clinical setting. METHODS: In the present study we evaluated a series of cases managed in a mixed medical, surgical and trauma ICU. Serum was collected from 26 patients who received midazolam, were 'slow to wake' and in whom there was suspicion of neurological damage. Patient outcome was followed in terms of mortality, neurological recovery and neurological damage on discharge. RESULTS: Out of 26 patients, 13 had detectable serum levels of midazolam and/or 1-OHMG after a median of 67 hours (range 36-146 hours) from midazolam cessation. Of these 13 patients in whom midazolam/1-OHMG was detectable, 10 made a full neurological recovery. Of the remaining 13 patients with no detectable midazolam/1-OHMG, three made a full neurological recovery; 10 patients were subsequently found to have suffered neurological damage (P < 0.002), eight of whom died and two were discharged from the ICU with profound neurological damage. CONCLUSION: These findings confirm that prolonged sedation after midazolam therapy should be considered in the differential diagnosis of neurological damage in the ICU. This can be reliably detected by the assay method described. The effects of midazolam/1-OHMG persist days after administration of midazolam has ceased. After prolonged sedation has been excluded in this patient group, it is highly likely that neurological damage has occurred.

APACHE↗

PubMed2004

Catalytic superoxide scavenging by metal complexes of the calcium chelator EGTA and contrast agent EHPG.

Metal ion chelators widely used in experimental protocols and clinical diagnosis are generally assumed to be inert. We previously reported that the ubiquitous chelator EDTA has high levels of superoxide suppressing activity. Here, we report that the common chelators calcium chelator EGTA and contrast agent EHPG have significant activities in suppressing superoxide levels depending on the nature of metal ion chelated. The most active species is Mn(II)-EGTA which exhibited an IC50 value of 0.19 microM for superoxide destruction. In addition, IC50 values for Mn(II)-EHPG and 2Cu(II)-EGTA were 0.69 and 0.60 microM, respectively. In conclusion, Mn(II) and Cu(II) complexes of the common chelators EGTA and EHPG exhibit considerable superoxide scavenging activities. Caution should be employed in their use in biological systems where superoxide has a key role and they may be useful for the development of catalytic anti-oxidants.

Animals↗

PubMed2004

A novel anti-oxidant and anti-cancer strategy: a peptoid anti-inflammatory drug conjugate with SOD mimic activity.

Activation of reactive oxygen and nitrogen species (RONS) by redox-active metal ions has been proposed to contribute to oxidative damage in inflamed tissues. Here, we report a dual-function anti-oxidant conjugate comprising an anti-inflammatory agent (5-aminosalicylic acid) and a chelator with potential as a superoxide dismutase mimic. The conjugate ethylenediaminetetraacetic acid bis-(5-aminosalicylic acid methyl ester) [EBAME] chelates Cu(II) ions in a 1:1 ratio, as assessed spectrophotometrically using Job's method. Superoxide dismutase (SOD) activity was determined for the Mn(II)-conjugate as 0.758+/-0.130 U at a concentration of 0.99 microM. In inflamed tissues, peptidase mediated release of active 5-ASA would also release the EDTA chelator which has significant SOD mimic activity when complexed to Cu(II) ions. Thus, EBAME has potential as a dual-function anti-inflammatory agent with reduced gastric irritability.

Aminosalicylic Acids↗

PubMed2004

Superoxide and hydrogen peroxide suppression by metal ions and their EDTA complexes.

Redox-active metal ions such as Fe(II)\(III) and Cu(I)\(II) have been proposed to activate reactive oxygen and nitrogen species (RONS) and thus, perpetuate oxidative damage. Here, we show that concentrations of metal ions and EDTA complexes with superoxide-destroying activities equivalent to 1 U SOD are Fe(III) 5.1 microM, Mn(II) 0.77 microM, Cu(II)-EDTA 3.55 microM, Fe(III)-EDTA 2.34 microM, and Mn(II)-EDTA 1.38 microM. The most active being the aquated Cu(II) species which exhibited superoxide-destroying activity equivalent to 2U of SOD at 0.29 microM. Hydrogen peroxide-destroying activities were as follows Fe(III)-EDTA ca. 70 U/mg and aquated Fe(III) 141 U/mg. In contrast, DTPA prevented superoxide-destroying activity and significantly depleted hydrogen peroxide-destroying activity. In conclusion, non-protein bound transition metal ions may have significant anti-oxidant effects in biological systems. Caution should be employed in bioassays when chelating metal ions. Our results demonstrate that DTPA is preferential to EDTA for inactivating redox-active metal ions in bioassays.

Antioxidants↗

PubMed2004

Iron supplements: the quick fix with long-term consequences.

Co-supplementation of ferrous salts with vitamin C exacerbates oxidative stress in the gastrointestinal tract leading to ulceration in healthy individuals, exacerbation of chronic gastrointestinal inflammatory diseases and can lead to cancer. Reactive oxygen and nitrogen species (RONS) have been ascribed an important role in oxidative stress. Redox-active metal ions such as Fe(II) and Cu(I) further activate RONS and thus perpetuate their damaging effects. Ascorbic acid can exert a pro-oxidant effect by its interaction with metal ions via a number of established RONS generating systems which are reviewed here. Further studies are required to examine the detrimental effects of nutraceuticals especially in chronic inflammatory conditions which co-present with anaemia.

Journal Article↗

PubMed2004

Metal ion chelating peptoids with potential as anti-oxidants: complexation studies with cupric ions.

The cupric ion binding characteristics of the chelator EDTA bis (ethyl tyrosinate) are reported. Potentiometric studies in aqueous solutions over the pH range of 2.0-12.0 allowed identification and quantification of the species in solution. The principal species CuA predominates over the physiological pH range of 4.0-8.0 pH units. The logarithm of the stability constant (log beta(pqr)) for this species is 16.43. The cupric ion binding characteristics were further assessed using electronic absorption spectroscopic investigations. These results support the use of this chelator as a metal binding anti-oxidant.

Antioxidants↗

PubMed2003

EDTA bis-(methyl tyrosinate): a chelating peptoid peroxynitrite scavenger.

Conjugation of ethylenediaminetetra-acetic acid (EDTA) to methyl tyrosinate generates a chelating peptoid EDTA bis-(methyl tyrosinate), (EBMT). Peroxynitrite-mediated nitration was studied for the free peptoid and its ferric and cupric complexes. The nitration products were monitored by electronic absorption spectroscopy at lambda(max) of 420 nm (mono-nitrated) and 440 nm (di-nitrated). Peak deconvolution was effected by pH manipulation as the mono-nitrated analogue of tyrosine exhibited a bathochromic shift from 365 nm (below its pK(a) of 6.8) to 420 nm. Rates of nitration were: free peptoid <Cu(II) complex <<Fe(III) complex. These results demonstrate the potential of EBMT to act as a radical scavenging chelating peptoid antioxidant.

Chelating Agents↗