7-8-dihydroneopterin and Inflammation

The rise in plasma neopterin observed with increasing severity of vascular disease is a strong indicator of the inflammatory nature of atherosclerosis. Plasma neopterin originates as the oxidation product of 7,8-dihydroneopterin secreted by gamma-interferon stimulated macrophages within atherosclerotic plaques. Neopterin is increasingly being used as a marker of inflammation during clinical management of patients with a range of disorders including atherosclerosis. Yet the role of 7,8-dihydroneopterin/neopterin synthesis during the inflammatory process and plaque formation remains poorly understood and controversial. This is partially due to the unresolved role oxidants play in atherosclerosis and the opposing roles of 7,8-dihydroneopterin/neopterin. Neopterin can act as pro-oxidant, enhancing oxidant damage and triggering apoptosis in a number of different cell types. Neopterin appears to have some cellular signalling properties as well as being able to chelate and enhance the reactivity of transition metal ions during Fenton reactions. In contrast, 7,8-dihydroneopterin is also a radical scavenger, reacting with and neutralizing a range of reactive oxygen species including hypochlorite, nitric oxide and peroxyl radicals, thus protecting lipoproteins and various cell types including macrophages. This has led to the suggestion that 7,8-dihydroneopterin is synthesized to protect macrophages from the oxidants released during inflammation. The oxidant/antioxidant activity observed in vitro appears to be determined both by the relative concentration of these compounds and the specific chemistry of the in vitro system under study. How these activities might influence or modulate the development of atherosclerotic plaque in vivo will be explored in this review.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Atherosclerosis; Biomarkers; Calcium; Free Radical Scavengers; Humans; Inflammation; Lipoproteins, LDL; Macrophages; Neopterin; Oxidants; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Knee arthroplasty surgery is significant trauma, leading to an activated immune system causing inflammation and oxidative stress. Many current biomarkers are invasive, costly, and often slow to analyse, limiting their use for rapid inflammatory measurements.. We have examined the use of urinary neopterin and total neopterin in knee arthroplasty patients to non-invasively measure oxidative stress and inflammation from immune system activation. We aim to validate the use of these biomarkers for quick, cost effective and predictive measurements of post-surgical inflammation assessment.. 19 Knee arthroplasty patients were analysed pre-operatively and for a defined post-operative period to determine the urinary levels of neopterin and total neopterin (neopterin +7,8-dihydroneopterin) using high performance liquid chromatography with fluorescence detection. These results were then compared to a control group of 20 participants with normal knee function.. 7,8-Dihydroneopterin was stable in urine over 12 h when refrigerated. Knee arthritis was associated with an increase in pre-operative neopterin (oxidative stress) and total neopterin (inflammation). The subsequent arthroplasty surgery generated a significant increase neopterin and total neopterin. Both biomarkers were reduced immediately post-operatively, before becoming elevated on the following days. There was no clear evidence of an association between initial neopterin and total neopterin levels and a patient's level of inflammation during in-hospital recovery.. The stability of 7,8-dihydroneopterin in urine allows for its use as an inflammatory marker. Urinary neopterin and total neopterin provided a fast, non-invasive, and simple measure of oxidative stress and inflammation after knee arthroplasty.

Topics: Adult; Aged; Arthroplasty, Replacement, Knee; Biomarkers; Female; Humans; Inflammation; Male; Middle Aged; Neopterin; Preservation, Biological; Specimen Handling

Plasma neopterin is a clinical marker of inflammation. Interferon-gamma triggers 7,8-dihydroneopterin and its oxidation product, neopterin, to be released from macrophages. 7,8-dihydroneopterin is a potent antioxidant which can protect macrophages from oxidative damage in vitro. This study examined whether 7,8-dihydroneopterin/neopterin levels reach sufficient concentrations in human pus to provide antioxidant activity and be the source of plasma neopterin.. Pus was removed by needle aspiration from 19 patients and examined for total neopterin, protein-bound DOPA, dityrosine, alpha-tocopherol, lipid oxidation and protein carbonyls.. Total neopterin was detected between 50 nM and 1.2 microM, with an average concentration of 0.51 microM. Significant quantities of oxidized proteins and lipids were detected. alpha-Tocopherol concentrations positively correlate with total neopterin levels.. Total neopterin levels found in the pus was up to 100 times higher than that reported in plasma, suggesting plasma neopterin originates from inflammatory sites. The concentration of total neopterin suggests that 7,8-dihydroneopterin could act as an antioxidant during inflammation.

Topics: Abscess; Adult; Aged; Aged, 80 and over; alpha-Tocopherol; Dihydroxyphenylalanine; Female; Humans; Inflammation; Male; Middle Aged; Neopterin; Oxidative Stress; Suppuration; Tyrosine

The formation of oxidised low density lipoprotein (LDL) within the atherosclerotic plaque appears to be a factor in the development of advanced atherosclerotic plaques. LDL oxidation is dependent on the balance of oxidants and antioxidants within the intima. In addition to producing various oxidants, human macrophages release 7,8-dihydroneopterin which in vivo is oxidised to the inflammation marker neopterin. Using macrophage-like THP-1 cells and human monocyte-derived macrophages, we demonstrate that 7,8-dihydroneopterin is a potent inhibitor of cell-mediated LDL oxidation. 7,8-Dihydroneopterin scavenges the chain propagating lipid peroxyl radical, inhibiting both lipid and protein hydroperoxide formation. A significant amount of the hydroperoxide formed during cell-mediated LDL oxidation was protein hydroperoxide. 7,8-Dihydroneopterin oxidation to 7,8-dihydroxanthopterin was only observed in the presence of both cells and LDL, showing that 7,8-dihydroneopterin had no effect on initiating oxidant generation by the cells. 7,8-Dihydroneopterin did not regenerate alpha-tocopherol but competed with it for the lipid peroxyl radical. Although stimulation of both cell types with gamma-interferon failed to produce sufficient 7,8-dihydroneopterin to inhibit LDL oxidation in tissue culture, analysis of advanced atherosclerotic plaque removed from patients showed that total neopterin levels could reach low micromolar concentrations. This suggests that 7,8-dihydroneopterin synthesis by macrophages could play a significant role in the development of atherosclerotic plaques.

Topics: Atherosclerosis; Cell Line; Hemochromatosis; Humans; Hydrogen Peroxide; Inflammation; Interferon-gamma; Lipids; Lipoproteins, LDL; Macrophages; Monocytes; Neopterin; Oxidation-Reduction; Oxygen; Peroxides

Topics: Amidines; Animals; Antioxidants; Blood; Cattle; Free Radical Scavengers; Free Radicals; Hydroxyl Radical; Inflammation; Macrophages; Neopterin; Oxidants; Oxidation-Reduction; Peroxides; Proteins; Pteridines; Serum Albumin, Bovine