Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation

Abstract

The anti-inflammatory role of copper is well-known although still largely unexplained. On the other hand, the capacity of copper to induce the formation of damaging .OH radicals in vivo is no longer debated. These two aspects of the physiological activity of copper have been considered to be paradoxical. Arguments developed here show that they may actually derive from a single chemical process, the type of physiological effect observed depending on the ligand bound to the copper ions involved in Fenton chemistry. Both iron and copper are Fenton catalysts. Given its intrinsic coordination properties, however, copper induces more site-specific .OH damage to the ligands bound to it. It, therefore, appears that copper complexes with specific .OH-inactivating ligands (OILs) can be used as "lures" for the Fenton reaction, .OH radicals preferentially formed on these being immediately inactivated. The hypothesis is thus put forward here that copper-OIL complexes acting as effective Fenton catalysts are potential "catalase-like" anti-inflammatory drugs.

Copper(II) interactions with non-steroidal anti-inflammatory agents. III – 3-Methoxyanthranilic acid as a potential OH-inactivating ligand: A quantitative investigation of its copper handling role in vivo

“…It seemed at first sight paradoxical that copper could at the same time be part of an anti-inflammatory process and catalyze Fenton-type reactions that sustained that very inflammatory process, but this paradox was later shown to be only apparent [11]. The pro-oxidant role of copper in Fenton-like chemistry may effectively bear different, even opposing consequences depending on the nature of the ligand bound to the Cu(II) ion at the initiation of the Haber-Weiss cycle.…”

“…The pro-oxidant role of copper in Fenton-like chemistry may effectively bear different, even opposing consequences depending on the nature of the ligand bound to the Cu(II) ion at the initiation of the Haber-Weiss cycle. This led to the proposal of the general notion of Å OH-inactivating ligand (OIL) to define any chemical substance capable of rendering the pro-oxidant function of copper anti-inflammatory [11].…”

Antinociception and the New COX Inhibitors: Research Approaches and Clinical Perspectives

“…The actual role of copper in inflammation is, however, not well understood. The administration of copper causes an anti-inflammatory effect, whereas the concentration of copper in plasma increases during inflammation, and so, it is not clear whether copper can be considered a pro-or an anti-inflammatory agent (15). However, it seems evident that some substances have anti-inflammatory properties when administered as copper complexes, and some NSAIDs seem to be more effective than their parent compounds when combined with copper (95 and reference within).…”

Copper(II) interaction with 3,5-diisopropylsalicylic acid (Dips): New insights on its role as a potential OH inactivating ligand

“…Indeed, the paradox that it can play both anti-inflammatory and pro-oxidant roles is related to the nature of the biological molecules bound to the metal in vivo. In fact, its pro-oxidant action in Fenton chemistry may result in anti-inflammatory effect if the copper(II) complex is involved in the Haber-Weiss reaction and the ligand acts as a ''lure'' for hydroxyl radicals, which corresponds to the definition of an Å OH inactivating ligand (OIL) [2]. To be active in this kind of action, a potential OIL must firstly mobilize copper at the inflamed site.…”