Strategies For Antioxidant Therapy

In the broadest possible definition, an antioxidant is any chemical that attenuates the rate of oxidative degradation of the material or substrate under study. Halliwell and Gutteridge (1989) defined an antioxidant as "any substance that, when present at low concentrations compared to those of an oxidizable substrate, significantly delays or inhibits oxidation of that substrate". However, when considering pharmaceutical^ relevant antioxidants, one may also need to include compounds that do not behave exclusively as peroxidation inhibitors. Thus, for the present discussion, an antioxidant of biological relevance may be defined as a chemical that inhibits the pathological consequences of oxidative insult by reacting with biologically relevant oxidants or radicals.

The termination of radical chain reactions has been an important issue within areas such as polymer stabilization and food preservation for a very long time. The necessity to control oxidative degradation of synthetic

PHARMACEUTICAL ANTIOXIDANTS Scheme 2 Antioxidant mechanisms

PHARMACEUTICAL ANTIOXIDANTS Scheme 2 Antioxidant mechanisms

UV absorbers, hydroperoxide decomposers, transition metal chelators

UV absorbers, hydroperoxide decomposers, transition metal chelators polymers and lubricants has emerged similarly to the field of anticorrosion for metal preservation. There are hypothetically several approaches available mechanistically, when attempting to intercept oxidative degradation (Scheme 2). Thus, various approaches are at hand to impede initiation reactions (UV absorbers, hydroperoxide decomposers, transition metal chelators) as well as terminating radical chain reactions (reviewed by Scott, 1988). Chain-terminating agents can be envisaged to act by either reducing the peroxyl radicals (which are easily reduced) or oxidizing carbon-centred species. When considering the destructive peroxidation of mammalian tissues, the peroxyl radical is the species of primary importance. Thus, in the in vivo situation, where oxygen is abundantly distributed, only the donating chain-breakers have been studied to any appreciable extent.

In the pharmacological context, antioxidants are commonly divided into two groups depending on their principal mode of action. Agents that are thought to act primarily through attenuating the initiation step of peroxidation are called preventive antioxidants. It is important to note that such agents, perhaps especially peroxide-decomposing enzyme mimics, may well have pharmacodynamic properties that result from effects on the redox status (or "hydroperoxide tone") of the cells rather than from blocking indiscriminate membrane peroxidation. For example, the involvement of oxidative signalling in immune regulation has become increasingly recognized (Gougerot-Pocadilo and Revillard, 1993; Meyer et al., 1993). Compounds that act through terminating free radical chain reactions are referred to as chain-breaking antioxidants. This distinction has been made also in the following sections, although many substances could belong to both categories.

A collection of the most commonly occurring strategies for antioxidant therapy must include the following:

(1) Enhancement of tissue endogenous antioxidant levels (e.g. through administration of antioxidant vitamins or glutathione precursors).

(2) Prevention of initiation events by scavenging (commonly discussed for hydroxyl radical scavengers).

(3) Chelation of metal ions (by introducing multidentate complexing agents which prevent transition metals from decomposing hydroperoxides into radical products).

(4) Decomposition of peroxides and superoxide into non-radical products (using antioxidant enzymes or synthetic superoxide dismutase or glutathione peroxidase mimics).

(5) Termination of free radical peroxidation (through administration of generally lipophilic chain-breaking antioxidants).

2 Endogenous Defence Systems

Any over-production of ROS is normally controlled by different endogenous enzymatic and non-enzymatic antioxidants (Halliwell and Gutteridge, 1989, Sies, 1991; Salvemini and Botting, 1993). These include preventive antioxidants diminishing the rate of chain initiation as well as scavenging or chain-breaking agents interfering with propagation steps (Stocker and Frei, 1991). The oxidative stress on an organ is a function of the amount of ROS produced and the antioxidant capacity. Thus, oxidative damage can be a result of excessive oxidative stress or an insufficient antioxidant level.

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