2. Oxidative stress and redox-active metal ions

One of the most momentous events in the evolution of our now green planet was the appearance about 2.7 x 10⁹ years ago of cyanobacteria which were capable of using solar energy to split water molecules and evolve molecular dioxygen. This progressively transformed the previously essentially reducing atmosphere of earth into the oxidising atmosphere that we have today.

The positive side of the arrival of oxygen was that organisms, which developed respiratory chains, were able to extract almost 20 times more energy from metabolism than was available using redox-balanced fermentations. The down-side was that molecular oxygen proved to be toxic, particularly in the presence of redox-active metal ions like iron and copper. Since we live in an oxygen-rich environment, the consequence is that we continuously produce oxygen-derived free radicals, so-called Reactive Oxygen Species (ROS). The most potentially dangerous of ROS is the hydroxyl ion, OH^., a short-lived but highly reactive free radical, which causes enormous damage to biological molecules.  In addition to ROS, reactive nitrogen species (RNS) are also generated, notably NO^.. Under normal conditions, such free radicals will be rapidly detoxified by the body's defence systems, but when greater amounts of ROS and RNS are produced, this overwhelm the cellular defence mechanisms leading to oxidative stress.. This is the so-called oxygen paradox - oxygen is an absolute necessity for our energy-economical anaerobic life style, yet it is a potential toxin.

There is considerable evidence that both ROS and RNS are involved in a number of neurodegenerative pathologies., ROS, like the hydroxyl radical, can cause lipid peroxidation, attacking polyunsaturated fatty acids in membrane phospholipids with production of a series of reactive aldehydes (Figure 2, left). These can then lead to formation of protein carbonyls by Michael type addition to protein thiols, imidazoles and amines (Figure 2, right). These will have particularly deleterious effects causing tissue injury, frequently associated with cell death either by necrosis or by apoptosis.In many of the neurodegenerative diseases increased levels of lipid peroxidation, protein carbonyl and DNA damage have been identified indicating enhanced oxidative stress. An important point to emphasise here is the apparent reduced capacity of brain cells to protect themselves from ROS, the activity and levels of many of the cytoprotective enzymes and antoxidants are markedly reduced by comparison to other tissues apart from anerobic muscle. The brain, although it only constitutes 2% of adult body mass, is responsible for 20% of resting oxygen consumption (even when we are asleep). This is on account of its high demand for ATP production, around 50% of which is used to power the plasma membrane (Na⁺-K⁺)-ATPase, which maintains the membrane potential required for transmission of nerve impulses. The high oxygen consumption together with the decreased antioxidant status makes the brain more susceptible than many other tissues to oxidative stress.