Stress and free radicals

While many biological molecules may be targets for oxidant stress and free radicals, it is clear that the cell membrane and its associated proteins may be particularly vulnerable. The ability of the cell to control its intracellular ionic environment as well as its ability to maintain a polarized membrane potential and electrical excitability depends on the activity of ion-translocating proteins such as channels, pumps and exchangers. Either direct or indirect disturbances of the activity of these ion translocators must ultimately underlie reperfiision and oxidant stress-induced arrhythmias in the heart. A number of studies have therefore investigated the effects of free radicals and oxidant stress on cellular electrophysiology and the activity of key membrane-bound ion translocating proteins. 

Figure 7. Observed relationship between breaking stresses and free radicals. No the number of free radicals produced with no degradation N,-, same but with degradation

The authors cited a combination of ischemia and exci-totoxicity due to cocaine exposure as the possible cause of the brain injury. Oxidative stress and free radicals associated with cerebral hypoxia contribute to cell damage and death. 

F. Oxidative Stress and Free Radicals with Classic Examples... 

Oxidative stress and free-radicals The production of free-radicals and other reactive species has been much implicated in cytotoxicity. This topic is discussed in more detail elsewhere see ANTIOXIDANTS PREE-RADICAL SCAVENGERS nitric oxide synthase inhibitors. The production of these species in oxidative stress is well established. Advances in therapy may well be in the direction of boosting and augmenting natural defence processes, for example, by superoxide dismutase (SOD), catalase, a-tocopherol, glutathione, ascorbic acid and perhaps melatonin. Surprisingly, some forms of the enzyme SOD can be administered in vivo and are protective. 

Albano, E. (2006). Alcohol, oxidative stress and free radical damage. Proc. Nutr. Soc. 65, 278-290. 

At the molecular level, the following equation was derived between the applied stress and free radical concentration ... 

As hydroxyl or hydroxyl-like radicals are produced by the superoxide-driven Fenton reaction, superoxide overproduction must also occur in thalassemic cells. First, it has been shown by Grinberg et al. [382], who demonstrated that thalassemic erythrocytes produced the enhanced amount of superoxide in comparison with normal cells in the presence of prooxidant antimalarial drug primaquine. Later on, it has been found that the production of superoxide and free radical-mediated damage (measured through the MetHb/Hb ratio) was much higher in thalassemic erythrocytes even in the absence of prooxidants, although quinones (menadione, l,4-naphthoquinone-2-methyl-3-sulfonate) and primaquine further increased oxidative stress [383]. Overproduction of superoxide was also observed in thalassemic leukocytes [384]. 

Although GSH is found in many tissues, it is most abundant in the liver, where GSH levels may reach levels of 5mM or more [42]. GSH is maintained in the millimolar range by de novo synthesis and regenerative reactions however, levels may be severely depleted in times of oxidative stress, for example., as mentioned above in the case of acetaminophen (APAP) overdose and bioactivation, which leaves cellular proteins vulnerable to attack by electrophiles and free radicals. 

It therefore appears that neurons in the substantia nigra might ultimately be destroyed because genetic factors lead to neuronal protein accumulation and free radical-induced oxidative stress that causes the degeneration and death of these neurons. As indicated earlier, however, the influence of environmental factors should be considered.49,64 It has been theorized, for example, that environmental toxins (e.g., herbicides, insecticides, fungicides) accelerate the neuronal destruction in people with Parkinson disease.14 Much of this evidence is based on the finding that a compound known as l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) appears to be selectively toxic to these neurons and can invoke parkinsonism in primates.84... 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

On the other hand, defective respiratory function elicited by the mtDNA mutation contributes to an increase in the production of ROS and free radicals, thereby causing higher oxidative stress and severe oxidative damage in affected cells (P2, W6). Because either enhanced oxidative stress or disruption of calcium homeostasis is an important factor in the triggering of cell death, mitochondrial dysfunction in tissue cells from MELAS and MERRF patients may contribute significantly to the pathogenesis of these diseases. 

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