This Is MS Multiple Sclerosis Community: Knowledge & Support

In contrast to these previous studies, we show here that DNA and lipid oxidation is associated with ongoing demyelination and neurodegeneration in active multiple sclerosis lesions. Furthermore, we show for the first time that acute cell injury and cell death of oligodendrocytes, axons and neurons in multiple sclerosis is linked to profound cytoplasmic and nuclear oxidative damage. The reason for the different results between our current and previous studies is not entirely clear. The most likely explanation comes from our observation that oxidized DNA and lipids were mainly present in a small zone of active multiple sclerosis lesions, which represents that previously described as the area of initial demyelination (Marik et al., 2007) or the ‘prephagocytic’ lesion (Barnett and Prineas, 2004; Henderson et al., 2009). Such lesions or lesion areas may not have been included in earlier studies. It has been shown previously that oxidized phospholipids and MDA epitopes are present in apoptotic cells as well as in apoptotic bodies ingested by macrophages (Chang et al., 1999). Apoptotic oligodendrocytes are predominantly seen in multiple sclerosis lesions in areas of initial (prephagocytic) demyelination (Barnett and Prineas, 2004; Marik et al., 2007). Furthermore, apoptotic cell death through oxidative mechanisms may exert proinflammatory and immunogenic actions (Chang et al., 2004), which in part may explain the progressive increase in inflammation with lesion maturation in multiple sclerosis (Marik et al., 2007; Henderson et al., 2009).


In summary, our study provides evidence for an important role of oxidative damage in the pathogenesis of demyelination and neurodegeneration in multiple sclerosis lesions, which may act in addition to, or in cooperation with nitric oxide radicals, as described previously (Bagasra et al., 1995; Zeis et al., 2009). It further shows—for the first time—that the analysis of oxidized lipid epitopes in multiple sclerosis lesions allows identification of acute damage of oligodendrocytes, axons and neurons at different stages of lesion formation. Our data also suggest that oxidative damage is in part related to inflammation, that it affects different cellular components of the CNS, but that myelin, oligodendrocytes, neurons and axons may be more sensitive to oxidative damage than astrocytes.

The use of antioxidants to prevent disease is controversial. In a high-risk group like smokers, high doses of beta carotene increased the rate of lung cancer.[18] In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease.[19] In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed.[20][21] Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. However, AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.[22]
Oxidative stress (as formulated in Harman's free radical theory of aging) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,[23][24] recent evidence from Michael Ristow's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.[25] This process was previously named mitohormesis or mitochondrial hormesis on a purely hypothetical basis.[26] The situation in mammals is even less clear.[27][28][29] Recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence in humans (although the results were influenced by studies on smokers).[30]

Abstract:

Alzheimer's disease (AD) brain is characterized by amyloid β-peptide (Aβ) deposits, neurofibrillary tangles, synapse loss, and extensive oxidative stress. Aβ-induced oxidative stress is indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation and neuronal cell death. Oxidative stress is combated by antioxidants. Antioxidants and nutrition have long been considered as an approach to slow down AD progression. In this review, we focus on antioxidants that have been shown to protect against Aβ-induced oxidative stress, particularly vitamin E, ferulic acid, various polyphenols, including quercetin and resveratrol, α-lipoic acid, N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin gallate (EGCG), and γ-glutamylcysteine ethyl ester (GCEE). Brain-accessible antioxidants with both radical scavenging properties and ability to induce protective genes are hypothesized to be helpful in treatment for AD.

High altitude exposure results in decreased partial pressure of oxygen and an increased formation of reactive oxygen and nitrogen species (RONS), which causes oxidative damage to lipids, proteins and DNA.

(Note that this is almost exactly what the researchers found in the MS brain tissue due to oxidative damage)

Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzyme system. The antioxidant system is less in brain tissue and is very much susceptible to hypoxic stress. The aim of the present study was to investigate the time dependent and region specific changes in cortex, hippocampus and striatum on oxidative stress markers on chronic exposure to hypobaric hypoxia. The rats were exposed to simulated high altitude equivalent to 6100 m in animal decompression chamber for 3 and 7 days. Results indicate an increase in oxidative stress as seen by increase in free radical production, nitric oxide level, lipid peroxidation and lactate dehydrogenase levels. The magnitude of increase in oxidative stress was more in 7 days exposure group as compared to 3 days exposure group. The antioxidant defence system such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and reduced/oxidized glutathione (GSH/GSSG) levels were significantly decreased in all the three regions. The observation suggests that the hippocampus is more susceptible to hypoxia than the cortex and striatum. It may be concluded that hypoxia differentially affects the antioxidant status in the cortex, hippocampus and striatum.

Our bodies constantly react with oxygen as we breathe and as our cells produce energy. However, our use of oxygen is a double-edged sword: we need oxygen to survive, but as a consequence of using oxygen, highly reactive molecules, known as “free radicals,” are produced. Free radicals are atoms or molecules with electrons which have lost their partner electron, often as a result of our respiratory or metabolic process, or from outside influences. Free radicals can disrupt the balance of NO, damage the endothelium and leave it overly permeable, allowing toxins to pass into our tissues9. In most instances, our body has an adequate supply of antioxidants obtained from food to neutralize these free radicals, but if the body is depleted, or if there are too many coexistent factors, injury to the endothelium and a change in the balance of NO may occur.

Just a brain-storm... wouldn't it be better to be slightly anemic than hyperactively producing MMPs? Periodic clinical exsanguination perhaps? Lower Fe = lower O2 radicals?