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Oxidative Stress & Neurotoxicity

The basic premise of my initial research was that excessive oxidation of neurones was a primary process of neurodegeneration observed in ALS/MND. Whether a cause or a symptom, stopping or even slowing oxidation of neurones seemed a sensible thing to do. That was in 1994. Click here for more recent research and opinions.

The identification of a majority of the polypeptides in mitochondria would be invaluable because they play crucial and diverse roles in many cellular processes and diseases.

The endogenous production of reactive oxygen species (ROS) is a major limiter of life as illustrated by studies in which the transgenic overexpression in invertebrates of catalytic antioxidant enzymes results in increased lifespans. Mitochondria have received considerable attention as a principal source and target of ROS.

Mitochondrial oxidative stress has been implicated in heart disease including myocardial preconditioning, ischemia/ reperfusion, and other pathologies. In addition, oxidative stress in the mitochondria is associated with the pathogenesis of Alzheimer's disease, Parkinson's disease, prion diseases, and amyotrophic lateral sclerosis (ALS) as well as aging itself.

The rapidly emerging field of proteomics can provide powerful strategies for the characterization of mitochondrial proteins. Current approaches to mitochondrial proteomics include the creation of detailed catalogues of the protein components in a single sample or the identification of differentially expressed proteins in diseased or physiologically altered samples versus a reference control. It is clear that for any proteomics approach prefractionation of complex protein mixtures is essential to facilitate the identification of low-abundance proteins because the dynamic range of protein abundance within cells has been estimated to be as high as 10(7).

The opportunities for identification of proteins directly involved in diseases associated with or caused by mitochondrial dysfunction are compelling. Future efforts will focus on linking genomic array information to actual protein levels in mitochondria.

PubMedID: 11884366

Potential antioxidant actions of bioactive components in plant foods

"The study of free radicals and antioxidants in biology is producing medical revolution that promises a new age of health and disease management. From prevention of the oxidative reactions in foods, pharmaceuticals and cosmetics to the role of reactive oxygen species (ROS) in chronic degenerative diseases including cancer, autoimmune, inflammatory, cardiovascular and neurodegenerative illnesses..."

Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods. Source: Mutat Res 2003 Feb;523-524:9-20 Author(s): Aruoma OI. Institute: Department of Neuroinflammation, Faculty of Medicine, Division of Neuroinflammation and Psychological Medicine, Imperial College London, Charing Cross Hospital Campus, Fulham Palace Road, W6 8RF, London, UK Published: 02/01/03

Mayo Clinic researchers discovered that a modified antioxidant enzyme called catalase, when modified by a naturally occurring polyamine, putrescine, significantly delayed the onset and increased the survival of mice affected with familial ALS.

When putrescine-modified catalase reached the brain and spinal cord, it delayed the clinical course of the disease. Thispolyamine-modified catalase may decrease the levels of hydrogen peroxide and nitric oxide, which are thought to be elevated in ALS. These findings support a direct detrimental role for free radicals in ALS.

The largest increase in survival for any systemically administered drug in mice with ALS has been achieved. Other studies remain to be done before human clinical trials can begin but results are encouraging. They represent an important extension in the understanding ALS, and how best to proceed with research.

Aromatic amines and imines are effective against oxidative glutamate toxicity, glutathione depletion, and hydrogen peroxide toxicity. Their mode of action as direct antioxidants was experimentally confirmed by electron spin resonance spectroscopy, cell-free brain lipid peroxidation assays, and intracellular peroxide measurements. With half-maximal effective concentrations of 20-75 nM in different neuroprotection experiments, the aromatic imines phenothiazine, phenoxazine, and iminostilbene proved to be about two orders of magnitude more effective than common phenolic antioxidants.

This remarkable efficacy could be directly correlated to calculated properties of the compounds by means of a novel, quantitative structure-activity relationship model. We conclude that bridged bisarylimines with a single free NH-bond, such as iminostilbene, are superior neuroprotective antioxidants, and may be promising lead structures for rational drug development.

Oxygen-containing molecules may cause damage to cell membranes, proteins and nucleic acids, and alterations in the intra- andinter-cellular environments. The net effect of this damage has been termed oxidative stress.

Free radicals are oxygen atoms (or oxygen containing molecules) that are produced normally as intermediaries in cellular processes and respiration, and in the degradation of fatty acids. Free radicals are also generated by phagocytes (a type of immune cell) in the destruction of bacteria and virally infected cells, which leads some to speculate that increased oxidative stress occurs during inflammatory immune responses.

antioxidants are compounds with a chemical affinity for free radicals. They exist in abundance and bond with free radicals before they can cause damage. antioxidants are of five classes: enzymes, such as catalases, peroxidases, and superoxide dismutase (SOD); peptides, such as glutathione; phenolic compounds. like Vitamin E and plant flavonoids; nitrogen compounds. which includes various amino acids; and carotenoids, most notably beta-carotene. Other agents may have antioxidant effects through replenishing mechanisms - Vitamin C, for instance, helps to recycle Vitamin E, and NAC (N-acetyl cysteine) provides an important component of glutathione.

Low levels of free radicals are necessary for a number of important physiological functions including the inflammatory response, cell division, and white blood cell action against bacterial infection. Thus the importance of maintaining a system of checks and balances between antioxidants and free radicals and their compounds, where the balance is weighted on the side of antioxidants.

When the balance between free radicals and antioxidant supply is tipped, resulting oxidative stress can cause many problems. Part of the confusion stems from the dilemma: are increased free radicals a cause or effect of disease? There is no solid evidence in either direction.

This article will focus on the function of glutathione (GSH), and the theory and evidence to date of the role of the GSH replenishing drugs NAC (N-Acetyl Cysteine) and Procysteine (OTC). NAC and Procysteine NAC is a derivative of cysteine, an amino acid, which is essential for the synthesis of GSH in the body. In the U.S. it is available as the prescription aerosolised drug Mucomyst by Bristol Laboratories, a division of Bristol-Myers and is used to treat acetaminophen (Tylenol) overdose and chronic bronchitis.

In Europe where it has been used orally for decades it is marketed under the trade name of Fluimucil by Italy's Zambon group. The oral European version of NAC is available at buyers' clubs in the United States. Procysteine (OTC), a precursor of cysteine, is manufactured by Clintec Nutrition. It is not commercially available.

GSH is present in almost all human tissues. It is critical for a number of important cellular functions. Of primary importance, however, is its vital role as the principal intracellular defence against oxidation by free radicals and their compounds.

Staal et al, among others, state that: "NAC has anti retroviral effects in vitro, low toxicity in vivo, a long history of use in patients, can be given orally in a palatable form and is inexpensive." Side effects of oral administration of NAC are minimal, and are limited to nausea, vomiting or diarrhoea and, rarely, bronchospasms in patients with asthma. Diabetics should only use NAC under medical supervision.

In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon)-(carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon)-(carboxyethyl) lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable.

The control spinal cords displayed no significant immunoreactivities for any of these examined products. Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration.

Water-soluble derivatives of buckminsterfullerene (C(60)) derivatives area unique class of compounds with potent antioxidant properties. Studies on one class of these compounds, the malonic acid C(60) derivatives (carboxyfullerenes), indicated that they are capable of eliminating both superoxide anion and H(2)O(2), and were effective inhibitors of lipid peroxidation, as well.  Carboxyfullerenes demonstrated robust neuroprotection against excitotoxic, apoptotic and metabolic insults in cortical cell cultures. They were also capable of rescuing mesencephalic dopaminergic neurons from both MPP(+) and 6-hydroxydopamine-induced degeneration.

Although there is limited in vivo data on these compounds to date, we have previously reported that systemic administration of the C(3) carboxyfullerene isomer delayed motor deterioration and death in a mouse model of familial amyotrophic lateral sclerosis (FALS). Ongoing studies in other animal models of CNS disease states suggest that these novel antioxidants are potential neuroprotective agents for other neurodegenerative disorders, including Parkinson's disease.
Parkinsonism Relat. Disord. 2001 Jul;7(3):243-246 Dugan LL, Lovett EG, Quick KL, Lotharius J, Lin TT, O'Malley KL. Department of Neurology and Center for the Study of Nervous System Disease, Washington University School of  Medicine, 63110, St. Louis, MO, USA

Abstract: Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis.

A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. An increasing number of studies show that nutritional antioxidants (especially Vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed.

Neurodegenerative diseases and oxidative stress. PMID: 14739060