What follows are a series of Medical journal abstracts which I found in the last hour by doing a search in Pubmed: http://www.ncbi.nlm.nih.gov/Entrez/medline.html
My search terms included Neurodegenerative, radical, Parkinson, oxidant.
Read the below articles or do your own search on Pubmed and draw you own conclusions as to whether the theory that free-radical production is associated with many diseases of aging is a valid one. It matters not to me personally whether people buy Usana products or any brand name vitamin or anti-oxidant compound. The theory that anti-oxidants may provide some protection to prevent nerve cell death due to free-radical damage is what I find fascinating and the information on the theory (in laymen's terms) is what I thought the articles I posted yesterday were useful for and obviously why I have kept them around in my folder all this time.
I also found this article yesterday in the Parkinson's list archives. It includes a bit more explanation of what free-radical damage is and what anti-oxidants actually do.
http://www.ionet.net/~jcott/homepage/archive/103.html I was wondering if anyone knew what date this article was written as it seems important since it talks about a call for volunteers for a 2 year drug study. If it was from 1997 or earlier obviously it's of little use to anyone now other than to try to follow up to see what the results of the study were.
Again, my interest in all this lies in the fact that my mother-in-law passed away from Multiple System Atrophy, a Parkinson's Plus disorder. It currently has no specific treatment other than for managing a few symptoms and can in some cases progress very quickly. As MSA is very rare it gets little press and even less specific research funding. For that reason I follow research on various neurodegenerative disorders in the hopes that something new discovered about one disease can potentially help another.
Regards,
Pam
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Neurology 1996 Dec;47(6 Suppl 3):S161-70
Oxidative stress and the pathogenesis of Parkinson's disease.
Jenner P, Olanow CW
Neurodegenerative Diseases Research Centre, King's College London, UK.
Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.
Publication Types:
a.. Review
b.. Review, academic
PMID: 8959985, UI: 97119162
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Neurology 1997 Jul;49(1 Suppl 1):S26-33
Attempts to obtain neuroprotection in Parkinson's disease.
Olanow CW
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
It is suggested that oxidant stress is a contributing factor in the pathogenesis of Parkinson's disease (PD). Oxidant stress may contribute to cell death in PD because oxidative metabolism of dopamine has the potential to yield highly reactive and cytotoxic free radicals. Evidence for this hypothesis includes: (1) increased dopamine turnover with increased hydrogen peroxide formation; (2) decreased glutathione availability; and (3) increased reactive iron in the brains of patients with PD. Antioxidant therapies might be neuroprotective and could slow the clinical progression of the disease whereas metabolites of levodopa therapy may accelerate the rate of neuronal degeneration. Laboratory studies demonstrate that both selegiline and dopamine agonists can provide neuroprotective benefits. Selegiline-treated patients require less levodopa and have a delay in the progression of parkinsonian signs and symptoms. Dopamine agonists provide antiparkinson benefits and also diminish the need for levodopa.
Publication Types:
a.. Review
b.. Review literature
PMID: 9222272, UI: 97365445
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Mov Disord 1998 Mar;13(2):281-6
Increasing striatal iron content associated with normal aging.
Martin WR, Ye FQ, Allen PS
Department of Medicine (Neurology), University of Alberta, Edmonton, Canada.
Free-radical-mediated mechanisms may contribute to neuronal damage in Parkinson's disease (PD), other neurodegenerative conditions also associated with aging, and the aging process itself. Cytotoxic free radicals are generated in the brain by oxidation/reduction reactions that are catalyzed by transition metals such as iron. Any regional increase in brain iron concentration may increase the potential for local free-radical formation. The purpose of this study was to determine the relationship between age and basal ganglia iron content in 20 normal individuals ranging from 24 to 79 years of age. We used an in vivo magnetic resonance method to quantify the effects of paramagnetic centers sequestered inside cellular membranes, thereby enabling the determination of a quantitative index of local brain iron content. We observed a strong direct relationship between age and regional iron content in the putamen (r = 0.76, p < 0.0001) and caudate (r = 0.69, p < 0.001), but not in the globus pallidus (r = 0.32, p = 0.17) or thalamus (r = 0.13, p = 0.58). In conclusion, striatal iron content increases with advancing age. This increase may increase the probability of free-radical formation in the striatum, therefore representing a risk factor for the development of neurodegenerative disorders such as PD in which nigrostriatal neurons may be affected by increased oxidant stress.
PMID: 9539342, UI: 98198748
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Ann Neurol 1998 Sep;44(3 Suppl 1):S189-96
The causes of Parkinson's disease are being unraveled and rational neuroprotective therapy is close to reality.
Marsden CD, Olanow CW
Institute of Neurology, London, United Kingdom.
There has been significant progress in our knowledge of the cause, the pathogenesis, and the nature of the mechanism of cell death in Parkinson's disease (PD). Mutations in single genes have now been shown to be able to cause PD but likely only account for a small number of cases. Alternatively, there is evidence that environmental factors play a large role in the majority of cases of sporadic PD. Most likely, genetic factors predispose patients to develop PD if combined with other gene mutations or environmental toxins. Interest has thus focused on factors that contribute to the pathogenesis of neurodegeneration and the mechanism of cell death in an attempt to design a neuroprotective therapy. Oxidant stress, mitochondrial dysfunction, excitotoxicity with excess nitric oxide formation, and glia and inflammatory processes are all thought to contribute to the cell death process and agents that interfere with these events may be neuroprotective. It is now generally held that the final culmination of these events is the induction of apoptosis in nigral dopaminergic neurons and this too offers opportunities for providing neuroprotection. A rational argument can be made for investigating a large number of different approaches or combination of approaches in the hope of developing a meaningful neuroprotective therapy, using clinically relevant indices and neuroimaging markers of nigral dopaminergic neurons. It is evident that conventional approaches to trials that utilize large numbers of patients in search of small incremental effects are costly and time consuming. As such, it will be virtually impossible to test all of the potentially valuable neuroprotective agents that are now at hand, let alone those that will likely soon emerge. We suggest that it may be more profitable to test a large number of agents in a small number of selected patients in search of a more robust neuroprotective effect. In this way, we will reduce the risk of missing a powerful neuroprotective treatment with a treatment that might not otherwise have been studied because of a lack of time, money, or patients.
Publication Types:
a.. Review
b.. Review, tutorial
PMID: 9749592, UI: 98420021
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Int J Vitam Nutr Res 1999 May;69(3):213-9
Vitamin E and other antioxidants in neuroprotection.
Behl C
Max Planck Institute of Psychiatry, Munich, Germany.
Several pathological conditions are believed to be causally related to the generation of reactive oxygen species and free radicals including various neurodegenerative disorders. In the histopathology of Alzheimer's disease (AD) many signs of oxidative reactions can be found building the basis of the oxidative stress hypothesis of AD. One major player in the generation of an overall oxidative microenvironment for the nerve cells is the amyloid beta protein (A beta) of the senile plaques in brain areas affected in AD. A beta can be neurotoxic and this toxicity is mediated by peroxides and by the peroxidation of membrane lipids leading to the lysis of the cell. Consequently, lipophilic free radical scavengers such as vitamin E and the recently discovered antioxidant activity of the female sex hormone estrogen protects neurons against the oxidative toxicity of A beta and other AD-related oxidative insults. In a first clinical trial using vitamin E in therapy, this antioxidant could slow down the course of the disease launching further clinical investigations. Although antioxidants act as non-specific protective chemical shields for neurons and do not target specific pathological events, they are highly effective and further investigations on their activity might lead to an even more effective application of antioxidants. Since the knowledge of the pathways of neuronal cell death that occur during oxidative challenges is increasing, it will be of central interest how antioxidants can interfere with signal transduction mechanisms and therefore also modify genetic programs. As long as specific interventions are not available the optimistic data concerning the neuroprotective activity of antioxidants in vitro and in vivo underline an important role for antioxidative acting compounds for the prevention and therapy of oxidative stress-related conditions including AD.
PMID: 10389030, UI: 99317261
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Free Radic Biol Med 1999 Aug;27(3-4):428-37
Peripheral markers of oxidative stress in Parkinson's disease. The role of L-DOPA.
Martignoni E, Blandini F, Godi L, Desideri S, Pacchetti C, Mancini F, Nappi G
Center for Parkinson's Disease and Movement Disorders, Neurological Institute C. Mondino, University of Pavia, Italy.
[Medline record in process]
Oxidative stress plays a central role in the pathogenesis of Parkinson's disease (PD). L-DOPA, the gold standard in PD therapy, may paradoxically contribute to the progression of the disease because of its pro-oxidant properties. The issue, however, is controversial. In this study, we evaluated peripheral markers of oxidative stress in normal subjects, untreated PD patients and PD patients treated only with L-DOPA. We also measured platelet and plasma levels of L-DOPA, 3-O-methyldopa (the long-lasting metabolite of the drug), and dopamine. We found that isolated platelets of treated PD patients form higher amounts of 2,3-dihydroxybenzoate, an index of hydroxyl radical generation, than platelets of controls or untreated patients. In treated patients, platelet levels of 2,3-dihydroxybenzoate were positively correlated with platelet levels of L-DOPA, 3-O-methyldopa, and with the score of disease severity. Disease severity was correlated with platelet and plasma levels of L-DOPA, as well as with the daily intake of the drug. No significant differences in platelet levels of cytosolic and mitochondrial isoforms of the antioxidant enzyme superoxide dismutase were found between PD patients, either treated or untreated, and controls. Our findings lend further support to the hypothesis that L-DOPA might promote free radical formation in PD patients.
PMID: 10468218, UI: 99396294
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J Neurochem 1999 Aug;73(2):881-4 Related Articles
Evidence for oxidative stress in the subthalamic nucleus in progressive supranuclear palsy.
Albers DS, Augood SJ, Martin DM, Standaert DG, Vonsattel JP, Beal MF
Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Increased free radical production and oxidative stress have been proposed as pathogenic mechanisms in several neurodegenerative disorders. Free radicals interact with biological macromolecules, such as lipids, which can lead to lipid peroxidation. A well-established marker of oxidative damage to lipids is malondialdehyde (MDA). We measured tissue MDA levels in the subthalamic nucleus (STN) and cerebellum from 11 progressive supranuclear palsy (PSP) cases and 11 age-matched control cases using sensitive HPLC techniques. In PSP, a significant increase in tissue MDA levels was observed in the STN when compared with the age-matched control group. By contrast, no significant difference between tissue MDA content was observed in cerebellar tissue from the same PSP and age-matched control cases. These results indicate that lipid peroxidation may play a role in the pathogenesis of PSP.
PMID: 10428088, UI: 99355042
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J Neural Transm Suppl 1999;56:127-37
Mechanism and consequences of nerve cell death in Parkinson's disease.
Hirsch EC
INSERM U 289, Hopital de la Salpetriere, Paris, France.
The etiology of Parkinson's disease remains unknown, making it difficult to develop therapeutical approaches to stop the progression of the disease. The best known treatment to date is based on the use of L-DOPA or dopaminergic agonists. These are merely substitutive therapies and have limitations because of their side effects. Thus, the development of new therapeutical strategies will require a far better knowledge of the mechanism and the consequences of nerve cell death in Parkinson's disease. Parkinson's disease is characterized by a selective vulnerability of sub-populations of dopaminergic neurons in the mesencephalon. The fact that the neurons which degenerate in Parkinson's disease are already sensitive to oxidative stress in control subjects and the reported increased production of oxygen free radicals in Parkinson's disease suggest that oxidative stress may be involved in the mechanism of nerve cell death. Furthermore, oxygen free radicals are also involved in an oxygen-dependent pro-apoptotic pathway stimulated by the inflammatory reaction observed in Parkinson's disease. These data suggest that anti-oxidant or anti-inflammatory treatments may slow down the progression of the disease. On the other hand, new substitutive therapies may be developed by trying to restore the activity of the neurons located downstream from the nigrostriatal pathway. Indeed, the nigrostriatal denervation induces a hyper-activity of the output structures of the basal ganglia (internal segment of the globus pallidus and substantia nigra pars reticulata), as demonstrated in various animal models of the disease. These changes in the activity of the output structures of the basal ganglia seem to be directly induced by the hyperactivity of the glutamatergic afferent fibers from the subthalamic nucleus. The fact that L-DOPA treatment or a reduction in the activity of the subthalamic nucleus alleviate the symptoms of the disease and restore the activity of the output structures of the basal ganglia in parkinsonism suggests that these structures play a key role in the pathophysiology of the disease and could represent a potential therapeutic target.
Publication Types:
a.. Review
b.. Review, tutorial
PMID: 10370907, UI: 99299045
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J Neural Transm Suppl 1999;56:193-210
Free radical scavengers: chemical concepts and clinical relevance.
Gassen M, Youdim MB
Merck KGaA, Darmstadt, Federal Republic of Germany.
Free radicals are involved in the pathology of many CNS disorders, like Parkinson's disease, Alzheimer's disease, or stroke. This discovery lead to the development of many radical scavengers for the clinical treatment of neurodegenerative diseases. In this review, the different chemical concepts for free radical scavenging will be discussed: nitrons, thiols, iron chelators, phenols, and catechols. Especially catechols, like the naturally occurring flavonols, the synthetic drug nitecapone, or the endogenous catacholamines and their metabolites, are of great interest, as they combine iron chelating with radical scavenging activity. We present data on the radical scvenging activity of dopamine and apomorphine, which prevent lipid peroxidation in rat brain mitochondria and protect PC12 cells against H2O2-toxicity.
Publication Types:
a.. Review
b.. Review, tutorial
PMID: 10370913, UI: 99299051
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Biofactors 1999;9(2-4):261-6
Coenzyme Q10 administration and its potential for treatment of neurodegenerative diseases.
Beal MF
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114, USA.
Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport chain as well as an important antioxidant. Previous studies have suggested that it may exert therapeutic effects in patients with known mitochondrial disorders. We investigated whether it can exert neuroprotective effects in a variety of animal models. We have demonstrated that CoQ10 can protect against striatal lesions produced by both malonate and 3-nitropropionic acid. It also protects against MPTP toxicity in mice. It extended survival in a transgenic mouse model of amyotrophic lateral sclerosis. We demonstrated that oral administration can increase plasma levels in patients with Parkinson's disease. Oral administration of CoQ10 significantly decreased elevated lactate levels in patients with Huntington's disease. These studies therefore raise the prospect that administration of CoQ10 may be useful for the treatment of neurodegenerative diseases.
Publication Types:
a.. Review
b.. Review, tutorial
PMID: 10416039, UI: 99344528
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Neurosci Lett 1999 Sep 3;272(1):53-6
Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex.
Polidori MC, Mecocci P, Browne SE, Senin U, Beal MF
Institute of Gerontology and Geriatrics, Perugia University Hospital, Italy. [log in to unmask]
[Medline record in process]
Oxidative damage to DNA may play a role in both normal aging and in neurodegenerative diseases. Using a sensitive high-performance liquid chromatography (HPLC) assay, we examined concentrations of 8-hydroxy-2-deoxyguanosine (OH8dG) in mitochondrial DNA (mtDNA) isolated from frontal and parietal cerebral cortex and from cerebellum in 22 Huntington's disease (HD) patients and 15 age-matched normal controls. A significant increase in OH8dG in mtDNA of parietal cortex was found in HD patients as compared with controls, while there were no significant changes in frontal cortex or cerebellum. The present findings are consistent with regionally specific oxidative damage in HD, which may be a further evidence of a metabolic defect.
PMID: 10507541, UI: 99435375
