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The Role of Oxidative Stress in Alzheimer Disease
aging and is involved in a number of age-related disorders including atherosclerosis, ar-thritis, and neurodegenerative disorders. In the neurodegenerative diseases, oxidative stresshas been implicated in amyotrophic lateral sclerosis, Parkinson disease, Huntington dis- ease, and Alzheimer disease (AD). The neurodegenerative disorder receiving the most attentionhas been AD, in which an increase occurs in oxidation of brain lipids, carbohydrates, proteins, andDNA. Some of the products of oxidation have been found in the major histopathologic alterationsin AD: the neurofibrillary tangles (NFTs) and senile plaques (reviewed in Markesbery and Car-ney1 and Ceballos-Picot2). These oxidative modifications are closely associated with a subtle in-flammatory process in the brain in AD.
Oxidative stress refers to a state in which free radicals and their products are in ex- cess of antioxidant defense mechanisms.
This imbalance can occur as a result of in- posed of easily oxidized lipids, has a high oxygen consumption rate, and lacks strong crease in antioxidant defenses. Free radi- antioxidant defenses, it is quite vulner- able to oxidative injury. It has been dem- onstrated that there is an increase in oxi- lecular oxygen to water is a major source the most consistent risk factor for AD. An- of potent radicals. The initial step in this other factor that makes the brain more sus- ence of increased iron, a critical element dition of an electron. The reduction of hy- in the generation of ROS. The gradual ac- tive hydroxyl radical. These radicals plus singlet oxygen are called reactive oxygen the late-life onset and gradually progres- species, nitric oxide, and peroxynitrite also stress. These free radicals and others are capable of reacting with lipids, proteins, nucleic acids, and other molecules and al- of the oxygen is reduced to hydrogen per- tering their structure and function. Oxi- dative stress can lead to alterations in cells stressful conditions and in aging, the elec- tron transport system can increase ROS for- dria are both a source and a target of toxic ROS. Mitochondrial dysfunction and oxi-dative metabolism may play an impor- From the Sanders-Brown Center on Aging, Departments of Pathology and Neurology, University of Kentucky Medical Center, Lexington. other neurodegenerative diseases (see Beal3 1999 American Medical Association. All rights reserved.
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for review). Reduced cytochrome oxidase activity and PROTEIN OXIDATION
messenger RNA levels have been found in autopsied brainsof patients with AD. Using cybrid techniques, research- The oxidation of proteins by free radicals may also play ers have shown that AD cytochrome oxidase defects can a meaningful role in AD. Hydrazide-reactive protein car- be transferred into cybrid cell lines that demonstrate in- bonyl is a general assay of oxidative damage to protein.
creased cytosolic calcium concentrations and an in- Several studies demonstrate an increase in protein car- crease in free radical production.4 Overall, it seems that bonyls in multiple brain regions in subjects with AD and the mechanisms by which mitochondrial dysfunction can in their NFTs.10 The oxidation of brain proteins may be lead to neuron degeneration in AD is through impaired at the expense of enzymes critical to neuron and glial func- production of adenosine triphosphate, altered calcium tion. Two enzymes that are especially sensitive to oxi- homeostasis, ROS generation, activation of the mito- dative modification are glutamine synthetase and cre- chondrial permeability transition, and excitotoxicity.
atine kinase, both of which are markedly diminished inthe brains of subjects with AD. Oxidative alterations in LIPID PEROXIDATION
glutamine synthetase could cause alteration of gluta-mate concentrations and enhance excitotoxicity, whereas Increased lipid peroxidation occurs in the brain in AD and oxidative impairment of creatine kinase could cause di- is most prominent where degenerative changes are most pronounced.1 Brain membrane phospholipids are com- Pathologic aggregation of proteins into fibrils is a posed of polyunsaturated fatty acids, which are especially characteristic of AD. Oxidative modifications can cause vulnerable to free radical attack because their double bonds crosslinking of covalent bonds of proteins leading to fi- allow easy removal of hydrogen ions. Decreases in poly- bril formation and insolubility. Neurofibrillary tangles unsaturated fatty acids, primarily arachidonic and doco- are characterized by the aggregation and hyperphos- sahexaenoic acids, accompany lipid peroxidation in AD.
phorylation of tau proteins into paired helical fila- Oxidation of polyunsaturated fatty acids produces alde- ments. Phosphorylation is linked to oxidation through hydes, one of the most important of which is 4-hydroxynon- the microtubule-associated protein kinase pathway and enal (HNE), a highly reactive cytotoxic substance capable through the activation of the transcription factor NF␬B, of inhibiting glycolysis, nucleic acid and protein synthe- thus potentially linking oxidation to the hyperphos- sis, and degrading proteins. Four-hydroxynonenal levels phorylation of tau proteins. Oxidation of cysteine in tau are increased in autopsied specimens from multiple brain protein controls the in vitro assembly of paired helical regions and in the cerebrospinal fluid (CSF) in subjects with filaments. The role of oxidation damage in NFT forma- AD, and HNE adducts are present in NFTs.1 Glutathione tion is supported by the presence of protein carbonyls, transferases, a group of enzymes that inactivate the toxic nitrotyrosine (a marker of the potent radical peroxyni- products of oxygen metabolism including 4-hydroxy- trite), HNE, acrolein (another highly reactive aldehyde alkenals such as HNE, are markedly diminished in mul- product of lipid peroxidation), advanced glycation end tiple brain regions and in the CSF in subjects with AD, sug- products (AGE), and hemeoxygenase-1 (an antioxidant gesting a loss of protection against HNE.5 Four-hydroxynonenal causes degeneration and death of cultured hippocampal neurons by impairing ion- DNA OXIDATION
motive adenosine triphosphatase activity and disrupt-ing calcium homeostasis.6 Exposure of cultured hippo- Oxidation of DNA can produce strand breaks, sister chro- campal neurons to ␤-amyloid (␤A) peptide causes a matid exchange, DNA-protein crosslinking, and base significant increase in levels of free and protein-bound modifications. The DNA damage accumulating in non- HNE and increases ROS. Four-hydroxynonenal impairs dividing mammalian cells may play a major role in aging- glucose and glutamate transport and is capable of induc- associated changes. Several studies demonstrate an ing apoptosis in cultured neurons. Administration of HNE increase in oxidative DNA damage in the brains of sub- into the basal forebrain of rats causes damage to cholin- jects with AD (see Gabbita et al11 for review). The most ergic neurons, diminished choline acetyltransferase, and pronounced DNA adduct described is 8-hydroxy-2Ј- deoxyguanosine (8-OHdG), which is increased in nuclear The F2-isoprostanes are prostaglandin-like com- and mitochondrial brain fractions in AD. Elevations of pounds that are formed nonenzymatically by free 5-hydroxyuracil, 8-hydroxyadenine, and 5-hydroxycy- radical–induced oxidation of arachidonic acid. Oxida- tosine levels also have been found in nuclear brain frac- tion of docosahexaenoic acid forms F4-neuroprostanes.
tions in subjects with AD. The pattern of damage to mul- F2-isoprostanes are elevated in postmortem ventricular tiple bases is most likely due to hydroxyl radical attack CSF of subjects with AD,8 and in the lumbar CSF from on DNA. Elevations of 8-OHdG levels in intact DNA have living patients with probable AD, but not in the CSF from been described in the CSF of patients with AD, along with living patients with amyotrophic lateral sclerosis.9 F4- a decrease in free 8-OHdG, representing the repair prod- neuroprostane levels are elevated in postmortem ven- uct, suggesting that there is a double insult of increased tricular CSF8 and are more abundant in the brain than DNA damage and deficiencies in repair mechanisms re- F2-isoprostane levels. This suggests that these quantifi- sponsible for removal of oxidized bases in AD.12 able markers of brain lipid peroxidation potentially could The importance of finding increased products of be used to assess the efficacy of therapeutic agents to de- oxidation in the CSF of patients with in AD (HNE, F2- isoprostanes, F4-neuroprostanes, 8-OHdG) deserves fur- 1999 American Medical Association. All rights reserved.
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ther study. Perhaps, coupled with the elevated tau pro- that damage enzymes. They also generate radicals through tein levels and decreased levels of ␤A peptides in AD CSF,13 interaction with iron and zinc, both of which are in- they could possibly be used to improve the diagnostic ac- creased in the brain of subjects with AD.
Familial, early-onset, autosomal-dominant AD is as- sociated with mutations in the presenilin genes 1 and 2 GLYCO-OXIDATION
and the amyloid precursor protein. Experimental stud-ies using cultured cells and transgenic mice expressing Advanced glycation end products are posttranslational presenilin gene 1 mutations have yielded considerable modifications of proteins that are formed when the amino progress in understanding the pathogenetic mecha- group of proteins reacts nonenzymatically with mono- nisms of presenilin mutations.17 Neurons expressing mu- saccharides, and may play a role in AD that is linked to tant presenilin gene 1 exhibit increased levels of ␤A pep- oxidative modifications of ␤A peptides and tau.14 Ad- tides and altered calcium homeostasis in the endoplasmic vanced glycation end products are present in senile reticulum that lead to increased ROS production, mito- plaques in subjects with AD, and AGE-modified ␤A pep- chondrial dysfunction, and adenosine triphosphate deple- tides accelerate aggregation of soluble nonfibrillar ␤A pep- tion. This causes an apoptotic death of neurons that can tides. ␤-Amyloid peptide binds to the receptors for AGE be prevented by vitamin E and glutathione.
and generates ROS, activating ⌵F␬〉, which induces ex- Studies of transgenic mice and cultured neurons ex- pression of macrophage colony-stimulating factor, en- pressing the amyloid precursor protein mutations sug- hancing proliferation of microglia. Activated microglia gest that these mutations also lead to an increased pro- are capable of producing the superoxide radical and ni- duction of free radicals in neurons.16 Cultured cells tric oxide. Tau and AGE antigens are localized in NFTs, expressing mutated forms of amyloid precursor protein and glycated tau added to neuroblastoma cells in have an increased production of ␤A peptides and set in cultures induces lipid peroxidation.
motion a process of increasing oxygen free radicals, lipidperoxidation, and calcium dysregulation. Transgenic mice ENDOGENOUS ANTIOXIDANTS IN AD
overexpressing the amyloid precursor protein mutationdemonstrate HNE and hemeoxygenase-1 around ␤A pep- Multiple studies of copper/zinc– and manganese- tide deposits, and iron and pentosidine (an AGE) in the superoxide dismutase, glutathione peroxidase, glutathi- center of ␤A deposits, indicating an association be- one reductase, catalase activity, and gene expression in tween oxidative stress and ␤A deposition.18 autopsied brains of subjects with AD have not demon- Meta-analysis findings from 17 epidemiologic stud- strated a consistent pattern of change.1 Several studies ies suggest that nonsteroidal anti-inflammatory drugs play of brains from autopsies with short postmortem inter- a protective role against AD.19 A number of markers of val show elevation of activity and gene expression of these inflammation are present in the brain in AD, and some antioxidants in brain regions that demonstrate an in- are related to the morphological changes associated with crease of lipid peroxidation in AD, possibly reflecting a AD. Although the details of the inflammatory response compensatory rise in response to free radical genera- are beyond the scope of this review, it seems that the in- tion.1 Importantly, none of these major antioxidants is flammatory cascade is important in the pathogenesis of consistently diminished, indicating that this aspect of the AD and that microglia are key mediators of this re- defense mechanism against free radicals is intact. Recent sponse. The relationship between the inflammatory re- evidence suggests that methionine may act as an antioxi- sponse and free radical generation is of considerable theo- dant defense molecule in proteins by its ability to scav- enge oxidants and in the process undergo oxidation to form Although AD is probably associated with multiple methionine sulfoxide. The enzyme methionine sulfoxide etiologies and pathophysiologic mechanisms, it appears reductase reverses methionine sulfoxide back to methio- that oxidative stress is a part of the pathophysiologic pro- nine. Our recent study shows a statistically significant de- cess. It is not clear whether oxidative stress is a primary cline in methionine sulfoxide reductase in postmortem process in AD or the result of the disease, although emerg- brain specimens from subjects with AD,15 which may con- ing data indicate that oxidative damage is an early event tribute to an increase in protein oxidation in the AD brain.
in neurodegeneration in AD. Regardless of whether oxi-dative stress is a primary or secondary event, therapeu- CELL CULTURE AND TRANSGENIC
tic measures to decrease the level of oxidative stress and ANIMAL EXPERIMENTS
to reduce the risk or slow the progression of the diseaseare appropriate. Findings of a large multicenter trial sup- Data from cell culture and animal experiments by port this concept, showing that antioxidant therapy (vi- Mattson16 demonstrate that oxidative stress and dysregu- tamin E and/or selegiline hydrochloride) may slow the lation of calcium can damage neurons, which indicates progression of AD.20 Long-term treatment of subjects at a role for oxidative stress in the pathogenesis of AD. Ex- risk for AD, using more efficacious antioxidant thera- posure of cultured neurons to ␤A peptides causes an peutic agents, could potentially slow neuron degenera- increase in oxyradical formation and radical-mediated tion and delay or prevent the onset of the disease.
damage to membrane lipids and proteins. ␤-Amyloid–induced neuron death in vitro is attenuated by antioxi- Accepted for publication April 12, 1999. dants such as vitamin E and glutathione. ␤-Amyloid pep- This work was supported by grants 5P50 AG05144 and tides are capable of spontaneously forming oxygen radicals 1PO1 AG05119 from the National Institutes of Health, 1999 American Medical Association. All rights reserved.
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Bethesda, Md, and grants from the Abercrombie Founda- peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats. J Neuropathol Exp Neurol. 1998;57:257-267.
8. Montine TJ, Markesbery WR, Morrow JD, Roberts LJ. Cerebrospinal fluid F Dr Markesbery is on the scientific advisory board of prostane levels are increased in Alzheimer’s disease. Ann Neurol. 1998;44:410-413.
Centaur Pharmaceuticals Inc, but does not have stock or any 9. Montine TJ, Beal MF, Cudkowicz ME, et al. Increased CSF F2-isoprostane con- financial interest in the company. centration in probable AD. Neurology. 1999;52:562-565.
The author thanks Paula Thomason for editorial as- 10. Smith MA, Sayre LM, Perry G. Morphological aspects of oxidative damage in sistance and Jane Meara for technical assistance. Alzheimer’s disease. In: Beal MF, Howell N, Bodis-Wollner I, eds. Mitochondriaand Free Radicals in Neurodegenerative Diseases. New York, NY: Wiley-Liss; 1997: Reprints: William R. Markesbery, MD, 101 Sanders- Brown Building, University of Kentucky, Lexington, KY 11. Gabbita SP, Lovell MA, Markesbery WR. Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem. 1998;71:2034-2040.
12. Lovell MA, Gabbita SP, Markesbery WR. Increased DNA oxidation and de- creased levels of repair products in Alzheimer’s disease ventricular CSF. J Neu- 13. Kanai M, Natsubara E, Isoe K, et al. Longitudinal study of cerebrospinal fluid lev- 1. Markesbery WR, Carney JM. Oxidative alterations in Alzheimer’s disease. Brain els of tau, A␤1-40, and A␤1-42(43) in Alzheimer’s disease: a study in Japan.
2. Ceballos-Picot I. Oxidative stress in Alzheimer’s disease. In: Ceballos-Picot I, ed.
14. Munch G, Thome J, Foley P, Schinzel R, Riederer P. Advanced glycation end prod- The Role of Oxidative Stress in Neuronal Death. New York, NY: Springer Pub- ucts in aging and Alzheimer’s disease. Brain Res Brain Res Rev. 1997;23:134- 3. Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochim Bio- 15. Gabbita SP, Aksenov MY, Lovell MA, Markesbery WR. Decrease in peptide me- thionine sulfoxide reductase in Alzheimer’s disease brain. J Neurochem. 1999; 4. Parker WD, Davis RE. Primary mitochondrial defects as a causative event in Alz- heimer’s disease. In: Beal MF, Howell N, Bodis-Wollner I, eds. Mitochondria and 16. Mattson MP. Cellular actions of ␤-amyloid precursor protein and its soluble and Free Radicals in Neurodegenerative Diseases. New York, NY: Wiley-Liss; 1997: fibrillogenic peptide derivatives. Physiol Rev. 1997;77:1081-1132.
17. Mattson MP, Guo Q. The presenilins. Neuro-scientist. 1999;5:1-13.
5. Lovell MA, Xie C, Markesbery WR. Decreased glutathione transferase activity in 18. Smith MA, Hirai K, Hsiao K, et al. Amyloid-␤ deposition in Alzheimer transgenic brain and ventricular fluid in Alzheimer’s disease. Neurology. 1998;51:1562- mice is associated with oxidative stress. J Neurochem. 1998;70:2212-2215.
19. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as 6. Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP. A role for 4- hy- possible protective factors for Alzheimer’s disease: a review of 17 epidemio- droxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion ho- logic studies. Neurology. 1996;47:425-432.
meostasis and neuronal death induced by amyloid ␤-peptide. J Neurochem. 1997; 20. Sano M, Ernesto C, Thomas RG, A controlled trial of selegiline, alpha- tocopherol, or both as treatment for Alzheimer’s disease: the Alzheimer’s Dis- 7. Bruce-Keller AJ, Li YJ, Lovell MA, et al. 4-Hydroxynonenal, a product of lipid ease Cooperative Study. N Engl J Med. 1997;336:1216-1222.
1999 American Medical Association. All rights reserved.
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