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The adduct must still have an unpaired electron. A radical may be a reducing agent, donating a single electron. A radical may abstract a hydrogen atom from a C—H bond. A single initiation event thus has the potential to generate multiple peroxide molecules in a membrane by a chain reaction. Thus peroxidation of arachidonic acid gives six lipid hydroperoxides as well as cyclic peroxides and other products reviewed by Halliwell and Gutteridge including the isoprostanes IPs Fam and Morrow ; Morrow Similarly, eicosapentaenoic acid can give eight hydroperoxides and several cyclic peroxides, whereas docosahexaenoic acid, an important PUFA in brain lipids, can give 10 hydroperoxides plus a large number of cyclic peroxides.
Prostaglandin synthesis is intimately linked to lipid peroxidation, because low levels of peroxides accelerate cyclooxygenase action on PUFAs Smith For example, rupture of lysosomal membranes spills hydrolytic enzymes into the rest of the cell. These include the IPs, measurement of which is probably the best currently available assay of lipid peroxidation Morrow Increased formation of IPs is observed in many human including neurodegenerative diseases and after exposure of animals to a range of toxins Fam and Morrow Iron and copper ions accelerate lipid peroxidation, by two mechanisms Halliwell and Gutteridge In an analogous reaction, they can split lipid hydroperoxides.
All aerobic cells suffer oxidative damage, yet the mammalian brain is often said to be especially sensitive Halliwell , Hence it processes a lot of O 2 per unit tissue mass. The discrepancy is even more striking in young children, who have much smaller bodies but not proportionately smaller brains. A major reason for the high O 2 uptake is the vast amounts of ATP needed to maintain neuronal intracellular ion homoeostasis in the face of all the openings and closings of ion channels associated with propagation of action potentials and neurosecretion.
Thus interrupting mitochondrial function in neurons by toxins, or failing to supply O 2 or substrates for energy production, produces rapid damage. The death of cells or collapse of normal ion gradients e. Neurons treated with excess glutamate or other excitotoxins swell rapidly and die, usually by necrosis. Hydroxynonenal can readily damage glutamate transporters, slowing glutamate clearance Mattson and Chan Several neurotransmitters not glycine or glutamate are autoxidizable. Oxidation can be catalyzed by transition metal ions, as mentioned above, but if excess is present it can react with norepinephrine, dopamine and serotonin Wrona and Dryhurst to initiate their oxidation, which then continues with production of more ROS, quinones, etc.
Several brain areas e. Much iron in healthy brain is in ferritin, with some in hemosiderin. If insufficient dietary iron is available to babies and children there may be permanent impairment of brain function. Transferrin delivers most of the required iron across the blood—brain barrier, utilizing receptors located on the brain microvasculature Burdo and Connor In addition, products of lipid peroxidation can injure the brain. Other products of the IP pathway may also be neurotoxic, e.
Brain metabolism generates a lot of H 2 O 2 , not only via superoxide dismutases SODs see below but also by other enzymes. Especially important are monoamine oxidases A and B, flavoprotein enzymes located in the outer mitochondrial membranes of neurons and glia. The ammonia is disposed of by several mechanisms, including its use by glutamine synthetase. Antioxidant defenses are modest. In particular, catalase levels are low in most brain regions; levels are somewhat higher in hypothalamus and substantia nigra than in cortex or cerebellum reviewed by Halliwell Brain catalase is located in small peroxisomes microperoxisomes and its activity in rat or mouse brain is rapidly inhibited if aminotriazole is administered to the animals.
The catalase probably cannot deal with H 2 O 2 generated in other subcellular compartments. Cytokines can additionally be produced by activated astrocytes, which may again respond to them by iNOS induction. Thus microglia and astrocytes are major players in inflammatory processes in the brain Duncan and Heales CYP2E1 is also found. It is thus another potential source of oxidative stress. The magnitude of this may be small in normal brain because CYP2E1 levels are low. However, CYP2E1 metabolizes ethanol, acetone, halothane, related anesthetics and organic solvents such as CCl 4 and CHCl 3 , and its levels may be increased in human brain by ethanol and smoking.
RS, both directly e. Loss of trophic support can lead to oxidative stress and apoptosis in neurons, in part by activation of neuronal NADPH oxidase enzymes.
Hemoglobin is neurotoxic. This protein is normally safely transported in erythrocytes, which are rich in antioxidant defense enzymes. In addition, hemoglobin reacts with H 2 O 2 and other peroxides to form oxidizing species heme ferryl and various amino acid radicals capable of stimulating lipid peroxidation. One important defense may be to keep brain oxygen levels as low as possible consistent with normal function. Low O 2 decreases autoxidation reactions, mitochondrial production and oxidase activities.
Of course, keeping pO 2 low has a disadvantage; it renders the brain sensitive to interruptions of the O 2 supply.
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SODs must work together with enzymes that remove H 2 O 2. We have already mentioned catalases, but they are not very important to the brain, and are not present in brain mitochondria, where much is generated Turrens Glutathione peroxidases can additionally act on peroxides other than H 2 O 2 , e. They are a family of peroxidases that reduce H 2 O 2 and organic peroxides. They are homodimers and contain no prosthetic groups: the redox reactions are dependent on cysteine at the active sites.
Thioredoxin plays many other metabolic roles, including helping to repair oxidatively damaged proteins see below. Peroxiredoxins are generally slower at catalyzing H 2 O 2 removal than glutathione peroxidases, although the large amounts of peroxiredoxins present up to 0.
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Apparently even more odd, the eukaryotic peroxiredoxins are more susceptible to oxidation than bacterial ones Georgiou and Masip At low physiological H 2 O 2 concentrations, peroxiredoxins seem to dispose of much of the H 2 O 2 generated in animal cells. However, when the cell is exposed to extra H 2 O 2 e. However, too much peroxide can cause excessive peroxiredoxin inactivation and damage neurons. Indeed, in a study on rat brain using antibodies to detect total glutathione, in vivo levels appeared higher in neurons than in glia.
The brain is enriched in several low molecular mass antioxidants in addition to GSH, especially ascorbate vitamin C. Ascorbate concentrations in human CSF are higher than in plasma, and neurons and glia have transport systems that concentrate ascorbate even more, to millimolar intracellular levels Rice Neurons readily take up ascorbate, whereas astrocytes take up dehydroascorbate and convert it to ascorbate intracellularly Rice Levels of ascorbate in CSF and brain remain high even when the plasma level decreases, indicative of the importance of ascorbate to CNS function.
Mice lacking sodium—vitamin C transporter 2 show severely decreased ascorbate levels in the blood, brain and other tissues, indicating that this may be the most important transporter for brain ascorbate uptake. However, if iron or copper ions become available, e. Hence the net effect of ascorbate at sites of CNS injury is hard to predict. In general, the CNS is more severely affected than the peripheral nervous system, and sensory axons more than motor ones. Coenzyme Q may also be important Beal and Shults Some but not all reports suggest a protective effect of orally administered Ginkgo biloba extracts against the development of dementia.
Such effects if real are often attributed to the flavonoids present, which include myricetin and quercetin. Although largely synthesized in the liver, ceruloplasmin is additionally found in brain, largely in astrocytes, being anchored to glycosylphosphatidylinositol on the membrane. It plays an important role in brain iron metabolism Jeong and David ; the inborn disease aceruloplasminemia is associated with degeneration of the retina and basal ganglia and increased lipid peroxidation Miyajima Metallothioneins are major stores of intracellular zinc and also contain some copper.
Indeed, CO may be a neurotransmitter. Is HO good or bad? Enzymes that can repair damaged including oxidatively damaged DNA are present in neuronal nuclei and mitochondria Englander and Ma , and seem essential for normal function. Oxidatively damaged lipids can be cleaved from membranes by phospholipase A 2 and destroyed Nigam and Schewe Several mechanisms are available to deal with oxidatively damaged proteins. The reducing power is supplied by thioredoxin.
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MsrA has an essential cysteine residue at its active site. In some animal MsrB enzymes, a selenocysteine plays the same role Moskovitz and Stadtman There are several ways to destroy unwanted proteins. One is to dispatch them to the lysosomes, which contain hydrolytic enzymes, such as cathepsins. Lysosomes degrade proteins taken into cells by endocytosis, and also take up some cytoplasmic proteins and organelles e.
The devastating pathology of the neuronal ceroid lipofuscinoses, inborn defects in lysosomal function, illustrates the importance of this pathway to the nervous system Ezaki and Kominami The core of the system is the 20S proteasome, named for its sedimentation coefficient when spun in an ultracentrifuge. It is a cylindrical structure made of a stack of four rings, each containing seven protein subunits. The cylinder has three internal cavities: the central cavity contains proteolytic sites and access to it is controlled by gates from two outer cavities, too narrow to admit folded proteins.
In vivo , however, the 20S proteasome is often assembled into a larger structure, the 26S proteasome; the 20S cylinder plus additional groups of proteins 19S cap complexes attached at each end reviewed in Stefanis and Keller The 26S proteasome recognizes many of its targets e. Ubiquitination attachment of multiple ubiquitin molecules is ATP dependent.
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It is catalyzed by a group of enzymes that first attach ubiquitin to lysine residues on the target and then add more ubiquitins to lysines on the ubiquitin itself Fig. These E3 enzymes are largely responsible for the specificity with which proteins are targeted for degradation by the proteasome. If this does not happen, the cap structures recognize the polyubiquitinated protein, unfold it and feed it slowly into the proteolytic core using energy from ATP hydrolysis. Once inside, it is hydrolyzed into short peptides.
The 20S proteasome will not attack ubiquitinated proteins; recognition requires the cap complexes. Defects in the ubiquitin—proteasome system in PD. The green section shows recovery and recycling of ubiquitin molecules that are released from proteins. Also depicted are ways in which potential defects in the system cause PD. A variety of deletion and point mutations in the parkin gene can lead to PD.
Several inhibitors of the proteasome have been described.
Other inhibitors include epoxomycin, aclacinomycin A and MG a synthetic inhibitor. However, the role of ubiquitin is uncertain; the 20S proteasome alone seems able to recognize and degrade at least some oxidized proteins, but it is unclear how this happens. In addition, some oxidatively damaged proteins appear to inhibit proteasome function rather than being degraded by it.
It was noted earlier that many believe that excess production of causes O 2 toxicity. Removal of mitochondrial is therefore essential in the brain and elsewhere. Superoxide in aqueous solution does not react with many biomolecules, but the few that it does attack are very important. Second, inactivates several enzymes important in energy production and amino acid metabolism Imlay ; Liang and Patel Superoxide can also release iron from ferritins Paul , and we have already seen that degradation of heme proteins by H 2 O 2 can release iron Gutteridge The various neurodegenerative diseases have different symptoms, affect different parts of the brain, and have different causes.
I believe Halliwell , , that all these events constitute a vicious cycle, and any one of them could initiate neuronal cell death, rapidly recruiting the others to its evil purpose Fig.