Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 microM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drug-type specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease.
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PMID:Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease. 776 91

Iron and lipid peroxidation are believed to be involved in the degeneration of pigmented neurons in Parkinson's disease. Melanin-iron interaction is thought to play a role in iron accumulation and reactivity. The purpose of this study was to examine antioxidant properties of isolated natural and synthetic neuromelanin. Effect of neuromelanin from substantia nigra and its synthetic model, dopamine melanin, on lipid peroxidation, induced by ferrous ions and free-radical initiators, has been studied in methyl linoleate aqueous dispersions. 2,2'-Azobis(amidinopropane)dihydrochloride and 2,2'-azobis(2,4-dimethyl-valeronitrile) were used as water-soluble and lipid-soluble radical initiator, respectively. Rate of oxidation was followed quantitatively by measuring oxygen uptake and accumulation of lipid hydroperoxides. Melanin had a distinct protective effect on lipid peroxidation induced by ferrous ions or water-soluble free-radical initiator but was relatively inefficient when peroxidation was initiated with lipid-soluble compound. It also inhibited iron-catalyzed decomposition of methyl linoleate hydroperoxides in the presence of ascorbate. Extent of the inhibition depended on the ratio of melanin to iron. Taken together, these results provide strong support for the idea that neuromelanin of pigmented neurons can act as a natural antioxidant by sequestering redox-active metal ions.
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PMID:Antioxidant action of neuromelanin: the mechanism of inhibitory effect on lipid peroxidation. 777 78

Positron emission tomography (PET) is a method for quantitative imaging of regional physiological and biochemical parameters. Positron emitting radioactive isotopes can be produced by a cyclotron, eg. the biologically important carbon (11C), oxygen (15O), and nitrogen (13N) elements. With the tomographic principle of the PET scanner the quantitative distribution of the administered isotopes can be determined and images can be provided as well as dynamic information on blood flow, metabolism and receptor function. In neurology PET has been used for investigations on numerous physiological processes in the brain: circulation, metabolism and receptor studies. In Parkinson's disease PET studies have been able to localize the pathology specifically, and in early stroke PET technique can outline focal areas with living but non-functioning cells, and this could make it possible to intervene in this early state. With positron emission tomography a quantitative evaluation of myocardial blood flow, glucose and fatty acid metabolism can be made as well as combined assessments of blood flow and metabolism. Combined studies of blood flow and metabolism can determine whether myocardial segments with abnormal motility consist of necrotic or viable tissue, thereby delineating effects of revascularisation. In the future it will probably be possible to characterize the myocardial receptor status in different cardiac diseases. The PET technique is used in oncology for clinical as well as more basic research on tumor perfusion and metabolism. Further, tumor uptake of positron labelled cytotoxic drugs might predict the clinical benefit of treatment.
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PMID:[Positron emission tomography. A new measurement method for imaging of regional and biochemical parameters]. 781 6

The current research has demonstrated that MPP+ can induce lipid peroxidation in the nigrostriatal system of rat in vivo. Antioxidant agent U-78517F and .OH scavenger DMSO may protect against MPP+ toxicity through the inhibition of .OH radical-mediated oxidative injury in the substantia nigra. These findings indicate that the cytotoxic hydroxyl radical generated from dopamine oxidation in the iron-rich basal ganglia may contribute to the mechanism underlying the selective A9 melanized nigral degeneration in MPTP-Parkinsonism and possibly in idiopathic Parkinson's disease. In addition, the present studies also clearly demonstrate that deprenyl can substantially protect dopaminergic neurons against MPP+ toxicity in the substantia nigra zona compacta in vivo. The neuroprotective effect provided by deprenyl may not be the consequence of its inhibition of MAO-B activity or prevention of the uptake of MPP+ by dopaminergic neurons. A unique antioxidant property of deprenyl by suppressing .OH formation and associated oxidative injury induced by MPP+ may contribute to the apparent neuroprotective action. In perspective, this putative antioxidant effect of deprenyl may provide another mechanism to its overt neuroprotective effects against oxygen radical-mediated oxidative injury in some neurotoxic chemicals, such as 6-OHDA and DSP-4, and probably in Alzheimer's disease and senescent changes. Finally, based on the present data, a possible neuroprotective therapeutic window of deprenyl in the treatment of early Parkinson's disease has been proposed. It is suggested that deprenyl should be introduced as early as possible in de novo Parkinsonian patients to achieve its full neuroprotective effect on nigral degeneration. Moreover, a combination of early detection of individuals at risk of developing Parkinson's disease and early intervention of deprenyl and/or other centrally active antioxidants to these patients may provide a new preventive therapeutic strategy in the future, in addition to the current conventional levodopa treatment of Parkinson's disease.
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PMID:Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). 783 30

In the last 4 years much progress has been made in the understanding of mitochondrial disorders. Point-mutations, deletions and depletion of the mitochondrial genome are associated with disorders like Leber's disease, MERRF (Myoclonus Epilepsia with Ragged Red Fibers), MELAS (mitochondrial Myopathy, Encephalopathy, Lactic acidosis and Stroke-like episodes) and several others. Recently, mitochondrial dysfunctions have been also related to neurodegenerative disorders like Parkinson's disease and to aging. Since the brain depends mostly on mitochondrial energy supply, mitochondrial dysfunctions may affect the nervous system more severely than other tissues causing or worsening diseases and playing a role in the biological deterioration of aging. Furthermore, the mitochondrial energy supply is associated with the production of highly reactive oxygen species. Ninety-five percent of the molecular oxygen is metabolized within the mitochondria by the electron-transport chain so that mitochondria are highly exposed to oxidative stress which may damage selected neuronal populations. Oxygen radicals created during respiration induce mitochondrial dysfunction which accelerates the production of more deleterious species of oxygen. The latter step further increases mitochondrial malfunction, thus intensifying and perpetuating the cycle. These two mechanisms combined may lead to cell death in brain and other tissues with high metabolic rate. Therefore, in neurodegenerative disorders such as Parkinson's disease mitochondrial dysfunction and oxidative stress may cause or worsen the clinical features.
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PMID:Oxidative stress and mitochondrial dysfunction in neurodegeneration. 784 18

The function of neuromelanin accumulation in the nigrostriatal dopamine neurons remains uncertain. Nevertheless, it is recognized that neuromelanin disappearance parallels the loss of dopamine neurons in Parkinson's disease, suggesting its participation in nigral cell death. It has been well known for some years that in systemic tissues melanin is a double-edged sword. On the one hand it can act as an antioxidant, but in the presence of transitional metals (primarily, iron) and drugs it promotes the formation of reactive oxygen free radicals. It is now apparent that synthetic dopamine-melanin and neuromelanin exhibit similar properties in vitro and nigrostriatal dopamine neuron co-culture studies. Thus, the identification of ionic iron in dopamine neurons of Parkinson's disease zona compacta and its association with neuromelanin has conferred a cytotoxic property to neuromelanin. This may explain the reported vulnerability of substantia nigra dopamine neurons in Parkinson's disease.
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PMID:The enigma of neuromelanin in Parkinson's disease substantia nigra. 788 93

We studied cerebral blood flow and oxygen metabolism in 6 patients with pure akinesia (PA), 8 patients with progressive supranuclear palsy (PSP), 16 patients with Parkinson's disease (PD), and 10 normal control subjects using positron emission tomography (PET). Regions of interest were studied in the cerebral cortex (the frontal, temporal, parietal, and occipital lobe), thalamus, cerebellar hemispheres, cerebellar vermis, and brainstem. In patients with PA, regional cerebral blood flow (CBF) was significantly decreased in the frontal cortex, thalamus, and brainstem compared with normal control subjects. PSP patients showed significantly decreased CBF in the entire cerebral cortex, thalamus, cerebellar hemispheres, and brainstem and regional cerebral oxygen metabolic rate (CMRO2) in the frontal cortex, thalamus, and brainstem, whereas patients with PD were revealed to be normal in both CBF and CMRO2 values. In conclusion, a part of patients with PA may be in the early stage of PSP or may be atypical presentations of PSP whose symptom is only akinesia judging from the followings. 1) PET findings demonstrated a close similarity between PA and PSP; a pattern of CBF and CMRO2 decrement especially in the frontal cortex, thalamus and brainstem. 2) Patients with PA were shown to have similar pathological changes to PSP in recent studies. 3) Several authors reported that some PSP cases could show only akinesia initially, later developing dementia, supranuclear ophthalmoplegia, pseundobulbar palsy, and nuchal rigidity during their illnesses.
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PMID:[Cerebral blood flow and oxygen metabolism in patients with pure akinesia and progressive supranuclear palsy]. 795 10

Oxidants are ubiquitous in our aerobic environment and could play an etiological role in aging and neurodegenerative diseases such as Alzheimer's disease. All cells contain several antioxidant enzymes, most importantly, superoxide dismutases (MnSOD and CuZnSOD), glutathione peroxidase (GSH-Px), glutathione reductase and catalase. The individual contribution of these antioxidant enzymes in neuronal protection during aging and under in vivo conditions remains unknown. We feel that the use of genetic manipulations to construct cells and/or transgenic mice that specifically overexpress or lack a single function represent a way to an understanding of the role of the individual antioxidant enzymes in neuronal aging. Copper-zinc superoxide dismutase (CuZnSOD) is one of the genes encoded by chromosome 21. As a consequence of gene dosage excess, CuZnSOD activity and protein are increased by 50% in all tissues of Down syndrome (DS) patients. It has been suggested that this increment, by accelerating hydrogen peroxide formation, might promote oxidative damage within DS cells and might be involved in the various neurobiological abnormalities found in DS such as premature aging and Alzheimer-type neurological lesions. Moreover, the level of CuZnSOD protein and mRNA is particularly high in pyramidal hippocampal neurons susceptible to degenerative processes in Alzheimer's disease, and in dopaminergic melanized-neurons vulnerable in Parkinson's disease. In order to test this hypothesis, we have created transfected cells and transgenic mice which express human CuZnSOD gene. An oversupply of this enzyme is not beneficial to the brain of transgenic mice and causes increased thiobarbituric-reactive substances (TBARS), an index of lipid peroxidation, and may be due to peroxides generated by an imbalance between enzymatic activities of CuZnSOD and GSH-Px. Unlike what has been observed in transfected cells with the human CuZnSOD gene, but similar to what was found in the DS fetal brain, the GSH-Px activity was not increased in the brain of transgenic mice. One possibility to explain this discrepancy could be the differential cellular localization of these two enzymes in the brain (CuZnSOD in neurons and GSH-Px in glial cells). This heterogeneous cellular distribution of the enzymes implicated in oxygen-free radicals detoxification could participate to a selective neuronal degeneration. Interestingly, overexpression of CuZnSOD in the brain of transgenic mice is associated with an increased MnSOD activity, the mitochondrial form of the enzyme. This increased MnSOD might be a defense response to protect mitochondria from oxidative damage.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Transgenic mice overexpressing copper-zinc superoxide dismutase: a model for the study of radical mechanisms and aging]. 801 10

Monoamine oxidase is an iron containing enzyme that exists as 2 isozymes, A and B, that have different affinities for various amines as substrates. The activity of monoamine oxidase helps to maintain neuron firing rates throughout the body within homeostatic limits. It does this by metabolizing in the liver bioactive amines absorbed into the bloodstream from food, by metabolizing in the endothelial cells of cerebral vascular microvessels, as part of the blood brain barrier, bioactive amines in the bloodstream, and by metabolizing in the cytoplasm of neurons, molecules of biogenic amine neurotransmitters that are not enclosed in vesicles. Part of the biochemical activity of monoamine oxidase generates hydroxyl radicals, very toxic members of the oxygen free radical group, that may be involved in neurodegenerative disorders such as Parkinson's disease. Inhibiting monoamine oxidase with selegiline (1-deprenyl) seems to have neuroprotective actions but this may be due to inducing the release of neuronal growth factors rather than by preventing the formation of free radicals. Other drugs that inhibit monoamine oxidase are used to treat patients with atypical depression, panic attacks or post traumatic stress syndrome. It is hypothesized that the emotions act as positive or negative reinforcers of behavior patterns that increase the probability of survival of the organism. The original releasing stimuli for the emotions are related to the basic survival reflexes of the hypothalamus but the emotional response can be easily conditioned to formerly neutral stimuli by association. In the absence of the original releasing stimuli, these learned emotions increase the frequency of survival oriented behavior and decrease the frequency of behavior that jeopardizes survival. The emotional disorders are conditions in which the brain's reinforcement system is inoperative, the person loses contact with reality and the person's behavior bears no relationship to survival. Aversive stimulation evokes a negative emotional response that motivates the organism to escape from the aversive stimulation, and to avoid it, and any conditioned stimuli associated it, in the future. When the aversive stimulation and to avoid it, and any conditioned stimuli When the aversive stimulation is inescapable or unavoidable, the organism experiences stress. When the stressful aversive situation is not lethal, survival does not depend on escape but rather on conservation of energy. With repeated exposure, the negative emotional response to the aversive stimulation extinguishes, the organism adapts to the situation and takes on a passive, energy saving behavior pattern.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:On the functions of monoamine oxidase, the emotions, and adaptation to stress. 808 27

Nitric oxide (NO) is a recently discovered endogenous mediator of vasodilatation, neurotransmission, and macrophage cytotoxicity. NO is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration. NO is formed from L-arginine by the enzyme NO synthase (NOS), for which tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's disease (AD) and, to a lesser degree, Parkinson's disease (PD) are thought to be associated with increased microglial activity, suggesting that NO production may be increased. Alternatively, in circumstances of reduced levels of intracellular L-arginine or BH4, NO production is diminished and neurotoxic oxygen radicals may be produced. Since BH4 is decreased in AD and PD brains, these diseases may be associated with decreased NO production. We investigated these two alternatives by measuring the NO degradation products nitrite and nitrate in cerebrospinal fluid (CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy (MSA; n = 14) patients and controls (n = 20). We found for all patient groups, compared with controls, significantly decreased levels of nitrate, but not nitrite. This finding seems to indicate a decreased NO production of the central nervous system (CNS) in these neurodegenerative disorders.
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PMID:Decreased cerebrospinal fluid nitrate levels in Parkinson's disease, Alzheimer's disease and multiple system atrophy patients. 813 11


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