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)

Although many authors have suggested that dopamine and its metabolites producing free radicals have an harmful effect in the substantia nigra, experimental evidence has not been shown. Using a newly established enzyme immunoassay of the neurofilament protein, a reliable index for the number of survived neurons in tissue culture, we evaluate the effects of Dopa on the neurons of dorsal root ganglia from mice. Neurons were destroyed by the exposure of 0.5 mM Dopa with or without superoxide dismutase and catalase, but they were saved by the pretreatment with 1.0 mM deferoxamine mesylate, a powerful iron-chelating agent. Formation of malondialdehyde, an index of lipid peroxidation, was also observed in the reaction of 0.5 mM Dopa and cerebral cortical neurons from new-born rats only when iron was present. These results indicate that Dopa initiates lipid peroxidation of cell membrane in the presence of a small amount of iron in the culture with little or no participation of reactive oxygen species, leading to the destruction of the neurons. In Parkinson's disease, the cytotoxic mechanism of Dopa and iron may involve the neuronal degeneration in the substantia nigra abundant in iron and dopaminergic neurons.
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PMID:[Iron-dependent cytotoxic effects of dopa on cultured neurons of the dorsal root ganglia]. 211 13

Neurophysiological studies were performed on 8 patients with group A xeroderma pigmentosum during early childhood. EEG, ABR and NCV were normal during this period. In contrast, various sleep parameters detected by polysomnography showed abnormal findings even in the neurologically normal patient. Decreased % sleep REM was seen in a case, and decreased frequency of REMs were seen in another. Body movements were extremely high or low in frequency in 3 cases in whole night sleep. The distribution of body movements were abnormal; in control subjects, the frequency was higher in SREM and stage 1 than in slow wave sleep; in 7 cases, it was higher in slow wave sleep than in stage 1 or 2, or body movements were extremely frequent. Neurological examination revealed soft signs in various systems in early childhood. All cases except one showed hypotonia. Many cases were slow in learning to walk and the gait was unstable. Speech delay and decreased deep tendon reflexes, especially of patella, were seen in most cases. Since the neural deficits in XP may be related to the DNA repair defect, these findings indicate the possibility that some endogenous compounds distributing all over the nervous system might produce the DNA damages. Because the body movements during sleep are controlled by the nigrostriatal dopaminergic system, present data indicate that the basal ganglia might be one of the earliest degenerative systems in the CNS. Recently, some studies have suggested the possibility that oxygen radical mechanisms might be involved in the development of the dopamine neurodegenerative process in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Neurophysiological studies on group A xeroderma pigmentosum in early childhood]. 217 31

Degenerative diseases of the nervous system which are considered to be related to free radicals are Parkinson's disease and Alzheimer-type dementia (ATD). Parkinson's disease is characterized by appearance of Leyw's body and degeneration of nigrostriatal dopaminergic system. But the most fundamental cause of this disease remains still unknown. The fact that H2O2 is formed in the process of oxidative deamination of catecholamines and some substances which can cause Parkinsonism in animal experiments also produce active oxygen in the metabolic processes suggest the important role of free radicals in the pathogenesis of Parkinson's disease. We recently observed that addition of DOPA and Fe3(+)-ADP complex to the microsomal phospholipid system produced lipid peroxides without participation of active oxygen. Neurons cultured in vitro also decreased significantly with addition of DOPA and Fe3(+)-ADP complex and this harmful effect was prevented by desferoxamine (potent Fe chelating agent) or alpha-tocopherol (antioxidant). These results may suggest that lipid peroxidation can occur by interaction of naturally existing substances in the dopaminergic system and induce cell damage. As regards ATD, there is still no definite evidence to support the implication of free radicals in its pathogenesis. However, there are reports that lipid peroxides increase significantly in the brains of patients with ATD. Moreover, recent advances in the study of amyloid in the senile plaque revealed close relationship of ATD to chromosome 21.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Free radicals and degenerative diseases of the nervous system]. 220 Sep 16

Positron emission tomography allows an in vivo assessment of various physiological and biochemical processes, for example cerebral blood flow, metabolism, or interactions between ligands and receptors. Data quantification and interpretation rest on models describing in a simple way the behavior of the labelled molecules. The general principles are common, but each model has limitations. The different methods are first validated in and applied to normal populations under resting conditions. New techniques for rapid assessments of blood flow and metabolism make it possible to measure cerebral activation after sensori-motor, mental or pharmacological stimulation. This should allow the study of recovery or plasticity of the lesioned brain, after a stroke for example. PET measurements of cerebral blood flow, oxygen consumption and extraction, and cerebral blood volume are particularly well suited to investigate the physiopathology of cerebrovascular diseases. Remote metabolic disturbances give information on interregional cerebral connections, and on clinico-metabolic correlations. In epilepsy, PET is useful in localizing the epileptogenic focus in partial epilepsy: it is hypometabolic interictally. The meaning of the hypometabolism has still to be established. New information about the neurochemistry of the epileptogenic focus should become available from studies of benzodiazepine, excitatory amino acid or opiate systems, for example. PET has already enabled pathophysiological hypotheses to be tested in status epilepticus. Disturbances of metabolism and neurotransmission systems have been observed at various stages and in various types of neurodegenerative diseases. The modifications are not only an early reflection of anatomopathological lesions, but could give more direct information on the pathogenesis or symptomatology of these diseases and hence lead to new therapeutic endeavours, such as appropriate replacement therapy analogous by to dopatherapy in Parkinson's disease.
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PMID:[Functional metabolic neuroimaging by positron-emission tomography in man]. 223 91

We have already described that ragged red fiber (RRF), core/targetoid fiber and type 1 fiber predominance were found at autopsy in the diaphragm taken from patients with chronic obstructive pulmonary diseases. The purpose of the present study is to investigate morphological and histochemical changes in the diaphragm in denervating neurologic disorders. The diaphragm in the costal portion was taken from 22 autopsy cases including 4 with amyotrophic lateral sclerosis (ALS), 4 cerebrovascular diseases, 3 Parkinson disease, 2 olivopontocerebellar atrophy. In addition, 4 diaphragm muscles were biopsied at the time of surgery for lung cancer. In the diaphragm we observed not only RRF and core/targetoid fiber but also cytoplasmic body and ring fiber in many cases. These findings were, however, not specific for neurologic disorders. Focal cytochrome c oxidase deficiency was found in muscles with RRF. It should be emphasized that RRF was absent in 3 of 4 cases with ALS and in a case with elevated hemidiaphragm from phrenic nerve paralysis. In the previous report, we suggested that RRF was formed under the relative ischemic state in overworking diaphragm. The relative ischemia means a condition that oxygen (energy) demand for respiratory work exceeds over oxygen supply from the blood in the overworking diaphragm. The reason why no RRF was found in the denervated muscle is that the ischemic state in the denervated muscles is relieved by immobilization after denervation. Karpati et al conformed that denervation prevented ischemic state in the muscle. Other histochemical features in the diaphragm included cytoplasmic body and ring fiber.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Morphological changes in human diaphragm--ragged red fiber, core/targetoid fiber, cytoplasmic body, and ring fiber]. 255 86

Rat fibroblasts were infected with a retroviral vector containing the cDNA for rat tyrosine hydroxylase [TH; tyrosine 3-monooxygenase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2]. A TH-positive clone was identified by biochemical assay and immunohistochemical staining. When supplemented in vitro with pterin cofactors required for TH activity, these cells produced L-dopa and released it into the cell culture medium. Uninfected control cells and fibroblasts infected with the TH vector were grafted separately to the caudate of rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Only grafts containing TH-expressing fibroblasts were found to reduce rotational asymmetry. These results have general implications for the application of gene therapy to human neurological disease and specific implications for Parkinson disease.
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PMID:Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease. 257 72

The primary pathological change in Parkinson's disease is the destruction of dopamine containing cells in the zona compacta of substantia nigra. The cause of nigral cell death and the underlying mechanism remains elusive. However, the discovery of the selective nigral neurotoxin MPTP and its ability to inhibit mitochondrial energy metabolism via its metabolite MPP+ and to generate superoxide radicals suggests processes by which nigral cell death might occur. Recent postmortem evidence in brain tissue from patients dying with Parkinson's disease also suggests the occurrence of some on-going toxic mechanism. This may be a free radical process stimulated by an excess of iron within substantia nigra coupled to a generalised decrease in brain ferritin content. These data suggest altered iron handling occurs in Parkinson's disease which may lead to the generation of toxic oxygen species such as superoxide radicals. There is also evidence for an inhibition of mitochondrial function in the substantia nigra in patients with Parkinson's disease. So there may be a close association between the actions of the synthetic neurotoxin MPTP and the underlying cause of idiopathic Parkinson's disease.
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PMID:Clues to the mechanism underlying dopamine cell death in Parkinson's disease. 266 76

Radicals are species containing one or more unpaired electrons. The oxygen radical superoxide (O2-) and the non-radical oxidant hydrogen peroxide (H2O2) are produced during normal metabolism and perform several useful functions. Excessive production of O2- and H2O2 can result in tissue damage, which often involves generation of highly-reactive hydroxyl radical (.OH) and other oxidants in the presence of "catalytic" iron ions. A major form of antioxidant defence is the storage and transport of iron ions in forms that will not catalyze formation of reactive radicals. Tissue injury, eg. by ischaemia or trauma, can cause increased iron availability and accelerate free radical reactions. This may be especially important in the brain, since areas of this organ are rich in iron and cerebrospinal fluid cannot bind released iron ions. Oxidant stress upon nervous tissue can produce damage by several interacting mechanisms, including rises in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that iron-dependent free radical reactions are involved in the neurotoxicity of aluminium and in damage to the substantia nigra in Parkinson's disease are reviewed. Finally, the nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of iron ions may be more generally-useful protective agents than chain-breaking antioxidants.
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PMID:Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson's disease, Alzheimer's disease, traumatic injury or stroke? 269 33

Progress in the research on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is reviewed, and the impact given by MPTP to the studies on Parkinson's disease is discussed. Our data on the mechanism of the neuronal degeneration in MPTP-induced experimental parkinsonism are also presented. We studied the effects of the 1-methyl-4-phenylpyridinium ion (MPP+) on mitochondrial respiration. Mitochondria were prepared from mouse brains, and oxygen consumption was measured polarographically. Activity of Complex I was measured after the incubation of the mitochondria with NAD(+)-utilizing substrates in the TCA cycle and ADP. MPP+ significantly inhibited the state 3 respiration supported by glutamate. Amount of ATP synthesized was also significantly reduced by MPP+. Activity of Complex I was significantly inhibited by MPP+. This inhibition was observed with 0.05 mM of MPP+ when intact mitochondria were used. These observations suggest mitochondria as the most probable site of the action for MPP+. It appears to be important to search for endogenous or exogenous toxic substances with similar pharmacological properties as MPTP to elucidate pathogenesis of Parkinson's disease. In addition, studies on mitochondrial functions in Parkinson's disease seem to be also important. Some preliminary data are shown.
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PMID:[Contribution of MPTP to studies on the pathogenesis of Parkinson's disease]. 269 96

Levels of iron, copper, zinc, manganese, and lead were measured by inductively coupled plasma spectroscopy in parkinsonian and age-matched control brain tissue. There was 31-35% increase in the total iron content of the parkinsonian substantia nigra when compared to control tissue. In contrast, in the globus pallidus total iron levels were decreased by 29% in Parkinson's disease. There was no change in the total iron levels in any other region of the parkinsonian brain. Total copper levels were reduced by 34-45% in the substantia nigra in Parkinson's disease; no difference was found in the other brain areas examined. Zinc levels were increased in substantia nigra in Parkinson's disease by 50-54%, and the zinc content of the caudate nucleus and lateral putamen was also raised by 18-35%. Levels of manganese and lead were unchanged in all areas of the parkinsonian brain studied when compared to control brains, except for a small decrease (20%) in manganese content of the medial putamen. Increased levels of total iron in the substantia nigra may cause the excessive formation of toxic oxygen radicals, leading to dopamine cell death.
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PMID:Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. 272 38


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