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)

Postmortem changes in mitochondrial respiratory enzymes (Complex I-IV and NAD(+)-linked dehydrogenases in the TCA cycle) were studied in mouse brains and human frontal lobes. In mouse brains, activities of the enzymes studied were generally stable for as long as 12 h after cervical dislocation, except for the alpha-ketoglutarate dehydrogenase complex and NADP(+)-linked isocitrate dehydrogenase. In human frontal cortices, only NADH-ubiquinone reductase (Complex I) activity showed significant negative correlation with the duration between the patient's death and the freezing of the brain. No correlations between the activities of the enzymes studied and the age of the patients were noted. As most of our patients were 50 years of age or above, absence of the correlation cannot be extended to younger patients. From our observation, it was felt that analyses of these mitochondrial enzymes in human autopsy brains would give meaningful data. Preliminary observation in Parkinson's disease revealed a small but a significant decrease in the activity of Complex III in the striatum as compared with the control. Although, significance of our observation is not yet known, further studies on this line appear to be important to elucidate pathogenesis of Parkinson's disease.
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PMID:Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson's disease. 235 87

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

In this work, the tertiary butylhydroperoxide- (t-BuOOH) treated mouse was used as a model to study the oxidative stress that is associated with various neurodegenerative diseases. DNA was found to be an early target of t-BuOOH attack. Necrosis was associated with extensive DNA fragmentation that occurred in almost all regions of the brain within 20 min following intracerebroventricular (icv) injection of 109.7 mg/kg t-BuOOH. Apoptosis was associated with high levels of DNA fragmentation that was observed at 48 h after icv administration of 21.9 mg/kg t-BuOOH. Susceptibility to DNA damage was found to be age-dependent, since 24-mo-old mice exhibited consistently higher and more pervasive DNA damage than 8 mo-old-mice. Extensive DNA damage was seen in various brain regions in patients with Alzheimer disease (AD) and with both Alzheimer and Parkinson disease (AD-PD). These results directly implicate DNA damage in neurodegeneration. The DNA fragmentation ob-served can lead to both apoptosis and necrosis, as suggested by gel electrophoresis. Nicotinamide, a precursor of NAD in the brain, was able to prevent DNA fragmentation induced by low-dose t-BuOOH, when coadministered with the toxin.
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PMID:The effects of aging and neurodegeneration on apoptosis-associated DNA fragmentation and the benefits of nicotinamide. 943 58

Decreases in mitochondrial respiratory chain complex activities have been implicated in neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. However, the extent to which these decreases cause a disturbance in oxidative phosphorylation and energy homeostasis in the brain is not known. We therefore examined the relative contribution of individual mitochondrial respiratory chain complexes to the control of NAD-linked substrate oxidative phosphorylation in synaptic mitochondria. Titration of complex I, III, and IV activities with specific inhibitors generated threshold curves that showed the extent to which a complex activity could be inhibited before causing impairment of mitochondrial energy metabolism. Complex I, III, and IV activities were decreased by approximately 25, 80, and 70%, respectively, before major changes in rates of oxygen consumption and ATP synthesis were observed. These results suggest that, in mitochondria of synaptic origin, complex I activity has a major control of oxidative phosphorylation, such that when a threshold of 25% inhibition is exceeded, energy metabolism is severely impaired, resulting in a reduced synthesis of ATP. Additionally, depletion of glutathione, which has been reported to be a primary event in idiopathic Parkinson's disease, eliminated the complex I threshold in PC12 cells, suggesting that antioxidant status is important in maintaining energy thresholds in mitochondria. The implications of these findings are discussed with respect to neurodegenerative disorders and energy metabolism in the synapse.
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PMID:Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. 958

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson's disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson's disease.
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PMID:Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. 1031 60

Mitochondrial membrane potential (delta psi(m)) was determined in intact isolated nerve terminals using the membrane potential-sensitive probe JC-1. Oxidative stress induced by H2O2 (0.1-1 mM) caused only a minor decrease in delta psi(m). When complex I of the respiratory chain was inhibited by rotenone (2 microM), delta psi(m) was unaltered, but on subsequent addition of H2O2, delta psi(m) started to decrease and collapsed during incubation with 0.5 mM H2O2 for 12 min. The ATP level and [ATP]/[ADP] ratio were greatly reduced in the simultaneous presence of rotenone and H2O2. H2O2 also induced a marked reduction in delta psi(m) when added after oligomycin (10 microM), an inhibitor of F0F1-ATPase. H2O2 (0.1 or 0.5 mM) inhibited alpha-ketoglutarate dehydrogenase and decreased the steady-state NAD(P)H level in nerve terminals. It is concluded that there are at least two factors that determine delta psi(m) in the presence of H2O2: (a) The NADH level reduced owing to inhibition of alpha-ketoglutarate dehydrogenase is insufficient to ensure an optimal rate of respiration, which is reflected in a fall of delta psi(m) when the F0F1-ATPase is not functional. (b) The greatly reduced ATP level in the presence of rotenone and H2O2 prevents maintenance of delta psi(m) by F0F1-ATPase. The results indicate that to maintain delta psi(m) in the nerve terminal during H2O2-induced oxidative stress, both complex I and F0F1-ATPase must be functional. Collapse of delta psi(m) could be a critical event in neuronal injury in ischemia or Parkinson's disease when H2O2 is generated in excess and complex I of the respiratory chain is simultaneously impaired.
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PMID:Depolarization of in situ mitochondria due to hydrogen peroxide-induced oxidative stress in nerve terminals: inhibition of alpha-ketoglutarate dehydrogenase. 1038 74

3,4-Dihydroxyphenylacetaldehyde (DOPAL) has been reported to be a toxic metabolite formed by the oxidative-deamination of dopamine (DA) catalyzed by monoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by inhibition of the mitochondrial respiratory chain. Using inhibitors of mitochondrial complexes I, II, III and IV we found that inhibition of complex I and III increased levels of DOPAL and DOPET. Nerve growth factor-induced differentiation of PC12 cells markedly potentiated DOPAL and DOPET accumulation in response to metabolic stress. DOPAL was toxic to differentiated PC12 as well as to SK-N-SH cell lines. Because complex I dysfunction has been implicated in the pathogenesis of Parkinson's disease, the accumulation of DOPAL may explain the vulnerability of the dopaminergic system to complex I inhibition. The rapid appearance of DOPAL and DOPET after inhibition of complex I may be a useful early index of oxidative stress in DA-forming neurons.
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PMID:Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde. 1079 58

Parkinson's disease occurs in 1% of people over the age of 65 when about 60% of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+, the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.
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PMID:Parkinson's disease--redox mechanisms. 1137 51

This review aims to summarize the basic research in the field of intermittent hypoxia in the Soviet Union and the Commonwealth of Independent States (CIS) that scientists in other Western countries may not be familiar with, since Soviet scientists were essentially cut off from the global scientific community for about 60 years. In the 1930s the concept of repeated hypoxic training was developed and the following induction methods were utilized: repeated stays at high-mountain camps for several weeks, regular high altitude flights by plane, training in altitude chambers, and training by inhalation of low-oxygen-gas mixtures. To the present day, intermittent hypoxic training (IHT) has been used extensively for altitude preacclimatization; for the treatment of a variety of clinical disorders, including chronic lung diseases, bronchial asthma, hypertension, diabetes mellitus, Parkinson's disease, emotional disorders, and radiation toxicity, in prophylaxis of certain occupational diseases; and in sports. The basic mechanisms underlying the beneficial effects of IHT are mainly in three areas: regulation of respiration, free-radical production, and mitochondrial respiration. It was found that IHT induces increased ventilatory sensitivity to hypoxia, as well as other hypoxia-related physiological changes, such as increased hematopoiesis, alveolar ventilation and lung diffusion capacity, and alterations in the autonomic nervous system. Due to IHT, antioxidant defense mechanisms are stimulated, cellular membranes become more stable, Ca(2+) elimination from the cytoplasm is increased, and O(2) transport in tissues is improved. IHT induces changes within mitochondria, involving NAD-dependent metabolism, that increase the efficiency of oxygen utilization in ATP production. These effects are mediated partly by NO-dependent reactions. The marked individual variability both in animals and humans in the response to, and tolerance of, hypoxia is described. Studies from the Soviet Union and the CIS significantly contributed to the understanding of intermittent hypoxia and its possible beneficial effects and should stimulate further research in this direction in other countries.
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PMID:Intermittent hypoxia research in the former soviet union and the commonwealth of independent States: history and review of the concept and selected applications. 1216 64

It was established, that serotonin and dopamine content and dopamine uptake by brain nerve endings under experimental parkinsonism are decreased. Nicotinamide nicotinoyl-GABA administration leads to normalization these parameters. It was shown that NAm was more effective on serotonin content while nicotinoyl-GABA on dopamine one. Dopamine uptake was impaired at experimental parkinsonism and partially was normalized by incubation with NAD (10(-6) M). Thus, NAm, nicotinoyl-GABA and NAD are involved in the regulation of brain neurotransmission under experimental parkinsonism and can be useful in treatment of Parkinson's disease.
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PMID:[Correction by nicotinamide and nicotinoyl-GABA of dopamine metabolism in rat brain in experimental Parkinson's disease]. 1219 67


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