Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured metabolites of tyrosine and tryptophan (TRP) in the frontal cortex, putamen (PT), and pars compacta of the substantia nigra (SN) of control and Parkinson's disease (PD) brain tissues. Dopamine concentrations were significantly decreased in the PT and SN of PD tissue, regardless of L-dopa therapy. However, 3-O-methyldopa (3OMD) concentration showed a significant increase in each region of the PD group treated with L-dopa (PD[+]) as compared with both the control group and the PD group without L-dopa therapy (PD[-]). Therefore, 3OMD concentration appears to be a reliable marker of L-dopa therapy. Serotonin concentration was lower in each region of the PD groups than in the control group. Although the magnitude of decrease was greater in the PD(+) group, there was no statistical significance between the two PD groups. The same patterns of decrease were present in kynurenine (KYN) and kynurenic acid (KYA) concentrations, but the molar ratios of TRP to KYN and KYN to KYA were unchanged among three groups. In contrast, 3-hydroxykynurenine (3OHKY) concentration was increased in the PT PD(-) group and in three regions of the PD(+) group. Since the KYN pathway leads to formation of nicotinamide-adenine dinucleotide (NADH), the present results may be a further indication of a defect in NADH:ubiquinone oxidoreductase (complex I) in mitochondria in PD.
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PMID:Kynurenine pathway abnormalities in Parkinson's disease. 151 57

Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD50 = 90 micrograms. Norepinephrine was less effective with LD50 = 141 micrograms. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine significantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH dehydrogenase activity with IC50 = 8 microM, and that of norepinephrine was twice as much (IC50 = 15 microM). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.
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PMID:Dopamine neurotoxicity: inhibition of mitochondrial respiration. 783 65

Dopamine (DA) deficiency in Parkinson's disease is commonly treated with L-dihydroxyphenylalanine (L-dopa), the amino acid precursor to DA. L-dopa is neurotoxic in vitro and impairs survival of metabolically stressed neurons in vivo. We examined with microdialysis of substantia nigra in awake rats the local production of hydroxyl (OH) radicals before and after systemic L-dopa. We found a dose-dependent increase in OH radical output which paralleled the rate of dopa catabolism, was not blocked by deprenyl, and was increased further by acute inhibition of mitochondrial complex I activity. Following high L-dopa doses, catabolism of dopa-derived DA can exceed capacity of nigral mechanisms to reduce formation of or detoxify free radicals.
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PMID:L-dopa increases nigral production of hydroxyl radicals in vivo: potential L-dopa toxicity? 806 Dec 80

We report the effect of papaverine, tetrahydro-papaverine, laudanosine, dimethoxyphenylethylamine, dopamine, and its metabolites on mitochondrial respiration and activities of the enzymes in the electron transfer complexes, as mitochondrial toxins may be implicated in the etiology and the pathogenesis of Parkinson's disease. Papaverine was the most potent inhibitor of complex I and NADH-linked mitochondrial respiration among the compounds tested next to rotenone. Tetrahydropapaverine, dimethoxyphenylethylamine, and laudanosine also inhibited NADH-linked mitochondrial respiration and complex I activity in this order. Dopamine and its metabolites showed either no inhibition or only very week inhibition. Compounds with dimethoxy residues in the phenyl ring were associated with more potent inhibition of complex I than those without. Our results warrant further studies on these and some related compounds as candidate neurotoxins causing Parkinson's disease.
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PMID:Effect of dopamine, dimethoxyphenylethylamine, papaverine, and related compounds on mitochondrial respiration and complex I activity. 876 81

Dopamine deficiency causes disinhibition and overactivity of the subthalamic nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a neurotransmitter. They project to the external and internal segments of the globus pallidum (GPe and GPi), the substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that contain glutamate receptors. Stimulation of the STN induces bursting activity in SNc dopaminergic neurons. This raises the possibility that the disinhibition of STN neurons that occurs as a result of a dopamine lesion might induce excitotoxic damage in target structures, including the SNc. In addition, the reduction in complex I activity found in the nigra in Parkinson's disease (PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons vulnerable to even physiologic concentrations of glutamate. We postulate that the dopamine loss that occurs in PD produces augmented STN activity which, in turn, causes further damage to vulnerable dopaminergic neurons, thereby creating a scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby account for the development of parkinsonian features that do not respond to levodopa in patients with advanced disease. This hypothesis suggests that pharmacologic or surgical therapies that reduce STN neuronal overactivity or block glutamate receptors in the SNc and other target structures might be neuroprotective and might slow or halt the progression of neurodegeneration in PD.
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PMID:Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. 974 91

Mitochondrial damage in PC12 cells, a model for dopaminergic cells, was examined in terms of the contribution of oxidative stress, nitric oxide (*NO), and dopamine to impairment of mitochondrial respiratory control (RC). A kinetic analysis suggested that the oxidative deamination of dopamine catalyzed by monoamine oxidase (MAO) was not a significant source of hydrogen peroxide, because of constrains imposed by the low cytosolic level of dopamine. *NO induced irreversible damage of mitochondrial complex I in PC12 cells: this damage followed a sigmoid response on *NO concentration with a well-defined threshold level. Dopamine did not elicit damage of mitochondria in PC12 cells; however, the amine potentiated the effects of *NO at or near the threshold level, thus leading to irreversible impairment of mitochondrial respiration. This synergism between *NO and dopamine was not observed at *NO concentrations below the threshold level. Depletion of dopamine from the storage vesicles by reserpine protected mitochondria from *NO damage. Dopamine oxidation by *NO increased with pH, and occurred at modest levels at pH 5.5. In spite of this, calculations showed that the oxidation of dopamine in the storage vesicles (pH 5.5) was higher than that in the cytosol (pH 7.4), due to the higher dopamine concentration in the storage vesicles (millimolar range) compared to that in the cytosol (micromolar range). It is suggested that storage vesicles may be the cellular sites where the potential for dopamine oxidation by *NO is higher. These data provide further support to the hypothesis that dopamine renders dopaminergic cells more susceptible to the mitochondrial damaging effects of *NO. In the early stages of Parkinson's disease, *NO production increases until reaching a point near the threshold level that induces neuronal damage. Dopamine stored in dopaminergic cells may cause these cells to be more susceptible to the deleterious effects of *NO, which involve irreversible impairment of mitochondrial respiration.
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PMID:Mitochondrial damage by nitric oxide is potentiated by dopamine in PC12 cells. 1246 Jun 81

Impairment of the mitochondrial complex I has been found in Parkinson's disease and recently long-term treatment with the complex I inhibitor rotenone led to neurodegeneration and Lewy body-like inclusions in rats. To investigate the relationship of free radical formation, complex I inhibition, and dopamine release, rotenone (15 mg/kg s.c.) was injected in male Sprague Dawley rats. Complex I inhibition was measured in the striatum and substantia nigra using the lactate accumulation assay. Dopamine release and free radical formation was determined using striatal microdialysis in combination with the salicylate hydroxylation assay. In a second experiment, glutamate (10 mM) stimulation via the microdialysis probe was used to provoke hydroxyl radical formation and dopamine release 60 min after rotenone or vehicle pretreatment. Rotenone significantly increased striatal and nigral lactate levels. However, rotenone did not produce a significant increase in hydroxyl radical formation and dopamine release, but led to a pronounced hypokinesia. In contrast, rotenone in comparison to vehicle pretreatment produced a significant augmentation of glutamate-induced dopamine release (67-fold and 31-fold increase, respectively) and did not affect the glutamate-induced hydroxyl free radical formation (23-fold and 21-fold increase, respectively). The present study demonstrates that a single systemic rotenone administration does not lead to neurotoxicity, but rather to enhanced glutamate-induced dopamine release with no further increase of hydroxyl free radical formation. Thus, acute complex I inhibition in the presence or absence of high extracellular dopamine and glutamate levels is not critically involved in the formation of hydroxyl free radicals.
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PMID:Rotenone increases glutamate-induced dopamine release but does not affect hydroxyl-free radical formation in rat striatum. 1451 42

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.
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PMID:Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. 1513 Jul 72

Diclofenac (DCF) is a widely used non-steroidal anti-inflammatory drug, which also act as a mitochondrial toxin. As it is known that selective mitochondrial complex I inhibition combined with mild oxidative stress causes striatal dopaminergic dysfunction, we tested whether DCF also compromise dopaminergic function in the striatum. [3H]Dopamine ([3H]DA) release was measured from rat striatal slices after in vitro (2 h, 10-25 micromol/L) or in vivo (3 mg/kg i.v. for 28 days) DCF treatment. In vitro treatment significantly decreased [3H]DA uptake and dopamine (DA) content of the slices. H2O2 (0.1 mmol/L)-evoked DA release was enhanced. Intracellular reactive oxygen species production was not significantly changed in the presence of DCF. After in vivo DCF treatment no apparent decrease in striatal DA content was observed and the uptake of [3H]DA into slices was increased. The intensity of tyrosine hydroxylase immunoreactivity in the striatum was highly variable, and both decrease and increase were observed in individual rats. The H2O2-evoked [3H]DA release was significantly decreased and the effluent contained a significant amount of [3H]octopamine, [3H]tyramine, and [3H]beta-phenylethylamine. The ATP content and adenylate energy charge were decreased. In conclusion, whereas in vitro DCF pre-treatment resembles the effect of the mitochondrial toxin rotenone, in vivo it rather counteracts than aggravates dopaminergic dysfunction.
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PMID:Modulation of dopaminergic neurotransmission in rat striatum upon in vitro and in vivo diclofenac treatment. 1803 94

Dopamine (DA) neurons in the substantia nigra (SNDA neurons) are among the most severely affected in Parkinson's disease (PD). Mitochondrial complex I inhibition by rotenone or MPTP can induce SNDA neurodegeneration and recapitulate motor disability in rodents. We performed a transcriptional analysis of the midbrain response to complex I inhibition focused on selected metabolic transcripts using quantitative real-time RT-PCR in conjunction with laser-capture microdissection (LCM) of immunofluorescently targeted SNDA and ventral tegmental area (VTA) DA neurons. There were DA neuron-selective alterations in metabolic transcripts in response to generalized complex I inhibition dependent on the behavioral response of the animal, and vulnerable SNDA neurons were more dynamic in their metabolic transcriptional response than less vulnerable VTADA neurons. The metabolic transcriptional response of DA neurons may contribute significantly to the ultimate toxicity associated with mitochondrial inhibition, and better understanding of this response may provide insight into potential targets for neuroprotection in PD.
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PMID:Neuron-selective changes in RNA transcripts related to energy metabolism in toxic models of parkinsonism in rodents. 2030 67


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