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)

A Lewy body dementing syndrome in the elderly has been recently described and designated senile dementia of Lewy body type (SDLT) on the basis of a distinct clinicopathological profile. The pathological changes seen in SDLT include the presence of cortical Lewy bodies (LB) frequently, but not invariably, associated with senile plaque (SP) formation. Whilst neocortical neurofibrillary tangles (NFT) are sparse or absent, a proportion of these cases show involvement of the temporal archicortex by lesions comprising Alzheimer-type pathology (ATP, i.e. NFT, SP and granulovacuolar degeneration [GVD]). Thus the relationship between SDLT and senile dementia of Alzheimer type (SDAT) is complex and controversial. In this study quantitative neuropathology was used to compare the intensity and distribution of ATP in the hippocampus and entorhinal cortex of 53 patients from 3 disease groups (SDLT, SDAT, Parkinson's disease (PD)) and a group of neurologically and mentally normal elderly control patients. For most brain areas examined the extent of ATP between the patient groups followed the trend SDAT greater than SDLT greater than PD greater than control. Statistical comparison of these groups revealed significant differences between the mean densities of NFT, SP and GVD although individual cases showed considerable variability. These results confirm additional pathological differences between SDAT and SDLT regarding the intensity of involvement of the temporal archicortex by ATP. Many patients with Lewy body disorders (LBdis) show a predisposition to develop ATP albeit in a more restricted distribution (e.g. low or absent neocortical NFT) and at lower densities than is found in SDAT. Some cases of SDLT show minimal SP and NFT formation in both neocortex and archicortex supporting previously published data distinguishing this group from Alzheimer's disease.
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PMID:Quantitative neuropathological study of Alzheimer-type pathology in the hippocampus: comparison of senile dementia of Alzheimer type, senile dementia of Lewy body type, Parkinson's disease and non-demented elderly control patients. 180 62

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, it has been postulated that (a) MPTP-like toxin(s) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) may induce Parkinson's disease. As the neuronal degeneration in MPTP-induced parkinsonism is thought to be caused by the inhibition of the mitochondrial respiration by 1-methyl-4-phenylpyridinium ion (MPP+), we studied the effects of TIQ-like alkaloids including dopamine-derived ones on the mitochondrial respiration using mouse brains. TIQ, tetrahydropapaveroline (THP), and tetrahydropapaverine (THPV) produced significant inhibition of the state 3 and 4 respiration and respiratory control ratio supported by glutamate + malate, the activity of Complex I and the ATP synthesis. Among those compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were quite similar to that of MPP+. Our results support the hypothesis that (a) MPTP- or MPP(+)-like substance(s) may be responsible for the nigral degeneration in Parkinson's disease.
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PMID:Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain. 197 53

Effects of MPTP-like compounds on mitochondrial respiration, activity of NADH-ubiquinone oxidoreductase (complex I) and on ATP synthesis were reported. Mitochondria prepared from mouse whole brains were used. The compounds tested include tetrahydroisoquinoline (TIQ), tetrahydropapaveroline (THP), tetrahydropapaverine (THPV), and salsolinol. TIQ, THP, and THPV significantly inhibited the state 3 respiration supported by glutamate + malate, activity of complex I and ATP synthesis. Among these compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were similar to MPP+. Significance of our results was discussed with respect to etiology of Parkinson's disease.
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PMID:Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-like compounds on mitochondrial respiration. 212 45

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in 1983 as a parkinsonian neurotoxin, endogenous or exogenous MPTP-like substances have been extensively investigated. Tetrahydroisoquinoline (TIQ) is a trace amine newly discovered in parkinsonian and control human brains. Like MPTP, TIQ inhibits tyrosine hydroxylase and NADPH ubiquinone oxidoreductase to reduce dopamine and ATP in the nigrostriatal dopaminergic neurons. TIQ produced parkinsonian symptoms after chronic administration in monkeys, which were recovered by L-DOPA. However, TIQ does not cause neuronal cell death at least in young monkeys. If some MPTP-like neurotoxins could be the cause of Parkinson's disease, some other factors such as immunological, neurotrophic, or genetic factors may work together with the putative neurotoxins during the process of aging.
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PMID:[The search for endogenous or exogenous MPTP-like substances]. 251 47

It is known that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces Parkinson's-like disease in primates and humans, depletes hepatocytes of ATP and subsequently causes cell death. Incubation of rat liver mitochondria with MPTP and 1-methyl-4-phenyl pyridinium ion (MPP+) significantly inhibited incorporation of 32Pi into ATP.MPTP and MPP+ inhibited the development of membrane potential and pH gradient in energized rat liver mitochondria, suggesting that reduction of the proton motive force may have reduced ATP synthesis. Since deprenyl, an inhibitor of monoamine oxidase, prevented the formation of MPP+ and inhibited the decrease in membrane potential caused by MPTP, but not that caused by MPP+, these effects of MPTP, as well as cell death, probably were mediated by MPP+. This mechanism may play a role in the specific loss of dopaminergic neurons resulting in MPTP-induced Parkinson's disease.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine inhibits proton motive force in energized liver mitochondria. 254 Jul 15

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

Tyrosine hydroxylase (TH) activity of human postmortem brain tissues from controls and patients with Parkinson's disease (PD) was examined in the presence of Fe2+ and phosphorylation agents, such as cyclic AMP, exogenous protein kinase, calcium plus calmodulin (Ca2+-CaM), and ATP. TH activity from parkinsonian tissue was increased by 48% with statistical significance in the presence of exogenous protein kinase. Cyclic AMP alone had no effect, whereas Ca2+-CaM increased the activity by only 10%. The presence of acetylcholine resulted in a slight decrease in enzyme activity. Human TH was stimulated 13.17-fold in the presence of 1 mM Fe2+. For iron dependence, no significant differences could be shown for the Km values of TH in striata of PD, while the activity of TH was half of that of controls. Here stimulation with 1 mM Fe2+ raised the activity of TH 11-fold. Stimulation of rat, gerbil, pig, and human caudate nucleus TH with Fe2+ shows remarkable species differences. In particular, the sensitivity of human TH to stimulating processes is noteworthy. H2O2 decreases TH activity only at high concentrations. Species differences are noted for the combined incubation of Fe2+ and H2O2. In the gerbil caudate nucleus, H2O2 does not prevent the stimulating properties of Fe2+, while the pig shows a dose-dependent decline of TH activity. In conclusion, there are no significant changes in the stimulating properties of human caudate nucleus TH activity with Fe2+ in PD, while such differences are noted by using exogenous protein kinase. Furthermore, experimental evidence shows that TH activity declines at high concentrations of H2O2 only. Potentiation of this effect by Fe2+ seems to be species-dependent.
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PMID:Tyrosine hydroxylase activity in caudate nucleus from Parkinson's disease: effects of iron and phosphorylating agents. 289 84

When uptake of the Parkinson's syndrome inducing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its major brain metabolite MPP+ (1-methyl-4-phenylpyridinium ion) by human platelets were compared in platelet rich plasma, a much higher rate was observed for the metabolite. The uptake process was saturable (Km = 6.8 microM; Vmax = 0.064 nmole/min/mg protein) and could be blocked by inhibitors of serotonin uptake. The accumulation of MPP+ by the platelets was accompanied by a decrease in intracellular ATP and an inhibition of mitochondrial state 3 respiration. These findings are consistent with earlier reports of the effect of MPP+ on isolated mitochondria as a potential cytotoxic mechanism, but also demonstrate that the dopamine uptake system is not the only means by which this metabolite can be efficiently transported into cells.
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PMID:Interaction of 1-methyl-4-phenylpyridinium ion with human platelets. 325 55

1-Methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which induces Parkinson's disease in man, is a substrate of the monoamine uptake system of chromaffin granules. It is accumulated without chemical modification by bovine chromaffin granule membrane vesicles in the presence of ATP. The transport is saturable and is characterized by a Km value of 0.8 microM at pH 8.0, similar to that of serotonin (5-HT). Transport occurs through the monoamine transporter since it is competitively inhibited by 5-HT and since MPP+ competitively inhibits [3H]5-HT uptake. Moreover, [3H]MPP+ uptake is blocked by the monoamine transporter inhibitors tetrabenazine and reserpine. Finally, MPP+ efficiently displaces [3H]reserpine and [3H]dihydrotetrabenazine from their binding sites on the transporter. In the pH range 6-8, the Km for [3H]MPP+ uptake and the EC50 of MPP+ for the displacement of [3H]dihydrotetrabenazine decrease logarithmically with the pH. MPP+ is the first quaternary ammonium salt shown to be a substrate of the monoamine transporter and it has the same pH-dependency as monoamines.
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PMID:Characteristics of the transport of the quaternary ammonium 1-methyl-4-phenylpyridinium by chromaffin granules. 326 61

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces symptoms similar to idiopathic Parkinson's disease in primates. A metabolite of MPTP, MPP+ (1-methyl-4-phenylpyridinium), is actively accumulated by dopaminergic (DA) terminals and selectively destroys nigrostriatal DA neurons. The mechanism of this effect remains unknown but reports that MPP+ inhibits electron transport in isolated mitochondria and increases oxidation of cytochrome b in striatal slices suggest that depression of ATP production is involved. To relate metabolic effects of MPP+ with tissue electrophysiology, extracellular potassium ion activity [K+]o was measured by microelectrodes simultaneous to optical monitoring of reduction/oxidation (redox) activity of cytochrome b during superfusion of MPP+ onto rat striatal and hippocampal slices. MPP+ increased oxidation of cytochrome b and increased [K+]o in slices of striatum. These increases were greater than expected from a selective effect of MPP+ on DA terminals which likely comprise no more than 3% of the total striatal mass. These effects of MPP+ were slowed by a dopamine uptake inhibitor (mazindol) and did not occur in hippocampal slices. These findings indicate that MPP+ influences ion transport as well as metabolic activity and that these actions require the presence of functioning DA terminals. However, the large amplitudes of the MPP+-induced changes suggest that consequences of MPP+-neurotoxicity are not ultimately confined to DA terminals. Two hypothesis are proposed: that energy failure in DA terminals results in leakage of neurotoxic substances or metabolites altering membrane conductance properties of adjacent cells and thereby placing additional demand upon ion transport pumps and mitochondrial oxidative phosphorylation; or that there is secondary uptake of MPP+ leading to mitochondrial inhibition in cells neighboring DA terminals.
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PMID:MPP+-induced increases in extracellular potassium ion activity in rat striatal slices suggest that consequences of MPP+ neurotoxicity are spread beyond dopaminergic terminals. 326 70


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