Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotoxic actions of MPTP and its 4-(O-tolyl) analog (2'-Me-MPTP) on two breeds of rabbits were investigated. MPTP, but not 2'-Me-MPTP, causes a reduction (about 40%) in striatal dopamine content in rabbits of the "little silver-black" breed. The dopamine content of striata of "chinchilla" rabbits was not affected by either agent.
Mol Chem Neuropathol
PMID:Relative resistance of rabbits to MPTP neurotoxicity. 853 16

Administration of methamphetamine (METH) to animals causes loss of DA terminals in the brain. The manner by which METH causes these changes in neurotoxicity is not known. We have tested the effects of this drug in copper/zinc (CuZn)-superoxide dismutase transgenic (SOD Tg) mice, which express the human CuZnSOD gene. In nontransgenic (non-Tg) mice, acute METH administration causes significant decreases in DA and dihydroxyphenylacetic acid (DOPAC) in the striata of non-Tg mice. In contrast, there were on significant decreases in striatal DA in the METH administration caused decreases in striatal DA and DOPAC in the non-Tg mice, but not in the SOD-Tg mice. Similar studies were carried out with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), which also causes striatal DA and DOPAC depletion. As in the case of METH, MPTP causes marked depletion of DA and DOPAC in the non-Tg mice, but not in the SOD Tg mice. These results suggest that the mechanisms of toxicity of both METH and MPTP involved superoxide radical formation.
Mol Neurobiol
PMID:Neurotoxicity, drugs and abuse, and the CuZn-superoxide dismutase transgenic mice. 856 59

The effect of dopaminergic denervation, alone or followed by chronic intermittent L-DOPA administration, on the levels of mRNAs encoding for the two isoforms of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), were measured by in-situ hybridization in the caudate and putamen of macaque monkeys. When compared to control monkeys, the level of GAD67 mRNA was increased in the putamen and caudate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. On the other hand, GAD65 mRNA labeling in MPTP-treated monkeys was not significantly different from the controls. In MPTP-treated monkeys that received L-DOPA, a significant increase in both GAD67 and GAD65 mRNA levels was measured in the putamen when compared to control or MPTP-treated monkeys. The results suggest that the dyskinetic effect of L-DOPA is paralleled by an increased GABAergic activity in the striatum.
Brain Res Mol Brain Res 1996 Jul
PMID:L-DOPA regulates glutamate decarboxylases mRNA levels in MPTP-treated monkeys. 880 32

The scanning nuclear microprobe (nuclear microscope) is becoming a powerful instrument for the accurate measurement of minor and trace elements in biological tissue. Using the simultaneously applied techniques of Scanning Transmission Ion Microscopy (STIM) to image features in the tissue, Particle induced X-ray emission (PIXE) to measure trace element concentrations, and Rutherford Backscattering Spectrometry (RBS) to characterize the tissue matrix, accurate elemental analysis at the parts per million level can be obtained for most elements. This review describes briefly the results obtained using the nuclear microscope for the elemental analysis of Alzheimer's and Parkinson's tissue. In Alzheimer's disease (AD) the identification and subsequent analysis of neuritic plaque cores in unstained tissue, yielded an absence of aluminium at the limit of 15 parts per million. Previous analyses involving stained sections were prone to misinterpretation due to aluminium contamination from the staining procedures. Elemental iron, calcium, phosphorus and sulphur were elevated both in the plaques and the AD background tissue compared to age matched controls. Preliminary analyses of neurofibrillary tangles stained with toluidine blue showed increased levels of calcium, although the staining procedure may have distorted the results due to element redistribution. In Parkinson's disease (PD) nuclear microscope studies have concentrated on measurements of iron in the substantia nigra (SN) region of the brain; iron was observed to be elevated by a factor 2 in MPTP induced Parkinsonism in African Green monkeys, and by a factor of 1.25 in 6-OHDA induced Parkinsonism in Sprague Dawley rats. These studies are consistent with other studies showing a general increase in the concentrations of iron associated with PD, and support the theory that iron mediated free radical production may enhance or accelerate the degeneration of dopaminergic cells through oxidative stress.
Cell Mol Biol (Noisy-le-grand) 1996 Feb
PMID:Nuclear microscope analysis in Alzheimer's and Parkinson's disease: A review. 883 63

We have now applied the enzyme immunoassay using anti-NGF monoclonal antibody (MAb) 27/21 and a blocking test validating the specificity of the immunoreactivity for NGF in serum samples to examine NGF levels in normal rat sera, hemiparkinsonian rat sera, normal monkey sera, and MPTP-treated monkey sera. The levels of NGF in treated animals showed reductions when compared with serum from normal animals. The NGF level alterations observed in lesioned animals and in human parkinsonian patients evidence a relationship between this neurotrophic factor and the neurodegenerative changes observed in Parkinson disease (PD).
Mol Chem Neuropathol
PMID:NGF in experimental models of Parkinson disease. 887 63

The effect of L-3,4-dihydroxyphenylalanine (L-DOPA) on dopamine receptor gene expression in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys was investigated using in situ hybridization histochemistry with measures of changes in relative absorbance. In MPTP-lesioned monkeys, a decrease of D1 dopamine receptor mRNAs was observed in the rostral part of the caudate and putamen compared with control animals (-20% and -17%, respectively, in the lateral axis). Chronic treatment of MPTP-lesioned monkeys with L-DOPA returned their D1 receptor mRNA values to near those of control monkeys in the caudate and putamen (92% and 91% of control values, respectively). No lesion or drug-induced changes of D1 receptor mRNAs were observed in the more caudal parts of the striatum. A decrease of D1 receptor mRNAs was observed in the olfactory tubercule (-22%) in MPTP-lesioned monkeys compared with control animals but no change was seen in the nucleus accumbens. D1 receptor mRNAs in the anterior cerebral cortex were decreased in MPTP-lesioned monkeys (-19% compared with control animals). D1 receptor mRNAs in olfactory tubercle and in cerebral cortex of L-DOPA-treated MPTP-lesioned monkeys were not significantly different from control animals. For D2 receptor mRNAs, we observed an increase in the caudal part of the caudate and putamen (+24% and +23%, respectively, in MPTP-lesioned monkeys compared with control animals). Chronic L-DOPA treatment corrected this elevation to control values. No variation of D2 receptor mRNAs was seen in the more rostral parts of the striatum and in the nucleus accumbens in MPTP-lesioned monkeys as well as in MPTP-lesioned monkeys treated chronically with L-DOPA. Our results show for the first time that L-DOPA can influence gene expression of D1 and D2 receptors in MPTP-lesioned monkeys and correct the lesion-induced increase in the expression of D2 receptors, whereas the correction of the D1 receptor expression decrease is only partial. Furthermore, the changes in gene expression of D1 and D2 receptors in MPTP-lesioned monkeys are regional: they are restricted to the anterior striatum for the D1 receptors and the posterior striatum for the D2 receptors.
Mol Pharmacol 1996 Nov
PMID:Changes of D1 and D2 dopamine receptor mRNA in the brains of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: correction with chronic administration of L-3,4-dihydroxyphenylalanine. 891 37

The cellular expression of dopamine D2 receptor mRNA was examined in striatal (caudate nucleus and putamen) neurones of 9 Macaca fascicularis monkeys rendered parkinsonian by systemic injection of MPTP. Messenger RNA abundance was determined by quantitative in situ hybridization using human-specific 35S-labelled oligonucleotides. Control monkeys were untreated and received neither MPTP nor L-DOPA while the rest were rendered parkinsonian and received chronic levodopa therapy to induce dyskinesia. In the control brains a strong dopamine D2 receptor hybridization signal was detected overlying medium-sized and some large neurons in both the caudate nucleus and putamen. Neurons from the lateral and medial regions of the caudate nucleus, and from the dorsal and ventral regions of the putamen were analysed separately. A significant increase in the cellular abundance of dopamine D2 receptor mRNA was seen in the striatum of MPTP-treated monkeys; this increase being restricted to the population of medium-sized striatal cells. No such increase in dopamine D2 receptor mRNA was observed in (dyskinetic) L-DOPA-treated monkeys suggesting that levodopa-therapy normalises D2 receptor expression in post-synaptic striatal cells. The cellular abundance of dopamine D2 receptor mRNA expressed by large striatal neurons (putative cholinergic cells) was unaffected by either MPTP treatment or levodopa therapy. The implications of these findings for the development of levodopa-induced dyskinesias is discussed.
Brain Res Mol Brain Res 1996 Nov
PMID:Effects of L-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys. 891 94

The calcium-binding protein calbindin-D28k (CALB) has been localized in high concentrations in several neuronal populations within the central nervous system (CNS) and is believed to act as an intracellular calcium (Ca2+) buffer. There has been much interest and speculation concerning its potential neuroprotective function. However, there is little direct evidence linking CALB content of individual neurons to Ca2+ buffering ability, resistance to Ca(2+)-mediated excitotoxicity, or vulnerability to Ca(2+)-mediated degeneration. It is necessary to demonstrate these relationships on a cellular level so that more definitive conclusions can be made. We have utilized immunocytochemical and Western blot techniques to determine whether cellular CALB content is altered in the nucleus A10 dopaminergic region of the midbrain following administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our data demonstrate a significant increase in the CALB content of nucleus A10 neurons (up to 227 +/- 23% above control) 3 and 6 h after MPTP treatment. CALB elevation demonstrated both time and dosage dependence as 6-h groups exhibited larger increases than 3-h groups, and a 60 mg/kg dosage induced a larger increase than a 20 mg/kg dosage. These data support the hypothesis that MPTP is neurotoxic by causing increases in free intracellular Ca2+ and that increased CALB in the midbrain dopaminergic neurons is a protective response to elevated intracellular free Ca2+.
Brain Res Mol Brain Res 1996 Mar
PMID:The neurotoxin MPTP increases calbindin-D28k levels in mouse midbrain dopaminergic neurons. 896 54

Administration of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP; 4 x 15 mg/kg) to CD-1 mice was found to cause substantial decreases in cortical and hippocampal 5-hydroxytryptamine (5-HT) and norepinephrine (NE) to 20-30% of control 3 weeks after treatment. The magnitude of these depletions was similar to those reported previously in Swiss Webster and C57BL/6 mice given 4 x 20 mg/kg 2'-NH2-MPTP, and in keeping with these prior studies, striatal dopamine levels were unchanged by 2'-NH2-MPTP treatment in CD-1 mice. Subsequently, transgenic CD-1 mice producing high levels of human cytosolic Cu-Zn superoxide dismutase (SOD) were studied to assess the role of oxygen radicals in the mechanism of action of 2'-NH2-MPTP. In contrast to the results described above, 5-HT and NE levels were almost completely unaffected by 2'-NH2-MPTP treatment in homozygous SOD mice bearing 5-fold increases in brain SOD activity. In 2'-NH2-MPTP-treated heterozygous SOD mice, which showed an average 3-fold increase in brain SOD activity, only moderate depletions in cortical and hippocampal 5-HT (50-60% of control) and NE (30-40% of control) were observed. Additionally, the density of [125I]RTI-55-labeled 5-HT uptake sites was studied to further assess possible 5-HT terminal loss. In various cortical and hippocampal subregions of nontransgenic mice, 5-HT uptake sites were reduced to 20-35% of control after 2'-NH2-MPTP treatment, in comparison with homozygous SOD mice, which were affected only minimally by 2'-NH2-MPTP administration, and heterozygous SOD mice, which showed intermediate reductions in 5-HT uptake site density on the order of 55-80% of control. Together, these data indicate that mice genetically endowed with increased SOD activity are protected from 2'-NH2-MPTP-induced toxicity, thereby implicating superoxide radicals in the mechanism of action of a neurotoxin that selectively depletes 5-HT and NE without affecting dopamine.
Mol Pharmacol 1996 Dec
PMID:Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals. 896 72

Haloperidol (HP) and its tetrahydropyridine dehydration product 4-(4-chlorophenyl)-[4-(fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyrid ine (HPTP) are both metabolized in vivo to several pyridinium metabolites with potential neurotoxic properties similar to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a metabolite of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The effect of long-term HPTP treatment on the central nervous system of baboons (Papio ursinus) was studied using [123I]iodobenzamide (IBZM) and single photon emission computed tomography (SPECT) at 1-14 weeks after termination of HPTP treatment. Striatal dopamine receptor binding was measured semiquantitatively by calculating the IBZM count rate ratios of the basal ganglia to frontal cortex and basal ganglia to cerebellum. Relative striatal perfusion was assessed by similar 99mTc-HMPAO (hexamethylpropylene amine oxime) ratios. Time activity curves of IBZM from the brain structures suggest that HPTP treatment results in a marked reduction in central dopamine ligand binding, and in particular D2-like receptor binding. Increased washout of the ligand from all the brain structures investigated was seen in the HPTP-treated animals, also consistent with reduced binding. Cerebral blood flow in the control and HPTP-treated groups was similar, indicating that this did not account for the reduced dopamine receptor binding of the IBZM ligand. These data suggest that treatment with HPTP induces significant effects on dopamine receptor binding that may contribute to some of the neurological disorders observed in humans undergoing chronic HP treatment.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study. 903 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>