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)

The neurotransmitter dopamine (DA) plays a central role in the coordination of movement, attention, and the recognition of reward. Loss of DA from the basal ganglia, as a consequence of degeneration of neurons in the substantia nigra, triggers postural instability and Parkinson's disease (PD). DA transporters (DATs) regulate synaptic DA availability and provide a conduit for the uptake of DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson-like syndrome. Recently, we have explored the sensitivity of DA neurons in the nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6-hydroxydopamine (6-OHDA) and found striking similarities, including DAT dependence, to neurodegeneration observed in mammalian models. In this review, we present our findings in the context of molecular and behavioral dimensions of DA signaling in C. elegans with an eye toward opportunities for uncovering DAT mutants, DAT regulators, and components of toxin-mediated cell death.
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PMID:The Caenorhabditis elegans dopaminergic system: opportunities for insights into dopamine transport and neurodegeneration. 1241 22

Previous data suggest a relationship between the loss of response to levodopa in Parkinson's disease (PD) patients with the co-occurrence of dementia, but the role of alterations in the dopamine system has not been explored. We measured the extent of striatal DA loss and changes in striatal DA D(2) and D(3) receptors in postmortem striatum of PD patients who historically had or had not lost their clinical response to dopaminergic drugs and/or had an additional diagnosis of dementia. Clinical evaluation and retrospective chart reviews for PD and dementia, and neuropathological diagnoses were obtained. All PD cases (+/-dementia), regardless of response to dopaminergic drugs, exhibited a significant and similar degree and pattern of loss of tyrosine hydroxylase immunocytochemistry and DA transporter binding in striatum, and loss of tyrosine hydroxylase-immunoreactive neurons and brain-derived neurotrophic-immunoreactive neurons from the ventral midbrain. D(2) receptor concentrations were modestly elevated in the rostral striatum of all the PD cases (+/-dementia), whether or not they continued to respond to dopaminergic drugs. In contrast, loss of D(3) receptor concentration correlated with loss of response to dopaminergic drugs, independent of the presence or absence of dementia. A maintained response to dopaminergic drugs correlated with an elevation of D(3) receptors. Dementia with PD was highly correlated with a loss of response to dopaminergic drugs, and was also correlated with reduced D(3) receptors. The alterations in D(3) receptor concentrations were greatest in the nucleus accumbens, caudal striatum, and globus pallidus. Thus, loss of dopamine D(3) receptors may be a more important contributing factor to a loss of response to dopaminergic drugs than changes in the D(2) receptor.
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PMID:Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors. 1241 30

Nonimmunosuppressant immunophilin ligands have been shown to have neurotrophic properties in rodent models of Parkinson's disease (PD), although little is known about the effects of these ligands in primates. The immunophilin ligand, GPI-1046, promotes the regeneration of dopamine (DA) cells in association with functional recovery in rodent models. We explored the regenerative effects of GPI-1046 in an MPTP primate model of PD. We used single photon emission computed tomography (SPECT) and the DA transporter tracer (DAT), [(123)I]beta-CIT, to evaluate DAT density and clinical recovery before and after treatment with GPI-1046 or vehicle. Subsequent histological studies were also performed. No effects of GPI-1046 were found on any of these measures. These findings show that GPI-1046 does not have regenerative effects in MPTP-treated primates and suggest that there may be species differences with respect to the trophic effects of GPI-1046 on nigrostriatal DA neurons.
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PMID:The immunophilin ligand GPI-1046 does not have neuroregenerative effects in MPTP-treated monkeys. 1250 82

While levodopa-induced neurochemical changes have been studied in animal models of Parkinson's disease, very little is known regarding the effects of levodopa administration in normal animals. The present study investigates the effects normal and MPTP-lesioned mice chronically treated with two different doses of levodopa. We assess changes in striatal dopamine (DA) receptor binding, striatal DA receptor mRNA levels and striatal neuropeptide precursor levels (preproenkephalin-A [PPE-A]; preprotachykinin [PPT]; preproenkephalin-B [PPE-B]). The extent of the lesion was measured by striatal DA transporter binding and stereological estimation of the number of tyrosine hydroxylase immunoreactive neurones in the substantia nigra pars compacta (SNc). In non-lesioned animals, chronic levodopa treatment induced an increase in PPE-A mRNA, whereas both D3R binding and PPE-B mRNA levels were dramatically increased in the lesioned animals in a dose dependent manner. The present results show that chronic levodopa administration may induce pathophysiological changes, even in the absence of a lesion of the nigro-striatal pathway, suggesting that the sensitization process involves predominantly the indirect striatofugal pathway in non-lesioned animals, whereas the direct pathway is primarily involved in lesioned animals.
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PMID:Pattern of levodopa-induced striatal changes is different in normal and MPTP-lesioned mice. 1261 25

Transgenic technology, especially the use of homologous recombination to disrupt specific genes to produce knockout mice, has added considerably to the understanding of dopamine (DA) neuron develop, survival and function. The current review summarizes results from knockout mice with the target disruption of genes involved in the development of DA neurons (engrailed 1 and 2, lmx1b, and Nurr1), in maintaining DA neurotransmission (tyrosine hydroxylase, vesicular monoamine transporter, DA transporter, DA D2 and D3 receptors) and important for DA neuron survival (alpha-synuclein, glia cell line-derived neurotrophic factor and superoxide dismutase). As alterations in DA neurotransmission have been implicated in a number of human neuropathologies including Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder, understanding how specific genes are involved in the function of DA neurons and the compensatory changes that result from loss or reduction in gene expression could provide important insight for the treatment of these diseases.
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PMID:The control of dopamine neuron development, function and survival: insights from transgenic mice and the relevance to human disease. 1267 88

We investigated the role of variable number tandem repeat (VNTR) polymorphism of the dopamine transporter gene (DAT) in the pathogenesis of Parkinson's disease (PD) in Taiwanese. A case-control study was carried out to examine the association of the VNTR polymorphism within the DAT between 193 sporadic PD patients and 254 controls, matched by age and sex. Six alleles of VNTR polymorphism in the DAT, consisting of 6, 7, 8, 9, 10 and 11 copies of the 40-base-pair (bp) repeat sequence, were detected in the study. There were no differences of allele frequency (chi(2)=5.239, p=0.387) and genotype polymorphism of the DAT VNTR (chi(2)=11.873, p=0.157) in PD patients from the controls. Further analysis stratified by sex and age at onset did not show associations. However, PD patients carrying homozygote 10-copy genotype of the DAT VNTR polymorphism were 0.67 times fewer than controls (chi(2)=4.569, odds radio (OR)=0.67, 95% confidence interval (CI)=0.45-0.97, p=0.033). The reduced risk of the homozygosity with PD genotype was only in male PD patients (chi(2)=2.923, OR=0.48, 95% CI=0.25-0.93, p=0.026), but not in female PD patients (chi(2)=0.002, OR=1.02, 95% CI=0.49-2.11, p=0.966). In conclusion, the results of our study show that homozygote 10-copy genotype of the VNTR polymorphism within the DAT may confer a protective factor for male PD patients, but not for female PD patients.
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PMID:The homozygote 10-copy genotype of variable number tandem repeat dopamine transporter gene may confer protection against Parkinson's disease for male, but not to female patients. 1268 8

Exercise is thought to improve motor function and emotional well-being in patients with Parkinson's disease (PD). However, it is not clear if the improvements are due to neurochemical alterations within the affected nigrostriatal region or result from a more general effect of exercise on affect and motivation. In this study we show that motorized treadmill running improves the neurochemical and behavioral outcomes in two rodent models of PD: the unilateral 6-hydroxydopamine (6-OHDA) rat model and bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model in aged C57bl mice. Exposure to the dopamine (DA) toxins 6-OHDA or MPTP resulted in permanent behavioral and neurochemical loss. In contrast, when lesioned animals were exposed to treadmill activity two times a day for the first 10 days post-lesion they displayed no behavioral deficits across testing days and had significant sparing of striatal DA, its metabolites, tyrosine hydroxylase, vesicular monoamine transporter, and DA transporter levels compared to lesion sedentary animals. These results demonstrate that exercise following nigrostriatal damage ameliorates related motor symptoms and neurochemical deficits in rodent models of PD.
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PMID:Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease. 1280 9

Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.
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PMID:Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. 1289 Aug 83

We previously synthesised a novel dopamine (DA) partial agonist FAUC 329 with high affinity and selectivity for the DA D(3) receptor. This is the first in vivo study to investigate the protective effects of FAUC 329 in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Adult male C57bl/6 mice were injected with FAUC 329 (0, 0.1, 0.5, 0.75, or 1 mg/kg) 30 min before MPTP (2 x 30 mg/kg, 4 hr apart). One week later, accumbal and striatal tissue was processed for DA and metabolite HPLC determination as well as immunohistochemical analysis of DA transporter positive neurons in the substantia nigra pars compacta and ventral tegmental area was carried out. FAUC 329 showed a significant attenuation of MPTP-induced DA reduction in the nucleus accumbens (0.5, 0.75 and 1 mg/kg) in a dose-dependent manner. FAUC 329 (0.75 mg/kg) partly protected against DA depletion in the dorsal striatum as well as protected against loss of DA transporter immunoreactivity in the substantia nigra pars compacta. The highest dose of FAUC 329 (1 mg/kg), however, showed a non-significant tendency to augment the MPTP-induced striatal DA reduction. The protective effect of FAUC 329 against MPTP-induced DA depletion was most pronounced in the nucleus accumbens and appears to be linked to the preferential abundance of D(3) receptors in this region. Targeting the mesolimbic DA system may have implications for improvement of impaired motor behaviour and particularly non-motor functions related to the nucleus accumbens.
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PMID:Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by the novel selective dopamine D3-receptor partial agonist FAUC 329 predominantly in the nucleus accumbens of mice. 1296 89

Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease.
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PMID:Stimulation of postsynaptic alpha1b- and alpha2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice. 1455 32


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