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)

Considerable evidence implicates the involvement of mitochondrial dysfunction in neurodegenerative diseases. 6OHDA is a mitochondrial complex I inhibitor which is frequently used to model Parkinson's disease-like cell loss. We investigated the cell death pathways triggered by 6OHDA in PC12 and P19 cells with a view to shedding light on the molecular basis of Parkinson's disease. We found that 6OHDA triggered mostly necrosis and less than 5% apoptosis in PC12 cells, whereas 6OHDA-induced death in P19 cells was apoptotic. While desipramine, a dopamine uptake blocker, attenuated 6OHDA-induced apoptosis in PC12 cells, this compound had no effect on the large scale necrotic death. Furthermore, desipramine failed to reduce apoptosis in 6OHDA-treated P19 cells, suggesting that the mechanism of 6OHDA toxicity does not require uptake via the dopamine transporter. As cell death triggered by 6OHDA was not blocked by free radical scavengers or NMDA receptor antagonists, a non-specific extracellular mechanism may be involved.
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PMID:The toxicity of 6-hydroxydopamine on PC12 and P19 cells. 1035 Jun 40

We analysed the expression of dopamine receptor subtypes in the subthalamic nucleus by means of reverse transcriptase-polymerase chain reaction. We also studied, using autoradiography, all pharmacologically characterized dopamine receptors in four subregions of the subthalamic nucleus. For comparison, dopamine receptor subtypes were also evaluated in brain regions where they are more abundant and well characterized. The radioligands used were: [3H]SCH-23390, [3H]emonapride and [3H]2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene for dopamine D1, D2 and D3 receptors, respectively; and [3H]YM-09151-2 in the presence of raclopride for dopamine D4 receptors. Finally, we also evaluated the effect of unilateral 6-hydroxydopamine injection into the medial forebrain bundle on dopamine receptor levels expressed in the ipsilateral subthalamic nucleus. The lesion was estimated by decrease in the binding of [3H]WIN-35428, a specific dopamine transporter label. D1, D2 and D3 receptor messenger RNAs and binding sites were present in the subthalamic nucleus, but no messenger RNA for D4 receptors was found, although specific binding sites for these receptors were observed. As compared to the intact side, the 6-hydroxydopamine lesion did not change D1 receptors, increased D2 receptors, and decreased D3 receptors and the dopamine transporter. The results suggest that postsynaptic D1, D2 or D3 receptors can mediate the effect of dopamine on subthalamic nucleus neuronal activity. D4 receptors would mediate exclusively presynaptic effects. These results reinforce the idea that dopamine receptors in the subthalamic nucleus may play an important role in the physiology of the basal ganglia and in the pathophysiology of Parkinson's disease.
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PMID:Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography. 1036 12

Parkinson's disease (PD) is characterized by progressive neuronal loss associated with Lewy bodies in many subcortical nuclei leading to multiple biochemical and pathophysiological changes of clinical relevance. Loss of nigral neurons causing striatal dopamine deficiency is related to both the duration and clinical stages (severity) of the disease. The clinical subtypes of PD have different morphological lesion patterns: a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation. b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex. Rest tremor in PD is associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network suggesting an increased functional activity of thalamo-motor projections. In essential tremor, no significant pathomorphological changes but overactivity of cerebello-thalamic loop have been observed. c) In the akinetic-rigid forms of multisystem atrophy, degeneration is more severe in the lateral SNZC with severe loss of calbindin-IR cells reflecting initial degeneration of the striatal matrix in the caudal putamen with transsynaptic degeneration of striatonigral efferences that remain intact in PD. This fact and loss of striatal D2 receptors--as in advanced stages of PD--are reasons for negative response to L-dopa substitution. These data suggest different pathophysiological mechanisms of the clinical subtypes of PD that have important therapeutic implications. d) Involvement of extranigral structures in PD includes the mesocortical dopaminergic system, the noradrenergic locus coeruleus, dorsal vagal nucleus and medullary nuclei, serotonergic dorsal raphe, nucleus basalis of Meynert and other cholinergic brainstem nuclei, e.g. Westphal-Edinger nucleus (controlling pupillomotor function), posterolateral hypothalamus and the limbic system, e.g. amygdaloid nucleus, part of hippocampal formation, limbic thalamic nuclei with prefrontal projections, etc. Damage to multiple neuronal systems by the progressing degenerative process causing complex biochemical changes may explain the variable clinical picture of PD including vegetative, behavioural and cognitive dysfunctions, depression, pharmacotoxic psychoses, etc. Future comparative clinico-morphological and pathobiochemical studies will further elucidate the pathophysiological basis of specific clinical symptoms of PD and related disorders providing a broader basis for effective treatment strategies. Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and other subcortical neuronal systems leading to striatal dopamine deficiency and other biochemical deficits related to the variable clinical signs and symptoms of the disorder. (ABSTRACT TRUNCATED)
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PMID:Post mortem studies in Parkinson's disease--is it possible to detect brain areas for specific symptoms? 1037 Sep 1

Patients suffering from Parkinson's disease display severe and progressive deficits in motor behavior, predominantly as a consequence of the degeneration of dopaminergic neurons, located in the mesencephalon and projecting to striatal regions. The cause of Parkinson's disease is still an enigma. Consequently, the pharmacotherapy of Parkinson's disease consists of symptomatic treatment, with in particular L-dihydroxyphenylalanine (L-DOPA) and/or dopamine receptor agonists. These induce a dramatic initial improvement. However, serious problems gradually develop during long-term treatment. Therefore, a more rational, c.q. causal treatment is needed which requires the introduction of compounds ameliorating the disease process itself. The development of such compounds necessitates (1) more information on the etiopathogenesis, i.e., the cascade of events that ultimately leads to degeneration of the dopaminergic neurons, and (2) brain imaging methods, to estimate the extent of the degeneration of the dopaminergic neurons in the living patient. This is not only important for the early diagnosis, but will also allow to monitor the effectiveness of alleged neuroprotective compounds on a longitudinal base. In this paper, etiopathogenic mechanisms are highlighted along the line of the oxidative stress hypothesis and within this framework, attention is mainly focused on the putative role of glutathione, dopamine auto-oxidation and phase II biotransformation enzymes. Especially, drugs able to increase the activity of phase II biotransformation enzymes seem to elicit a broad-spectrum (neuro)protective response and look very promising leads for the development of neuroprotective treatment strategies in Parkinson's disease. New developments in brain imaging methods (single photon emission computed tomography (SPECT) and positron emission tomography (PET)) to visualize the integrity of the striatal dopaminergic neurons in humans are highlighted as well. Especially, the introduction of radioligands that bind selectively to the dopamine transporter seems to be a significant step forward for the early diagnosis of Parkinson's disease. Performing these brain imaging studies with fixed time intervals does not only create the possibility to follow the degeneration rate of the dopaminergic neurons in Parkinson's disease but also provides the opportunity to estimate therapeutic effects of putative neuroprotective agents in the individual patient.
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PMID:Leads for the development of neuroprotective treatment in Parkinson's disease and brain imaging methods for estimating treatment efficacy. 1044 66

Parkinson's disease (PD) is characterized by an uneven and progressive loss of nigrostriatal dopaminergic neurons. It is hypothesized that the physiological basis for the therapeutic response in early stages of PD is the ability for the partially and unevenly denervated dopaminergic system to restore and normalize dopaminergic influence in functionally segregated subregions of the basal ganglia. To investigate this hypothesis, patients with early and uncomplicated PD were investigated with positron emission tomography by using a two-tracer protocol yielding a measure of dopamine transporter-corrected dopamine synthesis capacity. Compared with controls, patients with PD exhibited a considerable increase in dopamine transporter-corrected dopamine synthesis capacity. The increase showed an inverse dependence on the structural integrity in as much as the highest rate was measured in the most denervated region, the dorsal part of putamen (198% of control value). A therapeutic challenge with antiparkinsonian medication state-dependently decreased dopaminergic activity. Thus, it is demonstrated that dopaminergic degeneration in PD is accompanied by a conspicuous acceleration of presynaptic dopaminergic activity, which is state-dependently down-regulated by dopaminomimetic treatment. It is suggested that homeostatic mechanisms acting to maintain congruity within the dopaminergic system are functionally intact in early PD.
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PMID:Regulation of dopaminergic activity in early Parkinson's disease. 1048 66

The plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2) are essential for normal dopamine neurotransmission. DAT terminates the actions of dopamine by rapidly removing dopamine from the synapse, whereas VMAT2 loads cytoplasmic dopamine into vesicles for storage and subsequent release. Recent data suggest that perturbation of the tightly regulated balance between these two transporters predisposes the neurone to damage by a variety of insults. Most notable is the selective degeneration of DAT- and VMAT2-expressing dopamine nerve terminals in the striatum thought to underlie Parkinson's disease. DAT and VMAT2 expression can predict the selective vulnerability of neuronal populations, which suggests that therapeutic strategies aimed at altering DAT and VMAT2 function could have significant benefits in a variety of disorders.
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PMID:Dopamine transporters and neuronal injury. 1049 56

Epidemiological data support a relationship between pesticide exposure and Parkinson's disease; however, no experimental evidence has been provided to support this association. Here we report that subchronic administration of the organochlorine insecticide heptachlor (0, 3, 6, 9, or 12 mg/kg given 3 times over a 2 week period) leads to a pronounced increase in both the plasma membrane transport of dopamine and the expression of the plasma membrane dopamine transporter (DAT), as well as the vesicular monoamine transporter (VMAT2) in the striatum of C57BL mice. To address possible mechanisms of increased DAT and VMAT2 expression, we performed transport studies in cell lines expressing the human forms of either DAT or VMAT2. In a DAT expressing cell line, acute treatment with the putative toxic species of heptachlor, heptachlor epoxide, did not alter plasma membrane dopamine uptake. In a VMAT2 expressing cell line, heptachlor epoxide significantly inhibited vesicular uptake of dopamine (45% reduction at 10 microM). Since DAT has been proposed to be the molecular gateway for dopaminergic toxins, such as the parkinsonism-inducing neurotoxin MPP, and VMAT2 has been proposed to protect cells from MPP and other toxins by sequestering the toxin into vesicles, the combined effects of heptachlor could increase the susceptibility of the nigrostriatal dopamine system to neurodegeneration. We further propose that altered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease.
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PMID:Heptachlor alters expression and function of dopamine transporters. 1049 61

The known dopaminergic abnormalities in Parkinson's disease have facilitated the development of radiolabeled biomarkers for diagnostic and research applications in humans. Presynaptic, intrasynaptic, and postsynaptic imaging now is possible using single-photon emission computed tomography. In particular, the development of new radiotracers that target the dopamine transporter located on degenerating dopamine neurons in Parkinson's disease and related disorders is directly relevant to improved clinical diagnosis, disease monitoring, and assessment of putative neuroprotective strategies in patients. In addition, the ability to characterize in vivo neuronal degeneration in these disorders provides a powerful research tool to better understand the natural course of these disorders and could provide clues to etiology.
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PMID:Single-photon emission computed tomography of the dopamine transporter in parkinsonism. 1054 Jun 2

We demonstrate the use of magnetic resonance imaging (MRI) for detection of neurotransmitter stimulation using the dopamine transporter ligands amphetamine and CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) as pharmacological challenges. We demonstrate that the unilateral loss of a hemodynamic response to either amphetamine or CFT challenge by unilateral 6-hydroxydopamine lesioning is restored by transplantation of fetal dopamine neurons in the striatum. The time course for the hemodynamic changes parallels the time courses for dopamine release, measured by prior microdialysis studies, and also for the rotational behavior in the unilaterally lesioned animals. Transplantation of the fetal cells results in hemodynamic time courses after CFT or amphetamine challenges at the graft site that are identical to those induced both before transplantation and on the intact contralateral side. The transplantation also results in complete behavioral recovery. The spatial extent of the dopaminergic recovery in the lesioned striatum is the same when measured using either PET of tracer levels of [11C]CFT binding or MRI. These results show great promise for the application of pharmacological MRI for application to studies of dopamine cell loss and potential recovery in Parkinson's disease.
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PMID:Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment. 1054 90

To investigate changes in the relation between presynaptic and postsynaptic dopaminergic functions in vivo in both nigrostriatal and mesocortical systems in Parkinson's disease (PD), 10 drug-naive early PD patients were studied twice using positron emission tomography with [11C]CFT (dopamine transporter probe) followed by [11C]SCH 23390 (D1 receptor probe). Regional binding potentials (k3/k4) of [11C]CFT and [11C]SCH 23390 in the striatum (nigrostriatal system) and the orbitofrontal cortex (mesocortical system) were estimated by compartment analyses. Levels of [11C]CFT k3/k4 in the two projection areas were shown to be significantly lower in PD, whereas [11C]SCH 23390 levels remained unchanged. Regression analysis showed that estimates of CFT k3/k4 were positively correlated with those of SCH 23390 k3/k4 in the striatum in normal control, whereas the two binding estimates were less positively correlated in the caudate and inversely correlated in the putamen in PD. No significant correlation was observed in the orbitofrontal cortex in both groups. These results indicated that dopamine transporters and D1 receptors change in parallel in the normal striatal synapses, but the association becomes asymmetrical because of reduction in presynaptic and relative elevation in postsynaptic markers in PD. Alterations in synaptic parallel regulation in the nigrostriatal system might reflect early pathophysiology in the parkinsonian brain.
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PMID:Presynaptic and postsynaptic dopaminergic binding densities in the nigrostriatal and mesocortical systems in early Parkinson's disease: a double-tracer positron emission tomography study. 1055 89


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