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)

Current research into the aetiology of the dementias is focused upon genetic factors which give rise to the disease process. Recently the Apolipoprotein E gene (APO E) and in particular the epsilon 4 allele has been shown to be a risk factor for late onset Alzheimer's disease (AD) where there is an increased frequency of the epsilon 4 allele. The epsilon 4 allele has also been shown to reduce the age at onset of dementia in AD in a dose dependent manner, with the epsilon 2 allele having an opposing effect. We have genotyped a large series of clinically and neuropathologically confirmed cases of AD and found the expected increase in the Apolipoprotein epsilon 4 allele frequency when compared to a control population. Similarly, in Lewy Body Dementia (LBD) an increased epsilon 4 frequency is also found though a normal epsilon 2 frequency exists, unlike in AD where the epsilon 2 frequency is reduced. No changes in APO E allele frequencies were found in presenile AD, Parkinson's disease with or without dementia, or in Down's syndrome. No association was found between any of the APO E alleles and the histopathological indices of AD, cortical senile plaques and neurofibrillary tangles, in any disease category. Neurochemical indicators of AD, loss of choline acetyltransferase activity was also unaffected by APO E genotype. Whilst their appears to be a strong association between the APO E allele and AD and also in LBD, other related neurodegenerative disorders associated with dementia do not show such a linkage. Changes in the epsilon 2 allele frequency may indicate a genetic difference between AD and LBD. The epsilon 4 allele does not appear to influence the burden of AD type pathology and this is particularly relevant given the relative lack of NFT in LBD indicating that factors other than SP or NFT may govern the onset of dementia.
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PMID:Molecular biology of APO E alleles in Alzheimer's and non-Alzheimer's dementias. 884 67

Current hypotheses of basal ganglia dysfunction in Parkinson's disease (PD) propose that neuronal hypoactivity in the globus pallidus externus (GPe), and hyperactivity in the output nuclei and the external and internal portions of the globus pallidus internus (GPi,e and GPi,i, respectively), result in the cardinal symptoms of PD. To test this theory, the nonselective D1- and D2-dopamine receptor agonist apomorphine (30-100 microg/kg SC) was administered to 14 levodopa-responsive PD patients who were off medication ("off" state) while recording neurons in GP. For 15 neurons that were continuously monitored, apomorphine was found to increase the firing rate of 3 neurons in GPe, and decrease the rate of 12 in GPi. The mean firing rates of many different neurons were determined before (n = 285) and at various intervals after (n = 184) the injection of the drug. The mean rates before apomorphine were as follows: GPe, 45 Hz (SD 15, n = 85); GPi,e, 67 Hz (SD 14, n = 125); and GPi,i, 85 Hz (SD 19, n = 75). At 25 to 35 minutes after APO, the rate of GPe neurons had increased to 72 Hz (SD 18, n = 7), the rate of GPi,e neurons had decreased to 39 Hz (SD 15, n = 15), and in GPi,i the rate decreased to 34 Hz (SD 22, n = 18). Eighty minutes after apomorphine administration, the mean firing rates returned to preadministration values. This study supports current models of basal ganglia dysfunction in PD and suggests that the therapeutic effect of apomorphine results from a normalization of the imbalance of neuronal activity in the direct and indirect pathways.
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PMID:Effects of apomorphine on globus pallidus neurons in parkinsonian patients. 939 76

Gait coordination was analyzed (four-camera 100 Hz ELITE system) in two groups of idiopathic Parkinson disease (PD) patients. Five patients underwent continuous infusion of apomorphine and were recorded in two different sessions (APO OFF and APO ON) in the same day. Three patients with a previous chronic electrode implantation in both internal globi pallidi (GPi) were recorded in the same experimental session with the electrodes on and off (STIM ON and STIM OFF). The orientation of both the trunk and the lower-limb segments was described with respect to the vertical in the sagittal plane. Lower-limb inter-segmental coordination was evaluated by analyzing the co-variation between thigh, shank, and foot elevation angles by means of orthogonal planar regression. At least 30 gait cycles per experimental condition were processed. We found that the trunk was bent forward in STIM OFF, whereas it was better aligned with the vertical in STIM ON in both PD groups. The legs never fully extended during the gait cycle in STIM OFF, whereas they extended before heel strike in STIM ON. The multisegmental coordination of the lower limb changed almost in parallel with the changes in trunk orientation. In STIM OFF, both the shape and the spatial orientation of the planar gait loops (thigh angle vs. shank angle vs. foot angle) differed from those of physiological locomotion, whereas in STIM ON the gait loop tended to resume features closer to the control. Switching the electrodes on and off in patients with GPi electrodes resulted in quasi-parallel changes of the trunk inclination and of the planar gait loop. The bulk of the data suggest that the basal-ganglia circuitry may be relevant in locomotion by providing an appropriate spatio-temporal framework for the control of posture and movement in a gravity-based body-centered frame of reference. Pallido-thalamic and/or pallido-mesencephalic pathways may influence the timing of the inter-segmental coordination for gait.
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PMID:Basal ganglia and gait control: apomorphine administration and internal pallidum stimulation in Parkinson's disease. 1036 37

In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D(1)-D(2) receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity. However, only R-APO prevented nigro-striatal neuronal cell degeneration, as indicated by the immunohistochemistry of TH positive neurones in substantia nigra and by western analysis of striatal TH content. R-APO prevented the reduction of striatal-GSH and the increase in the ratio of GSSG over total glutathione, caused by MPTP treatment. In vitro both R-APO and S-APO inhibited monoamine oxidase A and B activity at relatively high concentrations (100 and 300 micromol/L, respectively). The elevated activity of TH induced by the two enantiomers may contribute to the maintenance of normal DA levels, suggesting that one of the targets of these molecules may involve upregulation of TH activity. It is suggested that the antioxidant and iron-chelating properties, possible monoamine oxidase inhibitory actions, together with activation of DA receptors, may participate in the mechanism of neuroprotection by APO enantiomers against MPTP.
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PMID:Effects of R- and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss. 1127 70

Antioxidants have concentration-dependent neuroprotective and proapoptotic activities in models of Parkinson's disease. The aim of our study was to determine gene-protein pathways of the antioxidants, dopamine (DA), R-apomorphine (R-APO), melatonin, and green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), in neuroblastoma cells, using a customized cDNA microarray and quantitative reverse transcriptase-polymerase chain reaction gene expression techniques. We demonstrate a concentration-dependent correlation between these compounds and modulation of cell survival/cell death-related gene pathways. High toxic concentration of DA (500 microM), R-APO (50 microM), melatonin (50 microM), and EGCG (50 microM) exhibited a similar profile of proapoptotic gene expression, increasing the level of bax, caspase-6, fas ligand, and the cell-cycle inhibitor gadd45 genes, while decreasing antiapoptotic bcl-2 and bcl-xL. Conversely, the low neuroprotective concentrations (1-10 microM) of these compounds induced an antiapoptotic response. Melatonin displayed an extremely low index of mortality, which may be partially explained by the observation that a high concentration did not significantly affect the expression of mitochondrial Bcl-2 family members, bcl-2 and bax. Protein analysis of Bcl-2, Bax, and activated caspase-3 correlated with the gene expression pattern. Our results provide for the first time new insights into the molecular events involved in the dose-dependent neuroprotective and neurotoxic activities of catechols and indole amine compounds.
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PMID:cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells. 1262 34

Significant evidence has been provided to support the hypothesis that oxidant stress may be responsible for degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Dopamine (DA), R-apomorphine (R-APO), green tea polyphenol (-)-epigallocatechine-3-gallate (EGCG), and melatonin are neuroprotective and radical scavenger compounds. The aim of this study was to establish the mechanism of the concentration-dependent neuroprotective and pro-apoptotic action of these drugs via gene expression and protein determination. cDNA microarrays provide new prospects to study and identify various mechanisms of drug action. We employed this technique for the study reported in this paper. Total RNA was extracted from SH-SY5Y cells exposed to low neuroprotective and high toxic concentrations of the drugs, followed by synthesis of cDNA, and hybridization to a microarray membrane related to apoptosis, survival, and cell cycle pathways. We demonstrated a concentration and time-dependent correlation between R-APO, DA, EGCG, and melatonin in modulation of cell survival/cell death-related gene pathways. The results were confirmed by quantitative real-time PCR and protein profiles. Unlike the effects of low concentrations (1-10 micro M), where an antiapoptotic response was manifest, a proapoptotic pattern of gene expression was observed at high toxic concentrations (50-500 micro M) of the antioxidants (e.g., increase in caspases, fas, and gadd45). Our results have provided novel insights into the gene mechanisms involved in both the neuroprotective and proapoptotic activities of neuroprotective drugs. We have shown that DA, R-APO, EGCG, and melatonin exhibit similar gene expression and protein profiles.
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PMID:Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, R-apomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. 1285 28

This study analyzed the macrostructure and microstructure of sleep in 12 parkinsonian patients under basal conditions (T0) and during 1-night treatment (T1) with a new formulation of apomorphine. This new formulation consisted in a microemulsion of apomorphine administered by the transdermal route, able to provide a constant release of the drug over several hours (APO-TD). Sleep analysis at T1 compared with T0 revealed a 16% increment of total sleep time, a 12% increment of sleep efficiency, a 16% increment of stage 3 and 4 non-REM sleep, a 15% reduction of periodic limb movements index, a 22% reduction of arousal index, and a 23% reduction of cycling alternating patterns/non-REM. We conclude that APO-TD may be able to reduce nocturnal anomalous movements, akinesia, and rigidity in Parkinson's disease, and may reduce the disturbed sleep typical of Parkinson's disease.
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PMID:Nocturnal anomalous movement reduction and sleep microstructure analysis in parkinsonian patients during 1-night transdermal apomorphine treatment. 1459 90

The aim of our study was evaluation of the relationship between apolipoprotein E (APO E) genotype and the clinical parameters in Parkinson's disease (PD) with and without dementia. 104 PD patients were evaluated and within this group two subgroups were formed: 51 PD patients (25 males, 26 females; mean age: 70.4 +/- 6.03 years) with dementia and 53 (31 males, 22 females; mean age: 62.5 +/- 8.57 years) without dementia. The estimation of APO E genotype was executed by means of Polymerase Chain Reaction. The Unified Parkinson's Disease Rating Scale was used to quantify the severity of PD. Cognitive functions were assessed according to the Mini Mental State Examination. APO E genotype and allele frequencies did not differ between demented and nondemented parkinsonian patients.
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PMID:[Assessment of apolipoprotein E genotype in Parkinson disease patients with and without dementia]. 1518 44

Bertek Pharmaceuticals, a subsidiary of Mylan Laboratories Inc., is developing an intermittent subcutaneous formulation of apomorphine hydrochloride as a treatment for Parkinson's disease. Apomorphine injection (APO-go) for the treatment of Parkinson's disease was launched in the UK in May 2002. Bertek licensed the formulation from Britannia Pharmaceuticals in the UK for development and marketing in the US. In April 2004, apomorphine injection was approved as the first and only therapy in the US for the acute, intermittent treatment of hypomobility, 'off' episodes associated with advanced Parkinson's disease. This approval follows the fast-track status designation given by the US FDA in January 2003, and an approvable letter issued in July 2003. The product is expected to be available by July 2004.
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PMID:Apomorphine-subcutaneous--Bertek/Britannia. 1523 Jun 26

We investigated the possible neuroprotective effect of the dopamine (DA) receptor agonist R-apomorphine (R-APO) within the striatal 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. In one group of rats, R-APO administration (10 mg/kg/day, s.c.) started 15 min before 6-OHDA-injection. In a second group, R-APO administration started 24 h after lesion induction. Both groups received R-APO chronically for 11 days. Testing was carried out 2 weeks post-lesioning. R-APO treatment, whether started before or after the lesion induction, significantly reduced both the amphetamine-induced ipsiversive rotation and the size of the lesion at the level of the substantia nigra. Moreover, the dopamine cell shape and size resembled that observed in intact animals. R-APO treatment had no effect on the number of cells in the substantia nigra of intact rats, but significantly increased the number of cells in the ventral tegmental area (VTA), suggesting selective neurotrophic properties of R-APO in this region. R-APO treatment significantly attenuated the 6-OHDA-induced striatal DA depletion and DOPAC/DA ratios were normalized. Finally, an acute injection of 10 mg/kg R-APO was unable to scavenge 6-OHDA or MPP(+)-induced hydroxyl radicals as determined with the in vivo salicylate trapping technique. These data provide further evidence of the neurorescuing properties of R-APO. At least at the dose used in this study, this effect possibly occurs via mechanisms other than scavenging of hydroxyl radicals. In intact rats, we also show neurotrophic effects of the R-APO treatment. These seem to be limited to the VTA.
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PMID:Neuroprotective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinson's disease. 1547 1


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