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)

As an aid in the development of vector systems for use in gene therapy paradigms of central nervous system disorders such as Parkinson's disease, we have developed L-Dopa or dopamine-producing gene cassettes. Specifically, a human tyrosine hydroxylase cDNA (HTH-2) was rendered constitutively active by truncation of the N-terminal regulatory domain (tHTH). In addition, a bicistronic construct capable of directing the production of dopamine was created by inserting an internal ribosome entry site downstream of tHTH followed by the coding sequences of aromatic amino acid decarboxylase. All three constructs generated immunoreactive peptides of the predicted size, were enzymatically active, and produced L-Dopa (HTH-2, tHTH) or dopamine (bicistronic construct) following transient transfection of COS-7 cells. These constructs, in conjunction with viral or nonviral expression systems, may be efficacious in gene therapy approaches to Parkinson's disease.
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PMID:L-Dopa and dopamine-producing gene cassettes for gene therapy approaches to Parkinson's disease. 912 54

1. The effects of L-dopa methylester (LDME), an analogue of levodopa, on the spontaneous activity of dopamine sensitive neurones in the rat striatum, after 6-hydroxydopamine induced degeneration of the nigrostriatal tract were compared with those in unlesioned animals both in the absence and presence of benserazide, a peripheral DOPA decarboxylase inhibitor (PDI). 2. Studies were performed at 5-7 days post lesion (group 1 animals), at 21 days (group 2) when denervation supersensitivity was evident by contralateral turning to apomorphine and at the same time but following 7 days dosing with LDME plus benserazide (group 3). 3. In unlesioned animals, LDME alone inhibited spontaneous firing by some 45% over 60 min including a marked but transient early phase which was still present in all lesioned animals even though the later inhibition was significantly reduced in group 1 and 3 animals. 4. When given after benserazide in unlesioned animals LDME still produced a similar level of overall inhibition but without the early phase. The lesion reduced the overall inhibition, except in group 2 animals, and after chronic dosing (group 3) it was almost absent. 5. It is proposed that since the early inhibition with LDME alone is still seen after lesion of the nigrostriatal tract but not after the PDI benserazide, it is caused by peripherally formed dopamine and that as the delayed inhibition with LDME alone and after benserazide are all reduced by nigrostriatal lesions, as is its amphetamine like ipsilateral turning, that this depends on locally (striatal) synthesized dopamine. 6. This study also shows the chronic levodopa/PDI treatment reduces the compensating increased activity of surviving dopaminergic neurones and the functional supersensitivity to dopamine and suggests that the long term administration of levodopa may reduce its own utilization and activity in the striatum and in the treatment of Parkinson's Disease [corrected].
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PMID:Effect of L-dopa alone and with benserazide on the spontaneous activity of striatal neurones in normal and 6-hydroxydopamine-lesioned rats. 915 45

Postural instability and gait disorders (PIGD) are the primary causes of disability in many but not all advanced Parkinson's disease (PD) patients. We have measured the concentrations of serotonin, 5-hydroxytryptophan (5-HTP), 5-hydroxy-3-indoleacetic acid (5-HIAA), and homovanillic acid (HVA) in samples of ventricular cerebrospinal fluid from ten PD patients with severe disability from PIGD and from ten PD patients with tremor and levodopa induced dyskinesia as their predominant motor dysfunction. The two groups were prospectively matched for duration of disease and age. No significant differences between the two groups were found in the concentration (mean +/- SD in ng/ml, PIGD dominant vs. tremor-dyskinesia dominant) of 5-HIAA (106 +/- 50 vs. 99 +/- 34) or HVA (1,068 +/- 595 vs. 881 +/- 469). Serotonin concentration was significantly lower (0.7 +/- 0.5 vs. 1.5 +/- 0.9) and 5-HTP concentration was substantially higher (684 +/- 1,054 vs. 6 +/- 5) in the patient group with PIGD as their predominant symptoms. Thus, the distinguishing feature of patients with severe PIGD appears to be a derangement in indoleamine metabolism at the reaction step catalyzed by aromatic amino acid decarboxylase (AADC). These findings suggest that aggravation of PIGD in advanced Parkinson's may be related in part to impaired serotonergic transmission secondary to inhibition or down regulation of AADC.
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PMID:Concentrations of indoleamine metabolic intermediates in the ventricular cerebrospinal fluid of advanced Parkinson's patients with severe postural instability and gait disorders. 929 77

Investigations of gene therapy for Parkinson's disease have focused primarily on strategies that replace tyrosine hydroxylase. In the present study, the role of aromatic L-amino acid decarboxylase in gene therapy with tyrosine hydroxylase was examined by adding the gene for aromatic L-amino acid decarboxylase to our paradigm using primary fibroblasts transduced with both tyrosine hydroxylase and GTP cyclohydrolase I. We compared catecholamine synthesis in vitro in cultures of cells with tyrosine hydroxylase and aromatic L-amino acid decarboxylase together versus cocultures of cells containing these enzymes separately. L-DOPA and dopamine levels were higher in the cocultures that separated the enzymes. To determine the role of aromatic L-amino acid decarboxylase in vivo, cells containing tyrosine hydroxylase and GTP cyclohydrolase I were grafted alone or in combination with cells containing aromatic L-amino acid decarboxylase into the 6-hydroxydopamine-denervated rat striatum. Grafts containing aromatic L-amino acid decarboxylase produced less L-DOPA and dopamine as monitored by microdialysis. These findings indicate that not only is there sufficient aromatic L-amino acid decarboxylase near striatal grafts producing L-DOPA, but also the close proximity of the enzyme to tyrosine hydroxylase is detrimental for optimal dopamine production. This is most likely due to feedback inhibition of tyrosine hydroxylase by dopamine.
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PMID:Role of aromatic L-amino acid decarboxylase for dopamine replacement by genetically modified fibroblasts in a rat model of Parkinson's disease. 934 51

L-DOPA provides the most potent medication to treat Parkinson's disease, and such systemic treatment is usually combined with a peripheral amino acid decarboxylase inhibitor to amplify its central effectiveness. Since L-DOPA can lose its efficacy or can lead to adverse effects with prolonged application, current pharmacokinetic and dynamic research is aimed at improving the drug's applicability. In a previous study, performed with in vivo microdialysis in the anesthetized rat, we have shown that intranasal L-DOPA administration (without prior decarboxylase inhibition) can increase extracellular dopamine levels in the neostriatum. Using similar experimental conditions in the present experiment, we tested the neurochemical effects of L-DOPA treatment in combination with the peripheral amino acid decarboxylase inhibitor benserazide. In accordance with other data, it was found that the combination of i.p. benserazide and i.p. L-DOPA led to pronounced increases of extracellular levels of dopamine, dihydroxyplenylacetic acid and homovanillic acid in the neostriatum, whereas i.p. L-DOPA alone only moderately increased dopamine, but strongly increased the metabolite levels. Furthermore, increased dopamine levels, and weaker increases of dihydroxyplenylacetic acid and homovanillic acid were observed after i.p. benserazide followed by intranasal L-DOPA. Finally, we found that i.p. benserazide alone can lead to pronounced increases in neostriatal dopamine and moderate increases of dihydroxyplenylacetic acid levels, whereas it did not affect homovanillic acid. Thus, not only the combination of L-DOPA (i.p. or intranasal) with the presumed peripheral L-DOPA decarboxylase inhibitor benserazide, but also each component alone can affect dopamine activity in the brain. Especially the findings with benserazide treatment might be of relevance for understanding the mechanisms of current L-DOPA therapy, since they indicate that part of the treatment's actions may possibly be determined by central dopaminergic effects of the accompanying amino acid decarboxylase inhibitor.
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PMID:Increased neostriatal dopamine activity after intraperitoneal or intranasal administration of L-DOPA: on the role of benserazide pretreatment. 937 52

Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops. Chronic deprenyl treatment has also been suggested to cause down-regulation of release-modulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were therefore studied, by determination of steady-state tissue level of DOPA following administration of NSD-1015 (100 mg/kg i.p.). In addition, we assessed changes in the in vivo sensitivity of dopaminergic receptors from the reduction in DOPA extracellular level after systemic apomorphine administration (2.5 mg/kg s.c.), following elevation of microdialysate DOPA by systemic or local aromatic amino acid decarboxylase inhibition with NSD-1015. Chronic treatment with deprenyl (0.25 mg/kg s.c. daily for 21 days) caused a significant reduction in tyrosine hydroxylase activity to 60% of control, with no change in the apomorphine-induced reduction of microdialysate DOPA and DOPAC. The reduction in tyrosine hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic treatment with deprenyl. The increased extracellular striatal DA level could reduce tyrosine hydroxylase activity through activation of a negative feedback loop, by activation of either presynaptic or postsynaptic DA receptors.
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PMID:Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl. 942 34

Until the introduction of L-dopa in the therapeutics of idiopathic Parkinson's disease (IPD) at the end of the 60's, treatment was essentially limited to anticholinergic drugs and surgical procedures devised to produce discrete lesions in the pallidum, ansa lenticularis and thalamus. L-dopa, associated with dopa decarboxylase inhibitors and dopaminergic agonists, gave rise to an almost complete standstill of surgical procedures. Nevertheless, natural progression of IPD with motor fluctuations and the appearance of L-dopa related abnormal involuntary movements caused surgery to reappear as a primary treatment option. The MPTP epidemic in heroin addicts was responsible for obtaining an experimental model of IPD and became the starting point for a wealth of information concerning the physiopathology of basal ganglia circuitry, neurotransmitters and specific dopaminergic, gabaergic and glutamaergic receptor subtypes involved in motor control. This information, in the context of new stereotactic techniques with modern neuroimaging, enabled old surgical procedures on the internal globus pallidus (Gpi) and thalamus to be reformulated. Additional neurophysiological guidance further improved accuracy in target finding thereby giving rise to impressive results in the symptomatic improvement of IPD including L-dopa induced dyskinesias.
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PMID:[Parkinson's disease: from pallidotomy to L-dopa and back to pallidotomy]. 943 79

In vivo microdialysis in freely moving rats was used to study the biotransformation, consisting primarily of decarboxylation by aromatic amino acid decarboxylase (AAAD), of the precursors L-3,4-dihydroxyphenylalanine (L-DOPA), L-5-hydroxytryptophan (L-5HTP), and L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on extracellular levels of dopamine (DA), serotonin (5HT) and noradrenaline (NA), respectively. The precursors were administered locally through the microdialysis probe into the striatum and into the hippocampus. The different transmitter systems were compared with respect to the ability of the precursors to elevate extracellular levels of their associated transmitter. The basal extracellular concentrations of NA and DA were found to be tetrodotoxin (TTX, a blocker of fast sodium channels) sensitive in striatum and hippocampus, indicating the neuronal origin of the measured transmitters. The extracellular concentrations of 5HT (in hippocampus) were only 60% TTX-sensitive. L-DOPA and L-5HTP showed to be effective precursors of DA and 5HT, respectively, although their formation profile was quite different. The L-DOPA-induced increase in extracellular DA was large and short-lasting, while the L-5HTP-induced increase in 5HT was slower and less pronounced. The relative increase in extracellular DA or 5HT was more pronounced in the brain region where their baseline values were lower, but the absolute amount of transmitter formed from their precursor was similar in both brain regions. L-threo-DOPS was a poor precursor for NA and also failed to influence extracellular DA in striatum, questioning its use in the treatment of freezing gait in late stages of Parkinson's disease.
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PMID:Biotransformation of locally applied precursors of dopamine, serotonin and noradrenaline in striatum and hippocampus: a microdialysis study. 950 67

The trapping of decarboxylation products of radiolabelled dopa analogs in living human brain occurs as a function of the activity of dopa decarboxylase. This enzyme is now understood to regulate, with tyrosine hydroxylase, cerebral dopamine synthesis. Influx into brain of dopa decarboxylase substrates such as 6-[18F]fluorodopa and beta-[11C]dopa measured by positron emission tomography can be analyzed by solution of linear differential equations, assuming irreversible trapping of the decarboxylated products in brain. The isolation of specific physiological steps in the pathway for catecholamine synthesis requires compartmental modelling of the observed dynamic time-activity curves in plasma and in brain. The several approaches to the compartmental modelling of the kinetics of labelled substrates of dopa decarboxylase are now systematically and critically reviewed. Labelled catechols are extensively metabolized by hepatic catechol-O-methyltransferase yielding brain-penetrating metabolites. The assumption of a fixed blood-brain permeability ratio for O-methyl-6-[18F]fluorodopa or O-methyl-beta-[11C]dopa to the parent compounds eliminates several parameters from compartmental models. However, catechol-O-methyltransferase activity within brain remains a possible factor in underestimation of cerebral dopa decarboxylase activity. The O-methylation of labelled catechols is blocked with specific enzyme inhibitors, but dopa decarboxylase substrates derived from m-tyrosine may supplant the catechol tracers. The elimination from brain of decarboxylated tracer metabolites can be neglected without great prejudice to the estimation of dopa decarboxylase activity when tracer circulation is less than 60 minutes. However, elimination of dopamine metabolites from brain occurs at a rate close to that observed previously for metabolites of glucose labelled in the 6-position. This phenomenon can cause systematic underestimation of the rate of dopa decarboxylation in brain. The spillover of radioactivity due to the limited spatial resolution of tomographs also results in underestimation of dopa decarboxylase activity, but correction for partial volume effects is now possible. Estimates of dopa decarboxylase activity in human brain are increased several-fold by this correction. Abnormally low influx of dopa decarboxylase tracers in the basal ganglia is characteristic of Parkinson's disease and other movement disorders. Consistent with postmortem results, the impaired retention of labelled dopa is more pronounced in the putamen than in the caudate nucleus of patients with Parkinson's disease; this heterogeneity persists after correction for spillover. Current in vivo assays of dopa decarboxylase activity fail to discriminate clinically distinct stages in the progression of Parkinson's disease and are, by themselves, insufficient for differential diagnosis of Parkinson's disease and other subcortical movement disorders. However, potential new avenues for therapeutics can be tested by quantifying the rate of metabolism of exogenous dopa in living human brain.
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PMID:Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms. 955 74

As an alternative to virus-mediated gene transfer, we previously demonstrated a simple, safe, and efficient transfer of foreign gene into the central nervous system using continuous injection of a plasmid DNA-cationic liposome complex. To explore whether this approach can be applied to the treatment of certain neurological disorders, we used an experimental model of Parkinson's disease (PD) in the present study. Following continuous injection for 7 days, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) genes carried by a bovine papilloma virus-based plasmid vector were efficiently introduced into glial cells in the striatum of 6-hydroxydopamine-lesioned rats. Significant recovery in apomorphine-induced rotational behavior of PD models was obtained by transfection of TH gene and this effect continued for up to 5 weeks after injection. Moreover, cotransfection of TH with AADC genes was readily accomplished by this procedure and resulted in a greater and longer-lasting improvement of apomorphine-induced rotational behavior than was achieved by transfection of TH gene alone. We suggest that this approach is a controllable and manageable alternative to other methods of gene therapy for the treatment of PD.
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PMID:Significant behavioral recovery in Parkinson's disease model by direct intracerebral gene transfer using continuous injection of a plasmid DNA-liposome complex. 960 20


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