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 effect of sustained intrastriatal release of dopamine (DA) from polymer matrices on apomorphine-induced turning behavior in a 6-hydroxydopamine (6-OHDA) unilaterally lesioned rat model was analyzed. A biocompatible semipermeable tube was placed in a denervated striatum as a receptacle for DA-releasing polymer rods. In vitro kinetics showed sustained release of DA from a polymeric rod for 15 days. Implantation of a DA-releasing rod within the striatal receptacle significantly decreased apomorphine-induced rotational behaviour in lesioned animals. Upon removal of the DA-releasing system from the receptacle, rotational behaviour increased within 2 weeks and approached preimplant control values 4 weeks later. Acute microdialysis revealed that DA appeared in the extracellular space within 20 min after the implantation of a DA-releasing rod into a denervated striatum. Significant DA amounts were still measurable 7 days postimplantation, indicating sustained DA release from the polymer rod. Dopamine released from a polymer matrix through a semipermeable receptacle alleviates experimental parkinsonism in rats, suggesting that controlled intrastriatal release of DA from a polymer matrix may provide an alternative method for the treatment of Parkinson's disease.
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PMID:An encapsulated dopamine-releasing polymer alleviates experimental parkinsonism in rats. 250 16

Levodopa (+ dopa decarboxylase inhibitor) is the most active of all drugs used in the treatment of Parkinson's disease. It acts on both akinesia and rigidity and improves the prognosis of the disease by increasing life expectancy. But levodopa also produces late side-effects: it often induces abnormal movements, fluctuations in motor performance, on-off effects, psychotic hallucinations, etc. Since these late side-effects remain difficult to treat, it is always necessary to assess the benefits and risks of the first treatment with levodopa. Anticholinergic drugs, which mainly act on tremor, must be used with caution since they may induce memory alterations and often confusional states in aged parkinsonians. Dopamine agonists are prescribed as adjuvant therapy in the treatment of the late side-effects of levodopa. New drugs (selegiline), new pharmaceutical preparations (sustained release forms), the first treatment of the disease (levodopa alone versus agonists alone versus levodopa + agonists), together with the new pharmacological approaches (brain grafts, drug infusions) are now under clinical evaluation.
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PMID:[Antiparkinsonian drugs]. 256 51

Dopamine (DA) is degraded in part by MAO, an intraneuronal and glial enzyme localized at the outer mitochondrial membrane. DA is a good substrate for MAO-B and selegiline enhances DA-transmission and improves akinesia of Parkinson's disease (PD) by selective MAO-B blockade. Immunocytochemistry (ICC) and histochemistry (HC) demonstrate that neurons of substantia nigra (SN) lack MAO near totally (but see Moll et al 1988). Consequently, inhibition of MAO-B in this brain area occurs mainly in glial cells. Therefore an increase of DA in glia seems to be of long-lasting therapeutic benefit in PD. In addition, synthesis of hydrogen peroxide generated via MAO-B is blocked by selegiline. By this toxicity by endogenous free radicals is diminished. Furthermore, exogenous neurotoxicity by MAO-B substrates can be prevented by inhibition of MAO-B, while such MAO-A substrates are metabolized at the level of the MAO-A containing endothelium of capillaries. As conclusion, selegiline is a safe inhibitor of MAO-B that reduces neurotoxicity possibly triggering PD. (Table: see text).
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PMID:Neurochemical perspectives to the function of monoamine oxidase. 261 92

Intracerebral microdialysis was used to evaluate the long-term in vivo release of dopamine from ethylene-vinyl acetate (EVAc)-dopamine copolymer matrix discs for up to 65 days following striatal implantation. Dopamine release occurred through a single cavity present on one side of the disc, which was otherwise fully coated with an additional, impermeable layer of EVAc. At 20 days following implantation of the device, extracellular concentrations of dopamine within the striatum reached micromolar levels, over 200-fold greater than control values. Release of dopamine was shown to be stable and maintained for the 2-month duration of the experiment. Histological examination confirmed the biocompatible nature of the implant. There are potential applications of this technology to the treatment of Parkinson's disease and other neurological and psychiatric disorders.
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PMID:Controlled release of dopamine from a polymeric brain implant: in vivo characterization. 230 20

Catecholamine concentrations were measured in tissue samples of caudate and adrenal medulla in eight patients with Parkinson's disease who were taking L-dopa and were undergoing autologous transplantation of adrenal medulla to caudate nucleus. High-performance liquid chromatography with electrochemical detection was used for the measurement of analytes. Dopamine concentrations were quite similar in the caudate and the adrenal medulla; epinephrine and norepinephrine concentrations were some 600 times and 90 times higher, respectively, than that of dopamine in adrenal medulla but were barely detectable in caudate nucleus. Catecholamines and metabolites were also measured, before and after transplantation, in lumbar cerebrospinal fluid (CSF) and plasma 1 hour after the patients' first morning dose of L-dopa. The major fractions of the catecholamines in CSF were sulfoconjugated. The concentrations of sulfoconjugated but not free dopamine were modestly increased in CSF after the transplantation, although plasma concentrations were unchanged. CSF concentrations of free and conjugated norepinephrine and epinephrine, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid were unchanged after the transplantation. The data suggest that the grafted tissue does not retain its noradrenergic or adrenergic properties after transplantation, and that dopamine formation in the brain may be modestly increased. Plasma catecholamines were unaffected after the removal of one adrenal gland for the transplant.
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PMID:Catecholamines in CSF, plasma, and tissue after autologous transplantation of adrenal medulla to the brain in patients with Parkinson's disease. 275 5

The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.
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PMID:Continuous and intermittent levodopa differentially affect basal ganglia function. 277 88

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of L-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.
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PMID:Chronic pharmacological manipulation of dopamine receptors in brain. 288 59

Dopamine D-1 receptors were analyzed in the caudate nucleus, putamen, pallidum, substantia nigra and nucleus accumbens in 20 patients with Parkinson's disease and in 18 age-matched controls by the binding of [3H]flupenthixol. The binding was decreased in the substantia nigra in those parkinsonian patients who were not treated with levodopa. A significantly increased number of D-1 receptors was found in the putamen of patients with Parkinson's disease, especially in those who were treated with levodopa. The increased binding of [3H]flupenthixol was most prominent in those six parkinsonian patients who still had therapeutic response to levodopa. In addition, orofacial dyskinesias were seen in three of these patients. The results of this study indicate that there may be denervation supersensitivity of striatal neurons and also a loss of striatonigral neurons in Parkinson's disease.
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PMID:Dopamine D-1 receptors in the parkinsonian brain. 293 11

Dopamine exerts an inhibitory or stimulant action on some of the hormones produced by the anterior pituitary gland. The dopamine content of the hypothalamus is considerably reduced in patients with Parkinson's disease. We have tested the anterior pituitary endocrine function in such patients to evaluate the repercussions on this function of the dopaminergic deficiency: the secretion of pituitary stimulins was found to be unaltered both at baseline level and after pharmacological stimulation.
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PMID:[The anterior pituitary endocrine function in Parkinson's disease]. 295 51

Blink rate is determined by many factors, including local eye irritation, the state of the corneal tear film, factors related to general visual function, the amount of general facial movement, cognitive variables, and the level of arousal. These factors appear to be mediated by several neuroanatomic structures (Table 2). The timing and the nature of the interrelationship between neuroanatomic structures during blinking remains to be determined. Dopamine is the neurotransmitter that is most strongly linked to blinking, exerting its effect on blinking primarily through the D2 receptor. The reduced rate in Parkinson's disease seems to implicate the nigrostriatal system. Perhaps efferents of the nigrostriatal system, such as those to the superior colliculus, are primarily involved, as suggested by the reduced blinking in PSP. Changes in blinking produced in the sylvian aqueduct syndrome further suggest involvement of the periaqueductal structures. At best, however, these conclusions are tentative, as the biochemical neuroanatomy will probably prove more complicated than suggested by the initial studies using the dopaminergic paradigm. Nevertheless, insofar as blink rate represents a noninvasive probe of CNS dopamine activity, the failure to associate dyskinesias (except levodopa-induced dyskinesia) with increased blinking, indicates that the pathophysiology of these conditions may not involve hyperactivity of CNS dopamine systems. Fittingly, the current clinical potential of blink rate seems maximal in parkinsonism, both to follow the severity of the illness and to monitor side effects of dopamine agonist treatment.
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PMID:Physiology of normal and abnormal blinking. 296 73


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