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)

Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.
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PMID:The functional anatomy of basal ganglia disorders. 169 77

It has previously been shown that glutamatergic overactivity of the subthalamic nucleus (STN) is involved in hypokinetic movement disorders such as Parkinson's disease. Conversely, it has been hypothesized that hyperkinetic behavioral syndromes may be associated with reduced glutamatergic transmission of the STN to its target areas, the substantial nigra pars reticulata (SNR) and the globus pallidus pars interna (GPI). In the present experiment, apomorphine injected systemically into unilaterally dopamine-denervated rats induced the hyperkinetic syndrome of contralateral rotation. The involvement of glutamatergic input to the SNR in this hyperkinesia was investigated by pharmacological manipulation with an agonist or an antagonist at the AMPA subtype of glutamate receptors. Either the agonist AMPA or the antagonist CNQX was infused directly into the SNR at a dose of 1.0 nmol. Intra-SNR AMPA attenuated the contralateral rotation induced by apomorphine without eliciting any effects on rotation by itself. Infusions of the antagonist CNQX did not affect either apomorphine-induced or spontaneous rotation. These results support the notion that underactivity of the SNR and its glutamatergic afferent projection from the STN may underlie hyperkinetic movement disorders and that local stimulation of the AMPA subtype of glutamate receptors can ameliorate such syndromes.
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PMID:Intra-nigra infusion of AMPA attenuates dopamine-dependent rotation in the rat. 769 18

Monkeys exposed to low doses of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop difficulty in performing a previously learned delayed response (DR) task. In the present group of animals, performance deficits were manifested as a combination of mistakes or incorrect responses and no response errors, trials on which the animals failed to respond. Methylphenidate and the dopamine D2 receptor agonist LY-171555, at low doses, decreased the number of no-response errors but not mistakes. The partial D1 agonist SKF-38393 had no effects on no-response errors or mistakes. Thus, behavioral deficits associated with decreased task persistence may be amenable to treatment with dopamine agonists, and particularly D2 agonists, while cognitive performance per se may not be improved by such drugs. The similarities between this primate model and the cognitive/behavioral deficits associated with early Parkinson's disease and attention deficit hyperactivity disorder suggest that this may be a useful model for testing hypotheses concerning the pharmacological treatment of these disorders.
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PMID:Effects of dopamine agonists on delayed response performance in chronic low-dose MPTP-treated monkeys. 791 26

Monkeys exposed to low doses of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) develop cognitive deficits in the absence of gross motor dysfunction. Attentional deficits and task impersistence are now also described in these animals. The task impersistence correlated with no-response errors (i.e. errors of omission) on a delayed response task and improved with dopamine agonist therapy. In parallel studies, it was observed that there were significant differences in the ability of normal monkeys to learn to perform cognitive tasks. We found that monkeys classified as poor learners had similar deficits in task persistence as did MPTP-exposed monkeys, suggesting a relationship between poor cognitive performance and task impersistence in untreated as well as MPTP-treated monkeys. The possible significance of these results for two clinical disorders, early Parkinson's disease and attention deficit hyperactivity disorder is discussed. Cognitive and behavioral similarities between chronic low dose MPTP-treated monkeys, early Parkinson's disease patients and people with attention deficit hyperactivity disorder may suggest the existence of related pathophysiological mechanisms in these disorders.
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PMID:Task persistence and learning ability in normal and chronic low dose MPTP-treated monkeys. 800 41

Movement disorders have been coined for diseases characterized by excessive and abnormal movements occurring in a conscious patient. Movement disorders are frequent among neurologic and psychiatric patients. They have a behavioral, or psychiatric, component. Movement disorders are mostly associated with disordered function in the basal ganglia, brain stem, and cerebellum. Such diseases are characterized by the occurrence of involuntary movement. This paper describes general concept of movement disorder, and shows classification by WHO (1991) and by Joseph, AB. and Young, RR. (1992). The classification of WHO includes I. Extrapyramidal movement disorders: 1) Parkinson disease, 2) Secondary parkinsonism, 3) Other degenerative diseases of the basal ganglia, 4) Dystonia, and 5) Other extrapyramidal and movement disorders. II. Behavioral and emotional disorders with onset usually occurring in childhood and adolescence: 1) Hyperkinetic disorders, 2) Tic disorders, and 3) others.
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PMID:[Movement disorders--concept and grand classification]. 827 55

This article reviews the cytoskeletal abnormalities, morphologic lesion patterns, and resulting pathophysiology of the most frequent neurodegenerative movement disorders caused by dysfunction of the basal ganglia and related neuronal loops. The following topics are discussed: Among the akinetic-rigid Lewy body disorders is idiopathic Parkinson's disease, which reveals specific lesion patterns of pathophysiologic and therapeutic relevance. Dementia with Lewy bodies characterized by cortical Lewy bodies appears intermediate between Parkinson's and Alzheimer's diseases. Tau pathologic disorders may show some clinical and morphologic overlap. Multiple system atrophy has ubiquitous oligodendroglial inclusions as a cytopathologic hallmark. Secondary parkinsonism includes drug-related, toxic, and other symptomatic disorders. Hyperkinetic disorders include CAG-related inherited diseases, showing specific genetic defects and morphologic lesions. Dystonia syndromes show inconsistent pathologic findings, and myoclonus may be related to a variety of disorders. Consensus data on clinical and neuropathologic criteria already existing for some disorders, together with molecular genetic and biochemical data will provide further insight into the complex pathophysiology and pathogenesis of movement disorders.
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PMID:Neuropathology of movement disorders. 949 89

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Both environmental and genetic factors contribute to the etiology of this complex disease. In the current investigation, a catechol-O-methyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. Using a haplotype relative risk design and a parent-to-proband allele transmission test with 48 ADHD triads, we found an association between COMT and illness (chi(2) = 4.72, p = 0.03, df = 1). In particular, the impulsive-hyperactive type of ADHD (excluding inattention) ascertained by Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria (chi(2) = 8.34, p = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pearson chi(2) = 5.32, p = 0.02, df = 1) as well as by the Continuous Performance Test False Alarm scale (chi(2) = 2.78, p = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtained if genotype frequencies were compared. It should be noted that the association between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methylphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD.
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PMID:Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. 1049 Jul 6

Extraordinary progress has been made in the molecular, genetic, anatomical, and pharmacological characterization of dopamine D4 receptors in animal and human brain. Clarification of the neurochemical and physiological roles of these cerebral receptors is emerging. Postmortem neuropathological studies have inconsistently linked D4 receptors to psychotic disorders, and genetic studies have failed to sustain conclusive associations between D4 receptors and schizophrenia. However, associations are emerging between D4 receptors and other neuropsychiatric disorders, including attention deficit hyperactivity disorder, mood disorders, and Parkinson's disease, as well as specific personality traits such as novelty-seeking. Selective D4 agonists and antagonists have been developed as useful experimental probes. D4antagonists, so far, have proved ineffective in treatment of schizophrenia, but testing in a broader range of disorders may yield clinically useful drugs. D4 receptors appear to have broad implications for the pathophysiology of neuropsychiatric illnesses and their improved treatment.
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PMID:Dopamine D4 receptors: significance for molecular psychiatry at the millennium. 1057 34

There is a gender difference, or male predominance, in Parkinson's disease and attention deficit hyperactivity disorder (ADHD). Although the reason why it is predominantly the male who suffers from the diseases is still unknown, the female steroid hormone may be involved in the pathogenesis. Estrogen is a female sex hormone with a steroid structure. Like other steroid hormones, it binds to specific receptors in the nuclei and regulates gene transcription (genomic effects). In addition to the genomic effects, it can act as an antioxidant, a process not mediated by the estrogen receptor (nongenomic effects). Further, estrogen can have a novel action through a specific receptor located in the plasma membrane. In the central nervous system, estrogen provides neuroprotection mediated through multiple mechanisms. In this article, we review several possible mechanisms for the neuroprotective effects including antiapoptotic protection by estrogens as transcription factors, protection against oxidative stress by estrogens acting as antioxidants, and neurotrophic cross talk through the signal cascade shared with neurotrophic factors.
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PMID:Neuroprotective effects of estradiol in mesencephalic dopaminergic neurons. 1065 71

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.
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PMID:Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist. 1081 48


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