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)

Deep brain stimulation is a minimally invasive targeted neurosurgical intervention that enables structures deep in the brain to be stimulated electrically by an implanted pacemaker. It has become the treatment of choice for Parkinson's disease, refractory to, or complicated by, drug therapy. Its efficacy has been demonstrated robustly by randomized, controlled clinical trials, with multiple novel brain targets having been discovered in the last 20 years. Multifarious clinical indications for deep brain stimulation now exist, including dystonia and tremor in movement disorders; depression, obsessive-compulsive disorder and Tourette's syndrome in psychiatry; epilepsy, cluster headache and chronic pain, including pain from stroke, amputation, trigeminal neuralgia and multiple sclerosis. Current research argues for novel indications, including hypertension and orthostatic hypotension. The development, principles, indications and effectiveness of the technique are reviewed here. While deep brain stimulation is a standard and widely accepted treatment for Parkinson's disease after 20 years of experience, in chronic pain it remains restricted to a handful of experienced, specialist centers willing to publish outcomes despite its use for over 50 years. Reasons are reviewed and novel approaches to appraising clinical evidence in functional neurosurgery are suggested.
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PMID:Deep brain stimulation: indications and evidence. 1785 Jan 94

For 20 years, deep brain stimulation (DBS) at high frequency has been developed as a substitute for the classical lesioning methods previously used in stereotactic and functional neurosurgery. This method has proven its efficacy, based on its reversibility and adaptability: two factors that are responsible for low morbidity. The method has been initially developed for and applied to movement disorders in several target areas; such as the thalamus, the pallidum and the subthalamic nucleus. It has now also been extended to other indications, such as epilepsy, dystonias and cluster headache and, more recently, to psychiatric disorders, such as obsessive-compulsive disorder, Gilles de la Tourette tics and depression. Several other disorders are currently under investigation and these may become new indications in the future. The mechanism of action is likely to be complex; associating cell-firing inhibition, neurotransmitter depletion, jamming and excitation of inhibitory pathways that lead to functional inhibition, mimicking the effects of lesioning of the stimulated structures. High-frequency stimulation of the subthalamic nucleus induces neuroprotection in animal models but has not yet been demonstrated in human patients suffering from Parkinson's disease. Technological development will enhance and refine the effects of high-frequency stimulation, and allow further extension of this method to new targets and new indications.
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PMID:What the future holds for deep brain stimulation. 1803 54

Drugs targeting dopamine receptors have been the focus of much research over the past 30 years, in large part because of their role in treating multiple pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and hyperprolactinemia. Missense mutations in G protein-coupled receptors (GPCRs) can alter basal and/or ligand-induced signaling, which in turn can affect individuals' susceptibility to disease and/or response to therapeutics. To date, five coding variants in the human D1 receptor (hD1R; T37P, T37R, R50S, S199A, and A229T) and three in the human D2 receptor (hD2R; P310S, S311C, and T351A) have been reported in the NCBI single nucleotide polymorphism database. We utilized site-directed mutagenesis to generate cDNAs encoding these receptor isoforms. After expression in either HEK293 or neuronal GT1 cells, basal and ligand-induced signaling of each of these receptors was determined and compared to wild type. In addition, we investigated expression levels of each recombinant receptor and the effect of inverse agonist administration. Our data demonstrate that naturally occurring amino acid substitutions in the hD1R can lead to alterations in expression levels as well as in basal and ligand-induced signaling. The potency and efficacy of dopamine, synthetic agonists (i.e., fenoldopam, SKF-38393, SKF-82958, and SCH23390), and inverse agonists [i.e., flupenthixol and (+)butaclamol] were reduced at selected hD1R variants. Furthermore, inverse agonist induced effects on expression levels were sensitive to selected amino acid substitutions. In contrast to the hD1R variants, hD2R polymorphisms did not affect ligand function or receptor expression. The observation that the hD1R mutations induce significant alterations in pharmacologic properties may have implications both for disease susceptibility and/or therapeutic response to dopaminergic ligands.
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PMID:Pharmacological analysis of human D1 AND D2 dopamine receptor missense variants. 1821 Feb 31

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.
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PMID:Cannabinoids in health and disease. 1828 1

Positron emission tomography measurements of dopaminergic D2-like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The positron emission tomography (PET) radioligand [18F](N-methyl)benperidol ([18F]NMB) has high affinity and selectivity for D2-like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate the use of a graphical method utilizing a reference tissue region for [18F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (P<.0001 by repeated-measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward, thereby simplifying these measurements.
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PMID:Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans. 1835 89

Dopamine is a major neurotransmitter in the mammalian central nervous system (CNS) that regulates neuroendocrine functions, locomotor activity, cognition and emotion. The dopamine system has been extensively studied because dysfunction of this system is linked to various pathological conditions including Parkinson's disease, schizophrenia, Tourette's syndrome, and drug addiction. Accordingly, intense efforts to delineate the full complement of signaling pathways mediated by individual receptor subtypes have been pursued. Dopamine D1-like receptors are of particular interest because they are the most abundant dopamine receptors in CNS. Recent work suggests that dopamine signaling could be regulated via dopamine receptor interacting proteins (DRIPs). Unraveling these DRIPs involved in the dopamine system may provide a better understanding of the mechanisms underlying CNS disorders related to dopamine system dysfunction and may help identify novel therapeutic targets.
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PMID:Dopamine receptor interacting proteins (DRIPs) of dopamine D1-like receptors in the central nervous system. 1841 18

Central serotonergic and dopaminergic systems play a critical role in the regulation of normal and abnormal behaviours. Moreover, recent evidence suggests that the dysfunction of dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) neurotransmission might underlie the pathophysiology of neuropsychiatric disorders, including depression, schizophrenia, attention deficit hyperactivity disorders, drug abuse, Gilles de la Tourette's syndrome and Parkinson's disease.
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PMID:Serotonin-dopamine interaction: an overview. 1877 25

Although we have gained significant knowledge in the anatomy and microcircuitry of the thalamostriatal system over the last decades, the exact function(s) of these complex networks remain(s) poorly understood. It is now clear that the thalamostriatal system is not a unique entity, but consists of multiple neural systems that originate from a wide variety of thalamic nuclei and terminate in functionally segregated striatal territories. The primary source of thalamostriatal projections is the caudal intralaminar nuclear group which, in primates, comprises the centromedian and parafascicular nuclei (CM/Pf). These two nuclei provide massive, functionally organized glutamatergic inputs to the whole striatal complex. There are several anatomical and physiological features that distinguish this system from other thalamostriatal projections. Although all glutamatergic thalamostriatal neurons express vGluT2 and release glutamate as neurotransmitter, CM/Pf neurons target preferentially the dendritic shafts of striatal projection neurons, whereas all other thalamic inputs are almost exclusively confined to the head of dendritic spines. This anatomic arrangement suggests that transmission of input from sources other than CM/Pf to the striatal neurons is likely regulated by dopaminergic afferents in the same manner as cortical inputs, while the CM/Pf axo-dendritic synapses do not display any particular relationships with dopaminergic terminals. A better understanding of the role of these systems in the functional circuitry of the basal ganglia relies on future research of the physiology and pathophysiology of these networks in normal and pathological basal ganglia conditions. Although much remains to be known about the role of these systems, recent electrophysiological studies from awake monkeys have provided convincing evidence that the CM/Pf-striatal system is the entrance for attention-related stimuli to the basal ganglia circuits. However, the processing and transmission of this information likely involves intrinsic GABAergic and cholinergic striatal networks, thereby setting the stage for complex physiological responses of striatal output neurons to CM/Pf activation. Finally, another exciting development that will surely generate significant interest towards the thalamostriatal systems in years to come is the possibility that CM/Pf may be a potential surgical target for movement disorders, most particularly Tourette syndrome and Parkinson's disease. Although the available clinical evidence is encouraging, these procedures remain empirical at this stage because of the limited understanding of the thalamostriatal systems.
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PMID:The thalamostriatal systems: anatomical and functional organization in normal and parkinsonian states. 1880 68

Implantation of deep brain stimulation (DBS) electrodes via stereotactic neurosurgery has become a standard procedure for the treatment of Parkinson's disease. More recently, the range of neuropsychiatric conditions and the possible target structures suitable for DBS have greatly increased. The former include obsessive compulsive disease, depression, obesity, tremor, dystonia, Tourette's syndrome and cluster-headache. In this article we argue that several of the target structures for DBS (nucleus accumbens, posterior inferior hypothalamus, nucleus subthalamicus, nuclei in the thalamus, globus pallidus internus, nucleus pedunculopontinus) are located at strategic positions within brain circuits related to motivational behaviors, learning, and motor regulation. Recording from DBS electrodes either during the operation or post-operatively from externalized leads while the patient is performing cognitive tasks tapping the functions of the respective circuits provides a new window on the brain mechanisms underlying these functions. This is exemplified by a study of a patient suffering from obsessive-compulsive disease from whom we recorded in a flanker task designed to assess action monitoring processes while he received a DBS electrode in the right nucleus accumbens. Clear error-related modulations were obtained from the target structure, demonstrating a role of the nucleus accumbens in action monitoring. Based on recent conceptualizations of several different functional loops and on neuroimaging results we suggest further lines of research using this new window on brain functions.
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PMID:Contribution of subcortical structures to cognition assessed with invasive electrophysiology in humans. 1898 9

Deep brain stimulation (DBS) is a reversible surgical procedure that involves stereotactic implantation of electrodes into the targeted brain regions, with a subcutaneously placed pulse generator powering the electrodes via one or two leads. The mechanism of action can be explained by the stimulation-induced modulation of impaired network activity. So far, the main use of DBS has been for neurological conditions, such as essential tremor, motor symptoms in Parkinson's disease, dystonia, epilepsy, and chronic pain. In psychiatry, case series and open studies indicate treatment efficacy of DBS in Gilles de la Tourette syndrome, treatment-resistant obsessive-compulsive disorder, and refractory major depression. Neuroimaging studies have confirmed the effects of DBS on the brain regions implicated in specific neuropsychiatric disorders. It is a well-tolerated method with relatively few serious side effects. Additional well-designed and appropriately powered controlled clinical trials are needed to conclusively establish the efficacy and safety of DBS and to identify the patient population(s) who may benefit most. Ongoing research with stimulation techniques may also significantly contribute to our understanding of major neuropsychiatric disorders.
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PMID:Deep brain stimulation in psychiatry. 1902 77


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