Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to evaluate gastric myoelectrical and mechanical activities in idiopathic Parkinson's disease (IPD) patients. Twenty patients with IPD (14 male and 6 female, mean age 42 +/- 9 years) were studied. Patients were divided into two groups: group A--early stage of disease (no. = 6) and group B--advanced IPD (no. = 14). Electrogastrography (EGG) was performed in fasting and postprandial conditions (Synectics system). The cross-sectional area of the gastric antrum was measured by sonography (Hitachi EUB-240). The antral area in fasting conditions was 2.1 +/- 0.4 and 4.2 +/- 1.2 cm2 and gastric emptying was 75 +/- 5 and 125 +/- 12 min in groups A and B respectively. EGG showed dysrhythmias (range 1-6 cycles per minute) in about 75% of both groups of IPD patients without increase in signal amplitude after a meal. Our results suggest that gastric motility is particularly impaired in patients with advanced IPD. It may be caused by the primary degenerative process in the autonomic nervous system of the gut.
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PMID:Gastric electromechanical dysfunction in Parkinson's disease. 1084 59

Autonomic dysfunction in patients with Parkinson's disease (PD) has been recognized since the original description by James Parkinson in 1817. Autonomic failure can be the clinical presentation of other diseases like pure autonomic failure (PAF) and multiple system atrophy (MSA). Both the central and peripheral autonomic nervous systems can be affected in PD. Rajput and Rozdilsky described cell loss and Lewy bodies within the sympathetic ganglia and antibodies to sympathetic neurons have been detected in PD patients. Lewy bodies can be seen in autonomic regulatory regions, including the hypothalamus, sympathetic (intermediolateral nucleus of the thoracic cord and sympathetic ganglia), and parasympathetic system (dorsal, vagal, and sacral parasympathetic nuclei). Lewy bodies were also found in the adrenal medulla and in the neural plexi innervating the gut, heart and pelvis. Symptoms of dysautonomia are variable, and include cardiovascular symptoms, gastrointestinal, urogenital, sudomotor and thermoregulatory dysfunction, pupillary abnormalities and sleep and respiratory disorders. They may represent a useful tool in the differential diagnosis of "atypical" or "complicated" parkinsonisms.
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PMID:Autonomic dysfunction in Parkinson's disease. 1575 24

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.
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PMID:Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects. 1513 84

Transglutaminase 2 (TG-ase 2) is one of the enzymes which catalyzes the deamination and transacylation of proteins. The transfer of a glutamine acyl residue to a lysine amine group of the acceptor protein is one of the posttranslational covalent modifications regulating some polypeptide activities. The control of protein oligomerization by TG-ase 2 is a cause of the formation of detergent-insoluble macromolecular aggregates. These inclusions are present in degenerating cells during, for example, Alzheimer's and Parkinson's disease. Overexpression of TG-ase 2 has been noted in apoptotic cells. Protein reserves in cereals are rich in glutamine, a substrate of TG-ase 2. Deamination of glutamine is the most important reaction for the initiation of the inflammatory process during gluten-dependent disease of the gut (celiac disease). Grains that contain gliadin are a cause of inflammatory reaction in children with intolerance to glutene. Interactions of the TG-ase product-glutamate with antigens of the major histocompatibility complex type II (MHC II, or HLA DQ) cause autoimmunological reaction by CD4+ T lymphocytes. Knowledge of the kinetic and molecular character of TG-ase 2 has contributed to finding peptides to replace gliadin. These molecules do not evoke immunological events.
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PMID:[The involvement of transglutaminase 2 in autoimmunological diseases]. 1601 94

Selegiline orally disintegrating tablet is a potent, selective and irreversible inhibitor of monoamine oxidase type B. It is delivered in an innovative formulation that largely bypasses the gut and first-pass hepatic metabolism by allowing transbuccal absorption. Selegiline orally disintegrating tablet dissolves in the mouth within seconds and is rapidly absorbed directly into the systemic circulation, increasing parent drug bioavailability and lowering plasma metabolites compared with conventional oral formulations. Adding selegiline orally disintegrating tablet to levodopa in patients experiencing 'wearing-off' episodes significantly decreases off time and increases dyskinesia-free 'on' time. Adding selegiline orally disintegrating tablet to levodopa also significantly improves Unified Parkinson's Disease Rating Scale motor scores and patients' and physicians' ratings of disease severity. Selegiline orally disintegrating tablet has been demonstrated to be safe and well tolerated in placebo-controlled clinical trials.
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PMID:Selegiline orally disintegrating tablets for the treatment of Parkinson's disease. 1627 28

Neuroplastic changes in the enteric nervous system (ENS) may be observed in physiological states, such as development and aging, or occur as a consequence of different pathological conditions, ranging from enteric neuropathies (e.g., Hirschsprung's disease) to intestinal (e.g., inflammatory bowel disease) or extra-intestinal diseases (e.g., Parkinson's disease). Studying ENS plasticity may help to elucidate the pathophysiology of several diseases and have a bearing on the development of new pharmacological interventions. In the present review, we would like to focus on neuronal plasticity evoked by gastrointestinal inflammation occurring in inflammatory bowel disease and in a subset of patients with severe derangement of gut motility due to an enteric neuropathy characterized by an inflammatory infiltrate of the enteric plexuses. Major features of neuroplasticity within the enteric microenvironment encompass structural abnormalities ranging from nerve re-arrangement (e.g., hypertrophy and hyperplasia) to degeneration and loss of enteric ganglion cells; altered synthesis, content and release of neurotransmitters as well as up- or down-regulation of receptor systems; gastrointestinal dysfunction characterized by sensory-motor and secretory impairment of the gut. Interestingly, neuronal changes may also occur in segments of the gastrointestinal tract remote from the site of the original inflammation, e.g. the ileum may show neuroplastic changes during colitis. Sometimes, the inflamed site may even be outside the gut. Among potential mechanisms underlying ENS plasticity, neurotrophins and enteric glia deserve special attention. A better comprehension of ENS plasticity during inflammation could be instrumental to develop new therapeutic options for patients with IBD and inflammatory enteric neuropathies.
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PMID:Enteric neuroplasticity evoked by inflammation. 1662 34

Donepezil is a selective acetylcholinesterase inhibitor that is widely prescribed for Alzheimer's disease (AD). It has been shown to be of benefit in mild, moderate and severe stages of AD, vascular dementia and dementia associated with Parkinson's disease. Donepezil is absorbed slowly, but completely, from the gut, reaching peak plasma levels in 3-4 h and, with daily dosing, steady-state concentration in 15-21 days. Within a relatively narrow range, there is a linear relationship between dose and pharmacodynamic effects, measured as red blood cell acetylcholinesterase inhibition and clinical efficacy. Donepezil is principally excreted unchanged in the urine, but there is also hepatic metabolism; some of its metabolites may be active. Despite being 96% bound to plasma proteins, it has few interactions with other drugs, and the 5-mg dose can be given safely to patients with mild-to-moderate hepatic and renal -disease. Side effects, which are mainly a consequence of its cholinomimetic mechanism of action, are usually mild and transient. Although donepezil was originally developed to inhibit the breakdown of the neurotransmitter acetylcholine as symptomatic therapy for AD, recent studies raise the possibility of other effects this drug has on the pathogenesis of AD.
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PMID:Donepezil: a review. 1686 59

Loss-of-function mutations in the human PARK7 gene, encoding DJ-1, are a rare cause of autosomal recessive Parkinson's disease (ARPD). To facilitate generation of a novel vertebrate model, in which to examine the biochemical functions of DJ-1 in vivo, we cloned and characterized the zebrafish orthologue of DJ-1 (zDJ-1). The 0.95 kb zDJ-1 mRNA is expressed in adult zebrafish brain, muscle and gut, and in the embryo from 24 h post-fertilization. The zDJ-1 transcript encodes a 19.8 kDa, 189 amino acid protein, which is 83% identical to human DJ-1. Residues thought to be functionally important sites of post-translational modification in human DJ-1, and critical positions affected by pathogenic missense mutations in ARPD patients, are conserved in zDJ-1. The 14 kb zDJ-1 gene contains six exons and is located on zebrafish chromosome 8; the structure of the gene is highly homologous to human DJ-1, except that there are no alternatively spliced non-coding 5' exons. The single zDJ-1 first exon shows 5' end heterogeneity, reflecting multiple transcription start sites. In the adult zebrafish brain, zDJ-1 immunoreactivity was prominent in the cytoplasm of most neurons, and in the neuropil, but was less evident within white matter tracts, consistent with neuronal somatic and dendritic localization. Dopaminergic neurons in each of the major forebrain and diencephalic TH-positive cell groups expressed zDJ-1. These studies show that zDJ-1 is very similar to human DJ-1 and delineate essential resources, allowing further examination of the function and regulation of DJ-1, using the zebrafish as a model.
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PMID:Zebrafish DJ-1 is evolutionarily conserved and expressed in dopaminergic neurons. 1694 55

In mammals, dopamine 2-like receptors are expressed in distinct pathways within the central nervous system, as well as in peripheral tissues. Selected neuronal D2-like receptors play a critical role in modulating locomotor activity and, as such, represent an important therapeutic target (e.g. in Parkinson's disease). Previous studies have established that proteins required for dopamine (DA) neurotransmission are highly conserved between mammals and the fruit fly Drosophila melanogaster. These include a fly dopamine 2-like receptor (DD2R; Hearn et al. PNAS 2002 99(22):14554) that has structural and pharmacologic similarity to the human D2-like (D2R). In the current study, we define the spatial expression pattern of DD2R, and functionally characterize flies with reduced DD2 receptor levels. We show that DD2R is expressed in the larval and adult nervous systems, in cell groups that include the Ap-let cohort of peptidergic neurons, as well as in peripheral tissues including the gut and Malpighian tubules. To examine DD2R function in vivo, we generated RNA-interference (RNAi) flies with reduced DD2R expression. Behavioral analysis revealed that these flies show significantly decreased locomotor activity, similar to the phenotype observed in mammals with reduced D2R expression. The fly RNAi phenotype can be rescued by administration of the DD2R synthetic agonist bromocriptine, indicating specificity for the RNAi effect. These results suggest Drosophila as a useful system for future studies aimed at identifying modifiers of dopaminergic signaling/locomotor function.
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PMID:Locomotor activity is regulated by D2-like receptors in Drosophila: an anatomic and functional analysis. 1744 95

Elevated iron levels in the substantia nigra (SN) participate in neuronal death in Parkinson's disease (PD). While the mechanisms underlying the increased iron are still unknown, some iron transport proteins may be involved. The nigral iron accumulation could be a result of either increased import or decreased export. The mechanisms of iron import have received considerable attention, but little is known about iron export mechanisms. Ferroportin1 (FP1) and hephaestin (HP), two newly discovered iron export proteins, cooperate in the iron export in the gut. Here, we investigated their expression in the SN of rats lesioned by 6-hydroxydopamine (6-OHDA). Using immunofluorescence, we showed that FP1 and HP were both expressed on astrocytes, microglia, oligodendrocytes and neurons in the SN. By immunohistochemistry, we showed that 1 day after 6-OHDA lesion, the expression of the two proteins decreased compared with the control. When rats began showing rotation behaviour induced by apomorphine, usually 6 weeks after 6-OHDA lesion, they are considered PD models. In these PD models, a further decrease in the two proteins was observed. Reverse transcriptase-polymerase chain reaction showed that the mRNA levels of FP1 and HP decreased 1 day after 6-OHDA lesion compared with the control, and further decrease was also observed in the PD model rats. These results show for the first time that FP1 and HP co-localize in the rat brain, and suggest that decreased expression of these transporters in the SN can account for the increased iron levels.
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PMID:Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. 1756 42


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