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)

Water-suppressed chemical shift magnetic resonance imaging was used to detect neurochemical alterations in vivo in neurotoxin-induced rat models of Huntington's and Parkinson's disease. The toxins were: N-methyl-4-phenylpyridinium (MPP+), aminooxyacetic acid (AOAA), 3-nitropropionic acid (3-NP), malonate, and azide. Local or systemic injection of these compounds caused secondary excitotoxic lesions by selective inhibition of mitochondrial respiration that gave rise to elevated lactate concentrations in the striatum. In addition, decreased N-acetylaspartate (NAA) concentrations were noted at the lesion site over time. Measurements of lactate washout kinetics demonstrated that t1/2 followed the order: 3-NP approximately MPP+ >> AOAA approximately malonate, which parallels the expected lifetimes of the neurotoxins based on their mechanisms of action. Further increases in lactate were also caused by intravenous infusion of glucose. At least part of the excitotoxicity is mediated through indirect glutamate pathways because lactate production and lesion size were diminished using unilateral decortectomies (blockade of glutamatergic input) or glutamate antagonists (MK-801). Lesion size and lactate were also diminished by energy repletion with ubiquinone and nicotinamide. Lactate measurements determined by magnetic resonance agreed with biochemical measurements made using freeze clamp techniques. Lesion size as measured with MR, although larger by 30%, agreed well with lesion size determined histologically. These experiments provide evidence for impairment of intracellular energy metabolism leading to indirect excitotoxicity for all the compounds mentioned before and demonstrate the feasibility of small-volume metabolite imaging for in vivo neurochemical analysis.
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PMID:Non-invasive neurochemical analysis of focal excitotoxic lesions in models of neurodegenerative illness using spectroscopic imaging. 862 49

In a case-control study, we investigated the possible etiologic relevance to Parkinson's disease (PD) of rural factors such as farming activity, pesticide exposures, well-water drinking, and animal contacts; toxicologic exposures such as wood preservatives, heavy metals, and solvents; general anesthesia; head trauma; and differences in the intrauterine environment. We recruited 380 patients in nine German clinics, 379 neighborhood control subjects, and 376 regional control subjects in the largest case-control study investigating such factors and collected data in structured personal interviews using conditional logistic regression to control for educational status and cigarette smoking. The latter was strongly inversely associated with PD. There were significantly elevated odds ratios (OR) for pesticide use, in particular, for organochlorines and alkylated phosphates, but no association was present between PD and other rural factors. A significantly elevated OR was present for exposure to wood preservatives. Subjective assessment by the probands indicated that exposure to some heavy metals, solvents, exhaust fumes, and carbon monoxide was significantly more frequent among patients than control subjects, but this was not confirmed by a parallel assessment of job histories according to a job exposure matrix. Patients had undergone general anesthesia and suffered severe head trauma more often than control subjects, but a dose-response gradient was not present. Patients reported a significantly larger number of amalgam-filled teeth before their illness than control subjects. The frequency of premature births and birth order did not differ between patients and control subjects. Patients reported significantly more relatives affected with PD than control subjects. These results support a role for environmental and genetic factors in the etiology of PD.
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PMID:Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany. 862 66

The paradox of aerobic life, or the 'Oxygen Paradox', is that higher eukaryotic aerobic organisms cannot exist without oxygen, yet oxygen is inherently dangerous to their existence. This 'dark side' of oxygen relates directly to the fact that each oxygen atom has one unpaired electron in its outer valence shell, and molecular oxygen has two unpaired electrons. Thus atomic oxygen is a free radical and molecular oxygen is a (free) bi-radical. Concerted tetravalent reduction of oxygen by the mitochondrial electron-transport chain, to produce water, is considered to be a relatively safe process; however, the univalent reduction of oxygen generates reactive intermediates. The reductive environment of the cellular milieu provides ample opportunities for oxygen to undergo unscheduled univalent reduction. Thus the superoxide anion radical, hydrogen peroxide and the extremely reactive hydroxyl radical are common products of life in an aerobic environment, and these agents appear to be responsible for oxygen toxicity. To survive in such an unfriendly oxygen environment, living organisms generate--or garner from their surroundings--a variety of water- and lipid-soluble antioxidant compounds. Additionally, a series of antioxidant enzymes, whose role is to intercept and inactivate reactive oxygen intermediates, is synthesized by all known aerobic organisms. Although extremely important, the antioxidant enzymes and compounds are not completely effective in preventing oxidative damage. To deal with the damage that does still occur, a series of damage removal/repair enzymes, for proteins, lipids and DNA, is synthesized. Finally, since oxidative stress levels may vary from time to time, organisms are able to adapt to such fluctuating stresses by inducing the synthesis of antioxidant enzymes and damage removal/repair enzymes. In a perfect world the story would end here; unfortunately, biology is seldom so precise. The reality appears to be that, despite the valiant antioxidant and repair mechanisms described above, oxidative damage remains an inescapable outcome of aerobic existence. In recent years oxidative stress has been implicated in a wide variety of degenerative processes, diseases and syndromes, including the following: mutagenesis, cell transformation and cancer; atherosclerosis, arteriosclerosis, heart attacks, strokes and ischaemia/reperfusion injury; chronic inflammatory diseases, such as rheumatoid arthritis, lupus erythematosus and psoriatic arthritis; acute inflammatory problems, such as wound healing; photo-oxidative stresses to the eye, such as cataract; central-nervous-system disorders, such as certain forms of familial amyotrophic lateral sclerosis, certain glutathione peroxidase-linked adolescent seizures, Parkinson's disease and Alzheimer's dementia; and a wide variety of age-related disorders, perhaps even including factors underlying the aging process itself. Some of these oxidation-linked diseases or disorders can be exacerbated, perhaps even initiated, by numerous environmental pro-oxidants and/or pro-oxidant drugs and foods. Alternatively, compounds found in certain foods may be able to significantly bolster biological resistance against oxidants. Currently, great interest centres on the possible protective value of a wide variety of plant-derived antioxidant compounds, particularly those from fruits and vegetables.
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PMID:Oxidative stress: the paradox of aerobic life. 866 Mar 87

The direct application of recombinant human glial cell line-derived neurotrophic factor (rhGDNF) to the deep structures of the nigrostriatum has been shown previously to augment dopamine function and inhibit loss of substantia nigra neurons in rodent models of Parkinson's disease. The present studies were designed to determine whether administration of rhGDNF into the lateral ventricle, a more clinically accessible intracranial target, is capable of augmenting dopamine function of the nigrostriatal pathway in normal rats. Single bolus intracerebroventricular (i.c.v) injections of rhGDNF increased locomotor activity and decreased food and water consumption and body weight gain in a dose-dependent manner. rhGDNF increased concentrations of dopamine and dopamine metabolites in the substantia nigra, ventral tegmental area and hypothalamus, but had no significant effects in the striatum. rhGDNF had no effect on striatal or substantia nigral serotonin (5-HT) and 5-hydroxyindoleacetic acid levels, but these levels were significantly increased in the ventral tegmental area and hypothalamus respectively. The augmentation of the dopamine and 5-HT systems was detected 2 weeks but not 3 days or 6 weeks after rhGDNF administration. After a repeat injection of i.c.v rhGDNF (6 weeks after the initial injection), substantia nigral dopamine, 5-HIAA and noradrenalin levels were increased. These results indicate that i.c. v administration of rhGDNF has an influence on adult rat dopamine neurons. This route of administration may be useful for stimulating dopamine neurons in Parkinson's disease.
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PMID:Glial cell line-derived neurotrophic factor: the lateral cerebral ventricle as a site of administration for stimulation of the substantia nigra dopamine system in rats. 875 95

To clarify the role of heredity and of some environment risk factors in the etiology of idiopathic Parkinson's disease, we performed a case-control study in two regions of southern Italy, Campania and Molise. We selected two controls for each parkinsonian patient, the patient's spouse and a sex- and age-matched neurological control. One hundred sixteen consecutive outpatients with Parkinson's disease (77 men, 39 women; mean age +/- SD = 62.5 +/- 9.9) and the same number of spouses and neurological controls were interviewed about five environmental risk factors (cigarette smoking, well-water drinking, head trauma with loss of consciousness, strict diets, general anesthesia) and two genetic risk factors (family history of Parkinson's disease or of essential tremor). Well-water drinking and family history of Parkinson's disease or essential tremor showed a positive association with Parkinson's disease; smoking showed a negative association. The most relevant risk factor was history of familial Parkinson's disease (odds ratio = 14.6; 95% confidence interval = 7.2 - 29.6); 33% of our patients had at least one affected relative. We also showed a unilateral distribution of ancestral secondary cases on the paternal or on the maternal side, which suggests a dominant inheritance. Clinical and epidemiologic features of cases with familial Parkinson's disease showed no peculiarity. The study suggests a strong role of the genetic factors in the etiology of Parkinson's disease.
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PMID:Environmental and genetic risk factors in Parkinson's disease: a case-control study in southern Italy. 877 Oct 62

1. The neuroleptic malignant syndrome (NMS) may occur, occasionally, in Parkinson's disease (PD) after withdrawal of antiparkinsonian drugs. However, the circumstances in which the NMS occurs and the pathophysiologic mechanisms remain uncertain. 2. The authors studied a woman with PD, who developed hyperthermia, increased muscular tone, tremor, signs of autonomic dysfunction and stupor as symptoms of acute hyponatremia due to gastrointestinal loss of sodium in excess of water. 3. The correction of hyponatremia led to a complete recovery after about 6 hours. During this period the antiparkinsonian therapy was not modified. 4. An acute imbalance of sodium in the central nervous system may play a role in the pathophysiology of NMS.
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PMID:Acute hyponatremia and neuroleptic malignant syndrome in Parkinson's disease. 877 7

The purpose of this study was to examine the effects of low doses of apomorphine on motor performance. Six rats were rewarded with sugar water on a partial reinforcement schedule for pressing force-sensitive beams with a minimum force of 1 g. The kinetics of individual responses and the temporal characteristics of response sequences were measured; open field locomotor activity was also measured in a separate apparatus. Apomorphine (APO), amphetamine (AMP), and haloperidol (HAL) were administered systemically. It was found that low doses of APO (0.03 and 0.1 mg/kg, SC) produced weaker and longer beam presses. These decreases in response peak force resulted from decreases in the rate of rise of force. APO also caused disproportionate lengthening of beam release time. In addition, the low doses of APO increased the time intervals between consecutive components of response sequences. These low doses of APO are known to decrease dopaminergic tone. Hence, the observed pattern of motor dysfunctions produced by APO is similar to the bradykinesia seen in human Parkinson's disease.
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PMID:Low doses of apomorphine suppress operant motor performance in rats. 880 41

This review summarizes the amino acid sequences of the human dopamine and serotonin receptors and their human variants. The review also examines the receptor basis of the atypical antipsychotic drugs that elicit less parkinsonism than the typical antipsychotics. Because the dissociation constant of a drug varies with the radioligand, the dissociation constants of many neuroleptics are here summarized for the dopamine D2-, D4- and serotonin S2A-receptors using different radioligands. Radioligands of low solubility in the membrane (having low tissue/buffer partition) result in lower values for the neuroleptic dissociation constants, compared to radioligands of high membrane solubility. Such studies yield the intrinsic K value for a neuroleptic in the absence of a competing ligand. Clozapine, for example, has an intrinsic K value of 1.6 nM at the D4-receptor, in agreement with the value of 1.6 nM when directly measured with [3H]clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo clozapine concentration to occupy 75% of the dopamine D4-receptors is derived to be approximately 13 nM. This agrees with the value of 12 to 20 nM in the plasma water (or spinal fluid) observed in treated patients. Moreover, in L-DOPA psychosis (in Parkinson's disease), the clozapine concentration for 75% blockade of D4 is predicted to be approximately 3 nM. This agrees with the value of approximately 1.2 nM observed by Meltzer et al. in plasma water (Neuropsychopharmacology, 12, 39-45 (1995)). This analysis supports the concept and practical value of the intrinsic K values. Some atypical neuroleptics (remoxipride, clozapine, perlapine, seroquel and melperone) have high intrinsic K values (ranging from 30 to 88 nM) at the D2-receptor, making them displaceable by high levels of endogenous dopamine in the caudate/putamen. In contrast, however, typical neuroleptics (i.e., those that typically cause parkinsonism) have intrinsic K values of 0.3 to 6 nM, making them less displaceable by endogenous dopamine. A relationship exists between the neuroleptic doses for rat catalepsy and the D2/D4 ratio of the intrinsic K values. Thus, the atypical neuroleptics appear to fall into two groups, those that bind loosely to D2 and those that are selective at D4.
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PMID:Dopamine and serotonin receptors: amino acid sequences, and clinical role in neuroleptic parkinsonism. 885 1

The therapeutic concentrations of antipsychotic drugs in the patient's plasma water or spinal fluid are identical to their blocking potencies in vitro at the dopamine D2 receptor, with the exception of clozapine which acts at D4. The variation in K values between laboratories stems from the fact that the apparent K value for any antipsychotic drug depends on the affinity of the competing radioligand for the receptor or the membranes. Clozapine at the D2 receptor has a K value of 420 nM using [3H]nemonapride, 180 nM using [3H]spiperone and 82 nM using [3H]raclopride. These K values are related to the tissue/buffer partition coefficients of the ligands. Extrapolating down to either 1 or 0 partition yields the intrinsic K values for the antipsychotic in the absence of any competing ligand. The extrapolated or intrinsic K value for clozapine at D4 is 1.3 nM, in agreement with the value of 1.1 nM measured directly with [3H]clozapine at D4. Clozapine in vivo, however, must compete with endogenous dopamine in the synapse, estimated as 50 nM. Thus, the in vivo concentration of clozapine for 75% occupation of dopamine D4 receptors can be derived as approximately 14 nM, in agreement with the observed value of 12-20 nM in the plasma water or spinal fluid in treated patients. In L-DOPA psychosis in Parkinson's disease, the clozapine concentration (in the plasma water or spinal fluid) for 75% blockade of dopamine D4 receptors may be predicted as approximately 3 nM, in general agreement with the value of approximately 1.2 nM in Parkinson patients who have L-DOPA psychosis. These considerations provide strong support for the conclusion that clozapine primarily targets the D4 receptor in psychosis. Using the same considerations for haloperidol, it can be shown that the haloperidol therapeutic concentration required for 75% blockade of dopamine D2 receptors in vivo will be approximately 2-3 nM, in agreement with the observed value in the spinal fluid or plasma water of 1-3 nM.
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PMID:Therapeutic receptor-blocking concentrations of neuroleptics. 886 60

A new and portable electronic device called the "Digital Phagometer" is described for the time based counting of spontaneous swallowing. This device is composed of a piezoelectric sensor and a digital event counter/ recorder which can be downloaded to any IBM-compatible PC. The sensor of Digital Phagometer is placed and fixed on the coniotomy region between the cricoid and thyroid cartilage. In this way, it is capable of sensing each upward and downward movement of the larynx produced by spontaneous movement as a function of time. Spontaneous swallowing was measured 1-4 h after lunch in 21 normal subjects and 21 patients with Parkinson's disease (PD). The mean frequency of spontaneous swallowing was 0.8 counts/min in PD patients and 1.18 counts/ min in normal subjects (p < 0.05). During the intake of 200 ml water, the mean frequency of voluntary swallowing did not differ significantly between the two groups (24.6 counts/min in normals vs. 22.3 counts/min in PD patients), but the time necessary to swallow the same volume of water was longer in the PD group.
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PMID:An electronic device measuring the frequency of spontaneous swallowing: digital phagometer. 887 Mar 54


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