Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine D1-like and D2-like receptors on peripheral blood lymphocytes (PBL) were assayed in 50 de novo patients with idiopathic Parkinson's disease (PD), in 36 neurologic control subjects (multiple-system atrophy, n = 16; essential tremor, n = 10; other neurodegenerative diseases, n = 10), and in 26 healthy control subjects by radioligand binding assay techniques using [3H]SCH 23390 and [3H]7OH-DPAT as ligands. Patients with PD revealed a higher density (Bmax) of dopamine D1-like (p <0.001) and D2-like (p <0.00001) receptors on PBL than either neurologic or healthy control subjects, whereas no differences in Bmax were observed among patients affected by other neurologic diseases and healthy control subjects. The affinity (Kd) of both radioligands was similar in the groups investigated. The pharmacologic profile of [3H]SCH 23390 and [3H]7OH-DPAT binding was consistent with the labeling of dopamine D5 and D3 receptor subtypes, respectively. Twenty-five of the 50 patients with PD were retested after 3 months of therapy with levodopa or bromocriptine. Both treatments reduced the density of D1-like (p <0.001) and D2-like (p <0.001) receptors on PBL to values comparable to those of control subjects. The increased density of D1-like and D2-like receptors on PBL in de novo PD patients may represent an upregulation mechanism resulting from the diffuse impairment of the dopaminergic system in PD.
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PMID:Increased expression of dopamine receptors on lymphocytes in Parkinson's disease. 1049 37

Dopamine depletion induces a series of changes in the basal ganglia motor circuit that underlie the origin of the cardinal features of Parkinson's disease. It has now been established that hyperactivity of the subthalamic nucleus (STN) is an essential feature of the parkinsonian state. This leads to increased excitatory driving onto the globus pallidum internum (GPi) and substantia nigra reticulata (SNr) which, in turn, overinhibits the motor projections to the thalamus and brainstem. The STN and GPi have become the preferred targets for surgery to treat PD. In keeping with the classic pathophysiologic model, physiologic and neuroimaging studies in patients have shown that lesioning or functional blockades (by deep brain stimulation, or DBS) of these nuclei increased cortical activation, in parallel with clinical improvements of bradykinesia. Neuronal recording during surgery has also shown tremor-related activity in both the STN and GPi. However, the pathophysiologic model of the basal ganglia needs further refinement to provide a more detailed explanation of the origin of both tremor and rigidity in Parkinson's disease and to explain the antidyskinetic effect of surgery of the GPi and STN.
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PMID:Pathophysiologic basis of surgery for Parkinson's disease. 1118 78

Although all dopaminergic drugs are effective in reducing tremor, no single drug has been shown to be clearly superior in the treatment of tremor. Levodopa produces a mean improvement of 30 to 50% in the Unified Parkinson's Disease Rating Scale (UPDRS) subtest for rest tremor. Comparable improvement is achieved with the dopamine agonists. Dopamine agonists are particularly well suited for patients with newly diagnosed tremor-predominant disease and no cognitive impairment, but they are also useful in advanced patients with tremor that is refractory to levodopa and anticholinergics. The response of tremor to pharmacotherapy is variable, and clinicians must be prepared to try all of the available drugs before concluding that surgery is the only alternative.
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PMID:Tremor and dopamine agonists. 1190 86

Parkinson's disease (PD) is characterized by motor and nonmotor (cognitive and limbic) deficits. The motor signs of PD include hypokinetic signs such as akinesia/bradykinesia, rigidity and loss of normal postural reflexes, and hyperkinetic signs such as tremor. Dopamine depletion in the striatum is the hallmark of PD and of its animal models, still the pathophysiology of the parkinsonian symptoms and especially of parkinsonian tremor are under debate. The most extreme hypotheses argue about peripheral versus central nervous system origin, intrinsic cellular oscillator versus network oscillators, and basal ganglia-based pathophysiology versus cerebellar-thalamic based pathophysiology. Recent studies support the view that parkinsonian symptoms are most likely due to abnormal synchronous oscillating neuronal activity within the basal ganglia. Peripheral factors do only play a minor role for the generation, maintenance, and modulation of PD tremor and other signs. The most likely candidates producing these neuronal oscillations are the weakly coupled neural networks of the basal ganglia-thalamo-cortical loops. However, the present evidence supports the view that the basal ganglia loops are influenced by other neuronal structures and systems and that the tuning of these loops by cerebello-thalamic mechanisms and by other modulator neurotransmitter systems entrain the abnormal synchronized oscillations. Neurosurgical procedures, such as lesions or high-frequency stimulation of different parts of the loop, might resume the normal unsynchronized activity of the basal ganglia circuitry, and, therefore, ameliorate the clinical symptoms of Parkinson's disease.
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PMID:Pathophysiology of Parkinson's disease: from clinical neurology to basic neuroscience and back. 1194 53

Increased output from the subthalamic nucleus (STN) following chronic dopamine depletion has been linked to the rigidity and tremor seen in Parkinson's disease (PD). We used extracellular microelectrode recordings from rat brain slices to investigate effects of dopamine on STN neurons. In brain slices prepared from rats that received unilateral 6-hydroxydopamine (6-OHDA) treatment, the spontaneous firing rate of STN neurons was reduced by 63%, and the firing pattern was more irregular, compared to STN neurons from normal rats. However, treatment with levodopa (50 mg/kg, i.p., daily) for 4 weeks normalized the firing rate and pattern of STN neurons in the 6-OHDA-treated rats. Dopamine (3-300 microM), added to the superfusate, significantly increased the firing rates of STN neurons in a concentration-dependent fashion, and also produced a more regular firing pattern in 6-OHDA-lesioned tissue. This excitatory effect of dopamine was mimicked by a D2 receptor agonist (quinpirole), and was reduced by the D2 antagonists haloperidol, clozapine and sulpiride. Antagonists of the D1 receptor (SCH-23390) and ionotropic glutamatergic receptors (CNQX and AP5) could not block the effect of dopamine on firing rate. These results suggest that dopamine exerts a direct excitatory influence on STN neurons via the activation of D2-like receptors.
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PMID:Excitatory effects of dopamine on subthalamic nucleus neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa. 1211 49

The functions of oscillations within the basal ganglia are poorly understood. We discuss in the present paper, the possible physiological or pathological roles of oscillatory activities within the basal ganglia, and their relationship to cortical oscillations. Three aspects are presented: 1. What do we know from animal studies? 2. What do we know from neurophysiological studies in parkinsonian patients? 3. What is the effect of L-dopa treatment and electrical stimulation within basal ganglia circuits on cortical oscillations? Animal studies suggest that neuronal oscillations are spontaneously generated within the basal ganglia system, especially from the GPE and the subthalamic nucleus (STN), but are mainly synchronized by cortical activity via the striatal inputs. Dopamine depletion results in a global increase of oscillations within the whole basal ganglia system, particularly in the GP-NST network. Oscillations within the basal ganglia may, in part, be related to tremor since they are enhanced, especially in the globus pallidus internus (GPI) and the STN, in human and animal dopaminergic depletion. However, they also play a role in the physiology of movement as revealed by coherence analysis between cortex, muscles and GPI/STN in parkinsonian patients undergoing deep brain stimulation. It is known that the basal ganglia may influence cortico-muscular oscillations such as the Piper rhythm and other rhythms in the beta band. In off-drug parkinsonian patients, low frequency oscillations (4-10 Hz) are favoured, presumably resulting in bradykinesia and low force. When medically (Ldopa) or surgically (deep brain stimulation) treated, these low frequency oscillations are replaced by high frequency (70 Hz) oscillations that are important for motor programs to be correctly executed. Studies of cortical reactivity related to planning of voluntary movement in parkinsonian patients provide evidence that it is possible to influence cortical reactivity through the basal ganglia system.
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PMID:Relationship between oscillations in the basal ganglia and synchronization of cortical activity. 1249 73

Functional imaging of the dopamine transporter (DAT) defines integrity of the dopaminergic system and has its main clinical application in patients with mild, incomplete, or uncertain parkinsonism. Imaging with specific single positron emission computerised tomography ligands for DAT (FP-CIT, beta-CIT, IPT, TRODAT) provides a marker for presynaptic neuronal degeneration. Striatal uptake correlates with disease severity, in particular bradykinesia and rigidity, and monitoring of progression assists in clinical trials of potential neuroprotective drugs. DAT imaging is abnormal in idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy and does not distinguish between these disorders. Dopamine loss is seen even in the earliest clinical presentations of true parkinsonism; a normal scan suggests an alternative diagnosis such as essential tremor, vascular parkinsonism (unless there is focal basal ganglia infarction), drug-induced parkinsonism, or psychogenic parkinsonism. Congruence between working clinical diagnosis and DAT imaging increases over time in favour of baseline DAT imaging results. Additional applications are characterising dementia with parkinsonian features (abnormal results in dementia with Lewy bodies, normal in Alzheimer's disease); and differentiating juvenile-onset Parkinson's disease (abnormal DAT) from dopa-responsive dystonia (normal DAT).
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PMID:Role of dopamine transporter imaging in routine clinical practice. 1546

Parkinson's disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. Its primary clinical symptoms are akinesia, tremor, and rigidity, which usually start from one side, resembling the lateralization in hemiparkinsonian rats having 6-hydroxydopamine-induced unilateral lesion of the medial forebrain bundle. A novel exploratory Y-maze was designed to detect the lateralization of hemiparkinsonian rats in terms of biased turns in the maze. Dopamine agonists levodopa (L-3,4-dihydroxyphenylalanine, 10-30 mg/kg) and apomorphine (0.1-0.3 mg/kg), but not methamphetamine (0.5-2 mg/kg), improved the lateralization in the rat model. However, high doses of the dopamine agonists, 30 and 0.3 mg/kg, respectively, caused small movements in the arms that seemed to parallel the increase in counts per turn in the Y-maze. Interestingly, the muscarinic antagonists trihexyphenidyl and scopolamine improved lateralization moderately, while increasing total turns, an index of locomotive activity. (-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.3 mg/kg), an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, increased total counts, but did not alleviate the lateralization. The alpha2-adrenoceptor antagonist idazoxan (1 and 10 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 and 3 mg/kg), a non-NMDA glutamate receptor antagonist, did not affect any of the indices. These findings suggest that the clinical action of drugs on unbalanced movement in PD could be predicted by measuring their effects on lateralization of the 6-hydroxydopamine-lesioned rat model in this exploratory Y-maze.
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PMID:Dopaminergic agonists and muscarinic antagonists improve lateralization in hemiparkinsonian rats in a novel exploratory Y-maze. 1475 5

Parkinson's disease, a major neurodegenerative disorder in humans whose etiology is unknown, may be associated with some environmental factors. Nocardia otitidiscaviarum (GAM-5) isolated from a patient with an actinomycetoma produced signs similar to Parkinson's disease following iv injection into NMRI mice. NMRI mice were infected intravenously with a non-lethal dose of 5 x 10(6) colony forming units of N. otitidiscaviarum (GAM-5). Fourteen days after bacterial infection, most of the 60 mice injected exhibited parkinsonian features characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and postural instability. There was a peak of nocardial growth in the brain during the first 24 h followed by a decrease, so that by 14 days nocardiae could no longer be cultured. At 24 h after infection, Gram staining showed nocardiae in neurons in the substantia nigra and occasionally in the brain parenchyma in the frontal and parietal cortex. At 21 days post-infection, tyrosine hydroxylase immunolabeling showed a 58% reduction of tyrosine hydroxylase in the substantia nigra, and a 35% reduction of tyrosine hydroxylase in the ventral tegmental region. Dopamine levels were reduced from 110 +/- 32.5 to 58 +/- 16.5 ng/mg protein (47.2% reduction) in brain from infected mice exhibiting impaired movements, whereas serotonin levels were unchanged (191 +/- 44 protein in control and 175 +/- 39 ng/mg protein in injected mice). At later times, intraneuronal inclusion bodies were observed in the substantia nigra. Our observations emphasize the need for further studies of the potential association between Parkinson's disease or parkinsonism-like disease and exposure to various nocardial species.
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PMID:Nocardia otitidiscaviarum (GAM-5) induces parkinsonian-like alterations in mouse. 1506 17

Experimental infection of BALB/c mice with the Gram-positive bacterium Nocardia asteroides (strain GUH-2) results in life-long movement abnormalities including head shaking and spinning when held by the tail. The head shaking is temporarily inhibited by treatment with dopamine's precursor levodopa, suggesting that abnormalities in dopaminergic neurotransmission may be involved in these movement abnormalities. Cell-free filtrates from N. asteroides cultures induce > 70% dopamine depletion in rat pheochromocytoma PC12 cells, suggesting that Nocardia's effects on dopamine neurons may result in part from secreted factors. The nature of this dopamine-depleting activity was examined in the present study. Dopamine-depleting activity in N. asteroides culture filtrate was resistant to heat (100 degrees C x 30 min), proteases, and chloroform extraction, and was present in a low molecular mass (< 3 kDa) fraction. It was partially inhibited by decreasing (to 4.0) or increasing (to 10.0) the filtrate pH. GUH-2 filtrate increased cellular lactate dehydrogenase release by only 2%, and induced apoptotic morphology in only 11% of PC12 cells, suggesting that dopamine-depleting activity was not due to either cell injury or induction of apoptosis. These results suggest that a protease-resistant, low molecular mass substance secreted by N. asteroides may be responsible for its dopamine-depleting effects.
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PMID:Characterization of dopamine-depleting activity of Nocardia asteroides strain GUH-2 culture filtrate on PC12 cells. 1531 47


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