Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0233565 (bradykinesia)
 2,352 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A modified primate model of Parkinson's disease was developed to assess the effectiveness of various agents that act via dopamine, acetylcholine, serotonin or glutamate systems. Using a MPTP dosing regimen a reversible parkinsonian-like syndrome was produced in the marmoset. An obvious advantage of such a protocol is that it allows multiple drug studies to be undertaken in animals, without the need for prolonged anti-parkinsonian therapy to maintain their health. Results show that dopamine D2 agonists (bromocriptine, quinpirole, N,N-dipropyl,A,5,6-DTN, (+)3PPP and PHNO), anti-muscarinics (atropine, scopolamine and benztropine), in addition to L-DOPA and nomifensine, all reduced the bradykinesia induced by MPTP. The D1 agonist SKF-38393 and the partial dopamine agonist (-)3PPP were both ineffective. Finally, agents with potential therapeutic use in Parkinson's disease were also tested. However, a glutamate antagonist (MK801) and three serotonin antagonists (ritanserin, ketanserin and ICI 170,809) were all unable to alter the MPTP effects, at the doses used in our study.
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PMID:Effects of classical and novel agents in a MPTP-induced reversible model of Parkinson's disease. 197 76

beta-N-Oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) are chemically related excitant amino acids isolated from the seed of Lathyrus sativus (BOAA) and Cycas circinalis (BMAA), consumption of which has been linked to lathyrism (an upper motor neuron disorder) and Guam amyotrophic lateral sclerosis (ALS), respectively. Both diseases are associated with degeneration of motor neurons. Experimentally, single doses of BOAA or BMAA induce seizures in neonatal mice and postsynaptic neuronal oedema and degeneration in explants of mouse spinal cord and frontal cortex. Preliminary studies show that these behavioural and pathological effects are differentially blocked by glutamate-receptor antagonists. In macaques, several weeks of daily oral doses of BOAA produce clinical and electrophysiological signs of corticospinal dysfunction identical to those seen in comparably well-nourished animals receiving a fortified diet based on seed of Lathyrus sativus. By contrast, comparable oral dosing with BMAA precipitates tremor and weakness, bradykinesia and behavioural changes, with conduction deficits in the principal motor pathway. BOAA and BMAA (or a metabolite thereof) are the first members of the excitotoxin family to have been shown to possess chronic motor-system toxic potential. These observations provide a rational basis for searching for comparable endogenous neurotoxins in sporadic and inherited forms of human motor neuron disease.
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PMID:Discovery and partial characterization of primate motor-system toxins. 310 39

Huntington's disease is a progressive degenerative neurological disorder which produces a characteristic movement disorder termed chorea. Although chorea is associated with dysfunction of the basal ganglia, the underlying mechanisms by which dyskinesias such as chorea are produced, are poorly understood. Recent studies in primates have led to experimental models of chorea with postulated involvement of specific neural pathways. In the present study we attempted to determine the validity of the experimental models by measuring concentrations of gamma-aminobutyric acid (GABA), glutamate, substance P and met-enkephalin in the basal ganglia of Huntington's disease patients who manifested either chorea or rigidity/bradykinesia within 6 months of death. We also characterized changes in the Huntington's disease patients according to pathological grade, since this may be a confounding factor. We analysed post-mortem brain tissue from 12 controls, and 11 grade 3 and 12 grade 4 Huntington's disease patients. The grade 3 and 4 cases consisted of eight adult-onset choreic, nine adult-onset rigid and six juvenile-onset rigid patients. We also analysed the putamen and globus pallidus from 11 grade 2 adult onset choreic Huntington's disease patients. A model of chorea based on experimental studies in primates proposes that a loss of striatal GABAergic inhibitory projections to the globus pallidus externa leads to increased activity of the inhibitory globus pallidus externa GABAergic neurons which project to the subthalamic nucleus. It is believed that the loss of GABAergic inputs to the globus pallidus externa precedes a loss of GABAergic input to the globus pallidus interna, which occurs later in the disease and is associated with the development of rigidity and bradykinesia. In the choreic Huntington's disease patients whom we studied, there was a greater loss of GABA in the globus pallidus externa than in the globus pallidus interna, and the globus pallidus interna: globus pallidus externa GABA ratio was significantly increased compared with rigid patients. There were also increases in GABA in the subthalamic nucleus in the choreic patients, although this did not reach significance. A differential loss of met-enkephalin in the globus pallidus externa compared with substance P loss in the globus pallidus interna was not observed in either the choreic patients with advanced disease or the grade II patients. There was a significant increase in GABA concentrations in the ventroanterior nucleus of the thalamus in the choreic patients compared with rigid/bradykinetic patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurochemical substrates of rigidity and chorea in Huntington's disease. 769 98

Previous studies have shown that riluzole (2-amino-6-trifluoromethoxy-benzothiazole), a drug which interferes with glutamate neurotransmission, has a neuroprotective action in rodent models of global and focal cerebral ischemia. In this pilot study, the protective and palliative effects of riluzole have been examined using an animal model of Parkinson's disease. Two monkeys were rendered hemiparkinsonian by one intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and motor signs were evaluated using clinical examination and electromyographic recordings. When riluzole (4 mg/kg) was administered before the injection of MPTP, parkinsonian motor symptoms, in particular bradykinesia and rigidity, were absent. When injected daily in one monkey which presented stable motor symptoms, bradykinesia and rigidity were significantly reduce d. Riluzole pretreatment induced a persistent increase in dopamine turnover when compared to MPTP alone. Thus, a possible neuroprotection and a facilitation of dopamine release may explain the behavioural effects reported with riluzole treatment. These preliminary results suggest that riluzole could possess neuroprotective and palliative effects in a primate model of Parkinson's disease.
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PMID:Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study. 866 12

Parkinson's disease, a clinical syndrome with 4 cardinal features (bradykinesia, resting tremor, increased muscular rigidity and impaired postural balance), is mainly caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although levodopa remains the 'gold standard' in the treatment of the disease, several emerging strategies are currently being developed. The first concerns new symptomatic drugs that either potentiate the effects of levodopa (e.g. slow-release preparations of levodopa, catechol-O-methyltransferase inhibitors and new dopamine agonists) or target clinical symptoms resistant to dopaminergic drugs (e.g. glutamate antagonists). The second strategy is to find drugs that are able to prevent or delay the neuronal death observed in Parkinson's disease. Several neuroprotective drugs are now in development in experimental research, but clinical trials in this area are still lacking. The development of these new drugs also depends on the validation of new clinical methodologies.
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PMID:New directions in the drug treatment of Parkinson's disease. 887 11

Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.
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PMID:Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration. 1109 Aug 66

There is little debate that deep brain stimulation (DBS) has been an effective tool in the treatment of Parkinson's disease as well as other movement disorders. There remains however, considerable debate concerning the mechanism(s) underlying its beneficial effect. The comparable effect of stimulation to ablation in the thalamus on tremor, and in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) on the motor signs associated with PD, have led many investigators to conclude that DBS acts to suppress neuronal activity, decreasing output from the stimulated site. There are, however, data that do not support this argument. Microdialysis studies in GPi showed increased levels of glutamate during STN stimulation, suggesting activation of glutamatergic output from the STN to the GPi. Studies in parkinsonian primates have demonstrated increased mean discharge rates of neurons in GPi during chronic stimulation in STN, and GPi stimulation in humans has been associated with a suppression of neuronal activity in the thalamus. Contrary to what one would expect if stimulation inhibits output from the stimulated structure, stimulation in GPe has been demonstrated to improve bradykinesia. Although arguments for increased output from the stimulated structure seem to conflict with the hypothesis that stimulation acts to inhibit neuronal activity, it is possible to explain these observations through a common mechanism, e.g. activation of fiber pathways. Based on this mechanism, the effect of stimulation on cellular activity in the stimulated site would be increased or decreased dependent on the neurotransmitter of the afferent fibers projecting to that site. However, in addition to activation of afferent fibers, projection axons from neurons in the stimulated structure, also readily excitable by electrical stimulation, would also be tonically activated and discharge independently of the soma, thereby increasing output from the structure during extracellular stimulation. Thus, although high frequency stimulation may inhibit neurons via activation of inhibitory afferents, the output from that structure may be increased as the result of activation of axonal elements leaving the target structure. This hypothesis would explain the present experimental results, is consistent with excitability profiles of neuronal elements based on their biophysical properties, and fits with more recent models emphasizing the role of altered patterns of neuronal activity in the development of hypokinetic and hyperkinetic movement disorders.
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PMID:Mechanisms of deep brain stimulation: excitation or inhibition. 1194 56

We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinson's disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.
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PMID:Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism. 1261 22

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.
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PMID:Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats. 1267 1

In assessing and assimilating the neurodevelopmental basis of the so-called movement disorders it is probably useful to establish certain concepts that will modulate both the variation and selection of affliction, mechanisms-processes and diversity of disease states. Both genetic, developmental and degenerative aberrations are to be encompassed within such an approach, as well as all deviations from the necessary components of behaviour that are generally understood to incorporate "normal" functioning. In the present treatise, both conditions of hyperactivity/hypoactivity, akinesia and bradykinesia together with a constellation of other symptoms and syndromes are considered in conjunction with the neuropharmacological and brain morphological alterations that may or may not accompany them, e.g. following neonatal denervation. As a case in point, the neuroanatomical and neurochemical points of interaction in Attention Deficit and Hyperactivity disorder (ADHD) are examined with reference to both the perinatal metallic and organic environment and genetic backgrounds. The role of apoptosis, as opposed to necrosis, in cell death during brain development necessitates careful considerations of the current explosion of evidence for brain nerve growth factors, neurotrophins and cytokines, and the processes regulating their appearance, release and fate. Some of these processes may possess putative inherited characteristics, like alpha-synuclein, others may to greater or lesser extents be endogenous or semi-endogenous (in food), like the tetrahydroisoquinolines, others exogenous until inhaled or injested through environmental accident, like heavy metals, e.g. mercury. Another central concept of neurodevelopment is cellular plasticity, thereby underlining the essential involvement of glutamate systems and N-methyl-D-aspartate receptor configurations. Finally, an essential assimilation of brain development in disease must delineate the relative merits of inherited as opposed to environmental risks not only for the commonly-regarded movement disorders, like Parkinson's disease, Huntington's disease and epilepsy, but also for afflictions bearing strong elements of psychosocial tragedy, like ADHD, autism and Savantism.
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PMID:Brain sites of movement disorder: genetic and environmental agents in neurodevelopmental perturbations. 1283 21


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