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)

Administration of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces a parkinsonian syndrome in primates. Intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the common marmoset (Callithrix jacchus) produced symptoms of rigidity, akinesia and tremor which persisted for at least one month. However, after this time, considerable behavioural recovery occurred, although animals were still severely bradykinetic compared with controls. Marmosets were allowed to survive for 1, 3 1/2 or 7 months prior to histological and immunocytochemical analysis. Detection of catecholaminergic neurons using antibodies directed against the enzyme tyrosine hydroxylase revealed a profound (80%) loss of dopaminergic cells from the substantia nigra one month after initiation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. This was accompanied by a severe gliosis. Fewer cells were lost from the adjacent ventral tegmental area (45%), but dopamine-containing cells in other brain areas were not obviously affected. At longer survival times the substantia nigra was less damaged, with a proliferation of glia in the pars compacta and a loss of approximately 20% of the dopaminergic perikarya. Using immunohistochemical techniques, the distribution of neuropeptides substance P, [Met]enkephalin and dynorphin 1-17-like immunoreactivity were examined and found to exhibit distinctive patterns in the marmoset substantia nigra. The integrity of these systems appeared intact at all times after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. These results support the hypothesis that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces a clinical syndrome, indistinguishable from Parkinson's disease, via a selective destruction only of neurons with perikarya in the substantia nigra pars compacta and the ventral tegmental area. The findings that the peptidergic input to these cells together with most non-nigral dopaminergic cell groups are not damaged, indicate that the selectivity of the lesion produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine appears greater than that seen in idiopathic Parkinson's disease. The neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset may not be permanent since both behavioural and biochemical recovery were observed after several months.
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PMID:An immunohistochemical study of the acute and long-term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset. 289 93

Non-human primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been employed to study the clinical features of parkinsonism. Monkeys lesioned by unilateral intracarotid administration of MPTP display spontaneous and drug responsive turning behavior. However this seems to correlate poorly with their clinical deficits. We describe an objective measurement of arm movement velocity, applied in 4 cynomolgus monkeys before and after unilateral administration of MPTP. Reduced movement velocities correlated with clinical signs of unilateral flexed arm posture, rigidity, tremor and bradykinesia and could be reversed with L-DOPA therapy. This measurement technique has advantages for the quantitative assessment of parkinsonian deficits and will permit the evaluation of dopaminergic therapy and transplantation in non-human primates.
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PMID:A new device for the quantitative assessment of dopaminergic drug effects in unilateral MPTP-lesioned monkeys. 326 71

Our previous data demonstrated that both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) exerted potent inhibition on endogenous 3,4-dihydroxyphenylacetic acid (DOPAC) output and potent stimulation on endogenous dopamine (DA) release from the rat corpus striatum superfused in vitro. In this report, using a push-pull perfusion technique, we examined in vivo the acute effects of MPTP and MPP+ on DA metabolism in the rat caudate nucleus (CN). MPTP or MPP+ in modified Krebs-Ringer phosphate buffer at concentrations of 10(-6), 10(-5) and 10(-4) M was administered directly into the CN for 15 min, each 90 min apart. Thirty minutes after the infusion of 10(-6) M MPP+, DOPAC output was reduced to a significantly lower value and subsequent infusions of high concentrations of MPP+ further decreased DOPAC output. Homovanillic acid (HVA) output was also decreased by MPP+ infusions, however, at higher concentrations. In respect to DA release, 1 of 10, 4 of 10 and 7 of 10 animals responded with significant increases to 10(-6), 10(-5) and 10(-4) M MPP+, respectively. On the other hand, MPTP was effective in reducing DOPAC output only at 10(-4) M and ineffective in altering DA and HVA output at all doses tested. In addition, neither drugs had a significant effect on 5-hydroxyindoleacetic acid. Accompanying the dramatic changes in DA metabolism caused by MPP+, two uncommon behavioral syndromes were also observed; tremor-body twist and body shaking.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects on dopamine metabolism of MPTP and MPP+ infused through a push-pull cannula into the caudate nucleus of awake adult male rats. 331 41

Extracellular single unit activity was recorded in the globus pallidus of waking Macaca fascicularis during passive limb movement. The main upper and lower limb joints were investigated bilaterally. The animals were either intact or rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell counts showed that at least 90% of nigral neurons of the compacta-type were degenerated in the parkinsonian animals. In the intact animals, only 17% of the pallidal neurons responded to the natural stimulus. As already reported by others, the responses were typically related to movement about a single contralateral joint and in only one direction. In the parkinsonian animals, however, more neurons responded, often more vigorously, to the same stimulation. In many of these neurons the responses were elicited by movement about more than one joint of both upper and lower limbs or ipsi-and contralateral sides and in more than one direction. The increase in number and magnitude and loss of specificity of responses were much greater in the internal pallidal segment, where the number of responding neurons quadrupled. These results suggest that dopaminergic mechanisms regulate gain and selectivity in the basal ganglia. In animals with decreased dopaminergic functions, the excessive and unselective motor responses may explain all 3 major signs of parkinsonism: rigidity, tremor and akinesia.
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PMID:Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys. 335 86

Parkinson's disease is a neurodegenerative disorder characterized mainly by damage to the dopaminergic nigrostriatal system. Recently, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce damage in the nigrostriatal system, accompanied by Parkinson-like symptoms in humans. We present here evidence that MPTP treatment in aged 21-month-old mice produced a marked reduction in the presence and intensity of fluorescence in noradrenergic neurons of the locus coeruleus and in dopaminergic neurons of the ventral tegmental area in addition to extensive damage to the substantia nigra. Aged mice treated with MPTP also showed physical signs of movement disability characterized by marked akinesia, rigidity of the hind limbs, and an initial resting tremor of the entire body. Such symptoms were less evident in young mice treated with MPTP. These remarkable initial behavioral effects of MPTP treatment in aged mice and evidence of reduced catecholamine fluorescence in the locus coeruleus and ventral tegmental area suggest that aged mice are more sensitive to, and more severely affected by MPTP treatment than young mice. We suggest that these MPTP-treated aged mice provide a useful animal model for studying both anatomical and functional characteristics of Parkinson's disease.
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PMID:Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults. 349 Jun 39

The human neurological disorders--amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)--share certain features: they occur in later stages of adult life; are slowly progressive; and involve specific groups of nerve cells. Different clinical syndromes result from dysfunction and death of these specific groups of neurons. In ALS, patients are weak due to disease of motor neurons in the spinal cord. The clinical features of PD, e.g. slow movements, tremor and rigidity, are attributed, in part, to degeneration of dopaminergic neurons of the substantia nigra. Impairments of cognition and memory in AD result from disease of neurons in a number of regions, including brainstem, basal forebrain, amygdala, hippocampus, and neocortex. In each of these diseases, affected neurons exhibit abnormalities of the neuronal cytoskeleton: in ALS, neurofilaments accumulate and distend proximal motor axons; in PD, nigral perikarya show Lewy bodies-intracytoplasmic inclusions containing neurofilament antigens; in AD, neurons develop neurofibrillary tangles, Hirano bodies, granulovacuolar degeneration and filament-filled neurites in plaques. Certain features of ALS, PD and AD are recapitulated in animal models, three of which are described in this review. Hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited motor neuron disease, shows many clinical and pathological features in common with ALS, including weakness, muscle atrophy, neurofilamentous swellings of proximal axons, impaired transport of neurofilament proteins, and degeneration of motor neurons. In primates, intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome due to injury of nigral dopaminergic neurons and associated denervation of the striatum. Finally, aged macaques exhibit memory deficits, and their cerebral cortices show senile plaques and filament-filled neurites derived from a variety of transmitter-specific populations of nerve cells. In human diseases, the causes and mechanisms leading to dysfunction and death of nerve cells are unknown. Investigators have begun using a variety of techniques derived from neurobiology to study animal models in an effort to clarify the mechanisms, evolutions, and consequences of structural-chemical abnormalities occurring in different neuronal systems implicated in human disease. Understanding such processes in these models should provide important new insights into the pathogeneses of similar processes occurring in ALS, PD and AD.
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PMID:Dysfunction and death of neurons in human degenerative neurological diseases and in animal models. 355 88

A neurologic deficit characterized by hypokinesia, postural flexion, and to a lesser extent, rigidity, tremor and myoclonus, has been observed in cynomolgus monkeys following administration of 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol (MMPP), a novel 4-substituted piperidine. The syndrome, similar to that described for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), developed within 3-7 days after oral or i.v. dosing, and was accompanied by lesions in the substantia nigra. The behavioral syndrome was seen to a lesser extent in dogs but not in rats. MMPP contains a hydroxyl group on the 4-position of the pyridine ring; the corresponding dehydration product was inactive.
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PMID:A Parkinson-like neurologic deficit in primates is caused by a novel 4-substituted piperidine. 369 24

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rhesus monkeys (1.0-2.5 mg/kg i.v.) produces irreversible damage to nigrostriatal neurons. Dopaminergic neurons in the dorsolateral part of striatum were the most vulnerable. The major clinical signs of an extrapyramidal syndrome, but not resting tremor, appeared only in MPTP-treated monkeys suffering from more than 80% reduction in striatal dopamine. No chronic changes in the mesolimbic dopaminergic system were observed. Immunocytochemical staining of the mid-brain with a tyrosine hydroxylase antiserum indicated that MPTP produced a significant decrease of dopaminergic cell bodies in the A9, but not in the A10 ventrotegmental area. Despite greater than 80% decrease in A9 nigral cell bodies, the dopamine content decreased only by 50%. Sprouting of the surviving nigral A9 neurons was observed histologically and neurochemically in the area above substantia nigra. The present behavioral, neurochemical and histological results indicate that MPTP produces an ideal primate model for studying parkinsonism. Selective lesion of more than 80% of the nigrostrial neurons by MPTP is sufficient to produce the major clinical signs of the extrapyramidal syndrome in idiopathic parkinsonism.
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PMID:Primate model of parkinsonism: selective lesion of nigrostriatal neurons by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces an extrapyramidal syndrome in rhesus monkeys. 387 Dec 41

Nine monkeys (Macaca fascicularis) were used in this study. Four monkeys were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 0.5 mg/kg intravenously. Three animals were injected once daily for 4 days, and one animal once weekly for 4 weeks. Five animals were used as controls. All MPTP-treated animals demonstrated the same clinical features which included akinesia, bradykinesia, a flexed posture of the trunk and all extremities, decreased initiation of the threat response, decreased vocalization and difficulty in swallowing. An increase in rigidity and reflexes was noted in all extremities. Tremor was present in all animals. Determination of the local spinal metabolic rate of glucose (LSMRg) utilization revealed an increase (P less than 0.05) in LSMRg in Rexed layer I in all cord segments and in Rexed layer II in both cervical and lumbar segments. Rexed layer X demonstrated a significant (P less than 0.05) increase in LSMRg at the cervical cord. The LSMRg in the animal that received weekly injections was similar to the daily injected animals.
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PMID:Spinal cord metabolism of the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkey. 387 82

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to two monkeys led to hypokinesia, tremor, rigidity, adipsia and aphagia. Quantitative assessment of hypokinesia revealed increased reaction time, delayed onset of muscle activity and prolonged movement time in a forelimb reaching task after selective degeneration of the nigrostriatal dopamine (DA) system sparing mesocortical dopamine neurons. The losses of pars compacta cells of substantia nigra, of striatal [3H]mazindol binding and of striatal DA content (more than 90%) quantitatively paralleled the severity of behavioral deficits. Additional monoamine systems were affected with stronger MPTP effects.
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PMID:Deficits in behavioral initiation and execution processes in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism. 387 57


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