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)

MIF-1, a synthetic tripeptide with MSH-release inhibitory properties, has been reported to improve symptoms of Parkinson's disease, attenuate levodopa-related dyskinesias and diminish the dyskinetic movements of Tardive dyskinesia. More recently, MIF-1 has been reported partially to protect against the nigro-striatal dopamine depleting effects of MPTP in mice, raising the possibility that it may exert protective effects against the development of Parkinson's disease. There is evidence to suggest that MIF-1 increases nigro-striatal dopaminergic activity, but its ability to improve symptoms in patients with Parkinson's disease, levodopa-related dyskinesias and Tardive dyskinesia cannot be explained solely on the basis of the drug's effect on striatal dopaminergic neurons. MIF-1 has been reported to potentiate the melanocyte-lightening effect of melatonin in rats and its effects in patients with Parkinson's disease and Tardive dyskinesia are associated with marked mood elevation. It is, therefore, possible that the effects of MIF-1 in movement disorders are associated with increased melatonin secretion. Thus, hypothalamic MIF may modulate nigro-striatal dopaminergic functions in part via pineal melatonin. Such an interaction represents a novel mechanism by which hypothalamic peptides act to modulate the expression of movement disorders.
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PMID:MIF-induced augmentation of melatonin functions: possible relevance to mechanisms of action of MIF-1 in movement disorders. 197 68

The MPTP-treated monkey has become an important model for the study of Parkinson's disease. However, studies on the acute evolution of the neurotoxic effects of MPTP in primates are lacking. In the present study, 17 squirrel monkeys were given a single subcutaneous injection of MPTP (2.5 mg/kg). The behavioral effects and the concentrations of dopamine (DA), dihydroxyphenylacetic acid and homovanillic acid were determined in caudate, putamen and substantia nigra 1, 3, 5 (n = 3/time point) and 10 days (n = 6) after drug administration. Two animals were studied neuropathologically 8 and 9 days after MPTP. Profound parkinsonism was evident in all animals after 1 day and neuropathological examination revealed severe nerve cell destruction in the substantia nigra. Surprisingly, although 50-75% reductions in nigral DA were observed 1 and 3 days after MPTP, caudate DA was not reduced and putaminal DA was increased at these time points. The temporal sequence of these events differs markedly from that which occurs in the MPTP-treated mouse and suggests that, in the monkey, nigral cell bodies may represent an important initial site of MPTP-induced damage. Five and 10 days after MPTP, nigral DA depletions remained greater than 60% of control and striatal DA was reduced 50-85%. At these time points, the putamen was always more affected than the caudate. This interregional pattern of striatal DA deficits is similar to that seen in idiopathic Parkinson's disease.
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PMID:The evolution of nigrostriatal neurochemical changes in the MPTP-treated squirrel monkey. 198 Nov 62

Schwann cells from transected peripheral nerve segments are known to produce nerve growth factor (NGF). We performed adrenal medullary grafts or cografts of adrenal medulla and sciatic nerve into the striatum of MPTP-treated young adult mice, and compared the survivability of grafted chromaffin cells and the recovery of intrinsic host DA fibers using computerized image analysis of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers and neurochemical analysis with high performance liquid chromatography (HPLC). Adrenal medullary chromaffin cells cografted with sciatic nerve survived better than those in adrenal grafts alone; host DA fiber recovery was more prominent in mice with cografts than in mice with adrenal grafts alone. A large number of TH-IR surviving cells in cografted mice showed long neuronal processes which were rarely seen in the mice receiving adrenal graft alone. We conclude that cograft of adrenal medulla and sciatic nerve promotes intrinsic host DA fiber recovery better than adrenal medulla grafts alone, and that survivability of grafted chromaffin cell may promote host DA fiber recovery. Adrenal medullary autografts have been used in patients with Parkinson's disease; we suggest that if this approach is to be used in the future, methods to increase the survivability of grafted chromaffin cells, such as co-grafting with pieces of peripheral nerve, be considered to enhance the survivability of the chromaffin cells, which might be closely related to the functional recovery of the patients by this grafting procedure. Of course, such strategies as the present cografting approach must be demonstrated to work in older animals using older donor tissue before proceeding to this next step in humans.
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PMID:Cografts of adrenal medulla with peripheral nerve enhance the survivability of transplanted adrenal chromaffin cells and recovery of the host nigrostriatal dopaminergic system in MPTP-treated young adult mice. 198 43

Identification, cellular localization, and cDNA cloning of MAO subtypes A and B have increased the insight into the pharmacology of these enzymes, whose primary functions are intra- and extraneuronal inactivation of neurotransmitter (dopamine, noradrenaline and serotonin) and other biogenic amines. In addition, MAO oxidizes the inert uncharacteristic tertiary amine, MPTP, to the parkinson inducing dopaminergic neurotoxin, MPP+, and the novel secondary amine anticonvulsant milacemide to the inhibitory amino acid neurotransmitter, glycine. These recent developments have provided new therapeutic perspectives for the management of Parkinson's disease and seizure disorders via the use of selective inhibitors and amino acid amine prodrug substrates of MAO-B.
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PMID:New directions in monoamine oxidase A and B selective inhibitors and substrates. 198 26

Nigrostriatal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease results from the inhibition of mitochondrial respiration by 1-methyl-4-phenylpyridinium (MPP+). MPP+ blocks electron flow from NADH dehydrogenase to coenzyme Q at or near the same site as do rotenone and piericidin and protects against binding of and loss of activity due to these inhibitors. The 4'-analogs of MPP+ showed increasing affinity for the site with increasing length of alkyl chain, with the lowest Ki, for 4'-heptyl-MPP+, being 6 microM. The 4'-analogs compete with rotenone for the binding site in a concentration-dependent manner. They protect the activity of the enzyme from inhibition by piericidin in parallel to preventing its binding, indicating that the analogs and piericidin bind at the same inhibitory site(s). The optimum protection, however, was afforded by 4'-propyl-MPP+. The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q.
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PMID:Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase. 200 36

The cause of Parkinson's Disease remains unknown although environmental toxin/s and ageing are likely to play a significant role. Experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced parkinsonism can be prevented by monoamine oxidase B inhibitors. Monoamine oxidase B inhibitors have been shown to delay disease progression in early Parkinson's Disease and improve mortality. Symptomatic therapy remains the cornerstone of drug treatment, and should include levodopa replacement with concomitant dopamine agonist therapy in order to achieve maximum efficacy, and reduce side effects. Complicated Parkinson's Disease could be managed by better delivery systems like slow release preparations and parenteral infusions. Brain tissue transplants may offer hope of restoring the damaged nigrostriatal system.
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PMID:Drug treatment of Parkinson's disease: current concepts. 202 54

Monkeys made hemiparkinsonian by infusion of a solution of MPTP into one carotid artery appeared to ignore food presented from the contralateral side. Initial observations suggested neglect of visual stimuli presented as fruit treats by automated delivery system in the half-field contralateral to MPTP treatment. Further studies in which fruit treats were left in the 'neglected' visual field indicated that this apparent neglect, unlike neglect attending cortical lesions, was rather a marked delay in initiating movements (unilateral hypokinesia). These observations may explain apparent subcortical neglect and are consistent with the known role of nigrostriatal dopaminergic neurones in movement regulation. This is a useful animal model in which difficulties in initiation of movement (hypokinesia). a cardinal symptom of Parkinson's disease, can be studied separately from other deficits in motor performance.
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PMID:Apparent unilateral visual neglect in MPTP-hemiparkinsonian monkeys is due to delayed initiation of motion. 202 30

Less than 10 years have passed since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is capable of producing parkinsonism in both humans and non-human primates. In that time, there has been considerable interest in the possibility that the pathogenesis of idiopathic Parkinson's disease (PD) might involve a process analogous to that of MPTP toxicity. One hypothesis holds that PD might arise, at least in part, from exposure to an MPTP-like environmental toxin. Rapid progress has been made towards elucidating the precise mechanism by which MPTP exerts toxicity, and clarifying the relationship of MPTP toxicity to idiopathic PD. The goal of these efforts is to develop a therapy that inhibits the underlying disease process in PD.
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PMID:MPTP-induced neurotoxicity and the quest for a preventative therapy for Parkinson's disease. 203 21

Olfactory dysfunction is among the first signs of Alzheimer's disease (AD), idiopathic Parkinson's disease (PD), and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast, patients with progressive supranuclear palsy (PSP) and patients with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study, we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups, the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD, suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.
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PMID:Odor identification deficit of the parkinsonism-dementia complex of Guam: equivalence to that of Alzheimer's and idiopathic Parkinson's disease. 204 98

2-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were identified for the first time as novel endogenous amines in parkinsonian and normal human brains by gas chromatography-mass spectrometry. It is of interest that these tetrahydroisoquinolines are analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which produces Parkinson's disease.
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PMID:Presence of 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, novel endogenous amines, in parkinsonian and normal human brains. 204 84


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