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)

Eye blink rates were studied in African green monkeys following relatively specific destruction of substantia nigra and its dopamine projections with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys treated with MPTP had a significantly lower blink rate than controls over a period from two to five and a half months after treatment. Furthermore, the degree of parkinsonism expressed in treated animals was inversely correlated with blink rate. Pharmacologic studies further supported the role of dopamine receptors in the regulation of blink rate. PHNO (4-propyl-9-hydroxynaphoxazine), a potent and highly specific D2 agonist, effective in alleviating parkinsonism, caused a significant transient increase in blink rate, while sulpiride, a D2 antagonist, caused a decrease and blocked the effect of PHNO. Apomorphine and haloperidol, although less specific, had potent and predictable effects based on their interactions with dopamine systems. Blink rate may provide a nonintrusive measure of central dopamine activity that would help to evaluate the progress of Parkinson's disease or treatments which attempt to restore dopamine function.
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PMID:MPTP lesions and dopaminergic drugs alter eye blink rate in African green monkeys. 167 27

1-Methyl-3-phenyl-1,2,3,6-tetrahydropyridine (M-3-PTP) is an analogue to the Parkinson-producing dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), M-3-PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M-3-PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M-3-PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10-fold increase in the level of 3-methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M-3-PTP produced no acute or long-term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M-3-PTP does not inhibit monoamine oxidase B. Thus, the present data show that M-3-PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M-3-PTP for monoamino oxidase B.
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PMID:Investigation of the possible dopaminergic toxicity of 1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine, an isomer to the neurotoxin MPTP. 168 9

In cynomolgus monkeys, midbrain neurons immunoreactive (IR) for the calcium-binding protein calbindin D-28k (CaBP) occur principally in the dorsal tier of substantia nigra pars compacta (SNc) and in the ventral tegmental area (VTA), and most of these neurons co-express tyrosine hydroxylase (TH). In monkeys rendered parkinsonian (PD) after MPTP injections, CaBP-IR neurons are much less severely affected than TH-IR neurons in SNc and in VTA, and most spared neurons in SNc/VTA display both CaBP and TH immunoreactivity. These results reveal that, in contrast to the situation in other neurodegenerative diseases, CaBP may be used as a marker for a specific neuronal population that is less prone to degeneration in Parkinson's disease.
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PMID:Dopaminergic neurons expressing calbindin in normal and parkinsonian monkeys. 168 19

Deprenyl slows the progression of disabling symptoms in Parkinson's disease (PD) by an unknown mechanism. It can block the action of MPTP on substantia nigra compacta (SNc) neurons by inhibiting monoamine oxidase B necessary to mediate the conversion of MPTP to MPP+, its active metabolite, in astroglia. Mice were pretreated with saline or the PD-producing toxin, MPTP (30 mg/kg) daily for 5 days and then after a further 3 days (to allow for the metabolism and excretion of the MPTP) were treated with deprenyl (0.25 or 10 mg/kg) or saline 3 times weekly for 20 days. In three series of mice treated with MPTP alone or MPTP-saline, serial sections through the SNc showed that averages of 37-42% of tyrosine hydroxylase (TH) immunoreactive neurons were lost gradually over 20 days. Joint counts of the numbers of TH-immunoreactive and Nissl-stained SNc somata from immediately adjacent sections established that the reductions in the numbers of TH-immunoreactive somata at 20 days after MPTP treatment represented neuronal death. Deprenyl treatment reduced the loss of TH-immunoreactive SNc neurons to averages of 14-16% for the 10-mg/kg and 0.25-mg/kg doses, respectively, and joint Nissl/TH counts for adjacent sections showed that reduction in the loss of TH-immunoreactive soma represented the rescue of SNc neurons that would have died by 20 days. The gradual loss of SNc neurons over the 20 days following MPTP exposure may reflect the toxin's axotomy-like effects on SNc neurons or the prolonged action of sequestered MPP+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. 168 84

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.
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PMID:A review of the pharmacology of selegiline. 168 54

When all of the data concerning the role of D1 and D2 receptors in the control of unconditioned behaviors are taken together a fairly consistent picture begins to emerge. Considering first the normosensitive animals, it appears that D1 and D2 receptors are interdependent in their involvement in the control of locomotor activity. Stimulation of either receptor subtype leads to increases in activity although D2 agonists generally have a larger effect on activity than D1 agonists. Subeffective doses of D1 and D2 agonists (or D1 and D2 antagonists) have a synergistic action when co-administered. Injections of antagonists specific for either receptor subtype leads to a decrease in unstimulated locomotor activity or a diminution in the effects of agonists stimulating either receptor subtype. Besides locomotor activity, stimulation of D2 receptors produces yawning but a consistent effect on grooming has not been seen; D2 receptor stimulation also produces stereotyped behaviors. Again, there seems to be an interdependence between the two receptor subtypes; yawning or stereotypy produced by D2 receptor stimulation is blocked by either D2 or D1 antagonists. Stimulation of D1 receptors produces grooming and small perioral movements but not stereotyped behaviors like those typically seen following large doses of D2 agonists or DA agonists not specific a receptor subtype. Unlike D1 receptor-stimulated locomotor activity which is antagonized by D2 receptor blockers, grooming and perioral movements are not (but see Ref. 81). Thus, D1 receptor-mediated grooming and perioral movements seem to be exceptions to the otherwise general finding that co-stimulation of the two receptor subtypes needed for the expression of D1 or D2 agonist effects in normosensitive rats and mice. The apparent need to stimulate both D1 and D2 receptors to produce locomotor and some other unconditioned behaviors in normosensitive animals is lost in chronically denervated animals that are supersensitive to the effects of DA or DA agonists. However, there appear to be important species differences. Generally, in rodents undergoing unilateral or bilateral 6-OHDA-induced destruction of the nigrostriatal DA system, the locomotor effects of D1 agonists are not blocked by D2 antagonists and those of D2 agonists are not blocked by D1 antagonists. Similar results have been reported following chronic treatments with catecholamine depleting drugs. Thus, stimulation of either D1 or D2 receptors alone in DA supersensitive rodents appears to be sufficient to produce locomotor activity. In primates made DA supersensitive either with MPTP or as a result of Parkinson's disease, on the other hand, D2 but not D1 agonists are effective in reversing locomotor deficits.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor subtype-specific dopaminergic agents and unconditioned behavior. 168 45

The relationship between oxidative polymorphisms and the cause of Parkinson's disease is controversial. The drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces parkinsonism in humans and in some animal models, is metabolized by cytochrome P450 db1 isozyme (the same enzymatic system implicated in 4-hydroxylation of debrisoquine). In this study, we treated females of three rat species, which differ in their ability to hydroxylate debrisoquine, with MPTP (three doses of 30 mg/kg s.c. at 12-h intervals), and we measured their motor activity and brain monoamine levels. Female dark-adapted rats (poor metabolizers of debrisoquine) showed a more pronounced and more maintained reduction of their motor activity after treatment with MPTP. MPTP-treated, dark-adapted rats also had a depletion of noradrenaline in the diencephalon and a depletion of dopamine and serotonine and their respective metabolites in the limbic system when compared with the other two species. These results suggest that oxidative polymorphism of debrisoquine plays a role in the acute effects of MPTP.
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PMID:Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in a model of rat designated a poor metabolizer of debrisoquine. 171 Nov 1

Protracted long-term treatment of common marmosets with 15 doses (0.5-4.5 mg/kg, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose 25 mg/kg, given over 29 days) caused transitory changes in motor behaviour reminiscent of human Parkinson's disease. 16 days from the start of MPTP administration, all animals showed motor impairment, consisting of profound akinesia and a rigid posture, but in no case resting tremor. Biogenic amines were measured in nigrostriatal regions one month after finishing MPTP treatment. There was a profound loss of dopamine and serotonin in the substantia nigra and in the striatum; noradrenaline was only reduced in the putamen. Continuous analyses of the concentrations of biogenic amine metabolites in the CSF during this study revealed persistent dopaminergic disturbances and temporary alterations in serotoninergic and noradrenergic function.
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PMID:Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson's disease? 171 88

Aged common marmosets were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 0.5-2.0 mg/kg/week i.p.) for 16 or 24 weeks, observed for a total of 30 weeks and then killed for measurement of biochemical parameters in basal ganglia. The MPTP treatment induced a marked depletion in dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the caudate nucleus and putamen. In contrast, the concentrations of five neuropeptides: [Met5]-enkephalin, [Leu5]-enkephalin, cholecystokinin, substance P and neurotensin as measured by a combined HPLC/RIA method, remained unaltered in all basal ganglia regions examined. Enkephalin precursor levels, as reflected by cryptic [Met5]-enkephalin content, were increased in the putamen, but not in the caudate nucleus, as a consequence of MPTP administration. Cryptic [Leu5]-enkephalin content remained unchanged in the striatum of MPTP treated marmosets. Overall, these results suggest an increase in striatal [Met5]-enkephalin release following chronic MPTP treatment of aged marmosets. However, the chronic treatment of aged marmosets with MPTP does not reproduce the neuropeptide alterations characteristic of Parkinson's disease.
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PMID:Neuropeptide levels in the basal ganglia of aged common marmosets following prolonged treatment with MPTP. 171 7

We assessed clinical and electrophysiologic characteristics of tremor in patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Four of seven patients with moderate to severe MPTP-induced parkinsonism exhibited a tremor indistinguishable from the characteristic rest tremor of Parkinson's disease (PD). The pathology induced by MPTP in one human case is confined to the substantia nigra, but in nonhuman primates, the locus ceruleus or the ventral tegmental area can also be affected. These findings suggest that the pathophysiology of rest tremor in PD might result from damage to either the substantia nigra alone or in combination with damage to one or more of these other regions.
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PMID:Tremor in MPTP-induced parkinsonism. 843 27


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