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)

Infusion of MPTP (0.2-0.8 mg/kg) into the right internal carotid artery of monkeys produces toxin-induced injury to the right nigrostriatal pathway with sparing of other dopaminergic neurones on the infused side and with negligible or little injury to the opposite, untreated side. There are contralateral limb dystonic postures, rigidity, and bradykinesia, but the animals are able to eat and maintain health without drug treatment. Spontaneous motor activity is attended by circling towards the injured side, whereas treatment with L-DOPA/-carbidopa or apomorphine stimulates circling towards the intact side. Dopamine and dopamine metabolite levels are normal in the left caudate and putamen, but markedly depressed on the right (MPTP-treated) side. This animal hemiparkinsonian model will be useful in studies of volitional movement control, drug treatments of Parkinson's disease, and functional efficacy of brain tissue implants.
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PMID:Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 348 91

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.
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PMID:Chronic alterations in jejunal myoelectric activity in rats due to MPTP. 350 Dec 48

The CNS maintains a fundamental distinction between actions elicited by external stimuli and actions elicited by internal goals (acts of will). As a result the intact organism can monitor centrally three aspects of its own actions: (1) the action appropriate to current external stimulation (stimulus intention or meaning); (2) the action appropriate to current goals (willed intention); and (3) the action which was actually selected (corollary discharge). In Type I (acute) schizophrenic patients, intentions of will lead to actions, but these willed intentions are not monitored correctly. This apparent discrepancy between will and action gives rise to experiential (1st rank) positive symptoms (e.g. delusions of control and passivity). In Type II (chronic) patients, intentions of will are no longer properly formed and so actions are rarely elicited via this route. This gives rise to behavioural negative signs (e.g. poverty of speech). The behaviour of Type II schizophrenics has surface similarities to that shown by patients with Parkinson's disease and patients with frontal lobe lesions in that all three types of patient show a relative deficit of actions elicited by willed intentions. Dopamine blocking drugs reduce positive symptoms in Type I patients precisely because they induce Parkinsonism, i.e. reduce the likelihood of actions being initiated by willed intentions. This in turn reduces the likelihood that actions will occur for which the patient had no awareness of his intention to act.
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PMID:The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action. 362 24

Dopamine (DA) and serotonin (5-HT) innervations were revealed by radioautography in primary motor, premotor and supplementary motor (SMA) cortex in Cynomolgus monkeys, using uptake of tritiated amines in vibratome sections under specific conditions that were previously established. DA and 5-HT axons were distributed throughout all cortical layers. A denser DA innervation was found in layers I, III and to a lesser extent layer V with a striking cluster-like arrangement in layer III, particularly in the SMA. 5-HT axons appeared less numerous; their lower density in comparison with DA axons was especially apparent in layer III, particularly in the premotor and motor areas. A DA-5-HT complementarity was thus suggested in this layer. These results suggest that in addition to the motor control exerted through the nigrostriatal pathway, the cortical DA projections could directly modulate the neuronal activity in motor areas. This could be of major importance in the pathophysiology of motor disorders such as Parkinson's disease.
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PMID:Major dopamine innervation of the cortical motor areas in the cynomolgus monkey. A radioautographic study with comparative assessment of serotonergic afferents. 380 66

The effects of bromocriptine in patients with Parkinson's disease manifesting various problems in levodopa therapy were tested in a double-blind manner with the collaboration of 59 institutions. The slow and low principle was in part adopted. Either bromocriptine or placebo was added to levodopa. Twenty-nine % of the bromocriptine-treated patients (n = 108), in contrast to 14.8% of the placebo-treated (n = 108), showed either marked or moderate improvement (P less than 0.05). Twenty to 37% improvement was noted in most of the symptoms studied in those treated with bromocriptine. The significant superiority of bromocriptine was also noted in the effects on wearing-off phenomena and frozen gait. No irreversible side effects were noted. It is concluded that bromocriptine is useful in patients who are manifesting various difficulties in levodopa therapy. Our results are comparable to those using higher maintenance doses. Dopamine antagonistic actions were not observed. This is unlike the case with experimental animals.
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PMID:Effects of bromocriptine on parkinsonism. A nation-wide collaborative double-blind study. 390 50

25% of patients with Parkinson's disease demonstrate the first symptoms with 70 years. The deficiency of Tyrosinhydroxylase is the trigger of the decreased level of Dopamin in the basal ganglia. The implications are the typical symptoms (tremor, rigor and akinesia) and the psychopathological decompensations as depression, delirs and bradyphrenie.
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PMID:[Senile Parkinsonism: its motor and psychological defects]. 612 32

Dopamine agonists have yielded two important advances to our understanding of the basal ganglia--they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons--a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect. The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson's disease, but as yet there is no firm evidence. In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.
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PMID:Dopamine agonists in Parkinson's disease. 623 79

1. In view of previously demonstrated modulatory effects of PLG on the sensitivity of central dopamine receptors, we developed a radioligand binding assay to identify specific binding sites of PLG in rat and normal human brain. 2. 3H-PLG binds specifically to rat striatum exhibiting high affinity (KD = 4.69 +/- 0.50 nM) saturability (Bmax = 9.20 +/- 0.30 fmoles/mg protein) and reversibility; the highest density of specific PLG binding sites occurring in the striatum, followed by the hypothalamus and cerebral cortex. 3. Saturable, high-affinity binding sites of PLG were identified in human striatum. The substantia nigra was enriched with the highest level of specific PLG binding sites. 4. Dopamine receptors were identified in human lymphocytes. 5. The results are compatible with the hypothesis that differential modulation of CNS dopamine receptors by PLG is functionally associated with interacting with specific PLG binding sites in the rat and human brain, and pose implications for Parkinson's disease and tardive dyskinesia.
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PMID:CNS putative L-prolyl-L-leucyl-glycinamide (PLG) receptors, brain and lymphocyte dopamine receptors. 629 84

1 Dopamine deficiency in the brain is the prime biochemical deficit in Parkinson's disease, but loss of noradrenaline and 5HT also may contribute. 2 In rats, 5HT-containing neurones originating from the dorsal and median raphe nuclei innervate forebrain dopamine-containing areas so as to impose an inhibitory regulatory tone on dopamine function. However, this interaction between brain dopamine and 5HT-containing neuronal systems is complex, and the effect produced appears dependent on the relative activity of each system. 3 Anatomical evidence for innervation of dopamine-containing brain regions by noradrenaline fibres in the rat is scanty, but functional studies suggest the existence of inputs which facilitate dopamine function. 4 Drug therapy designed to increase or decrease brain 5HT function has had no consistent effect in Parkinson's disease. 5 Manipulation of brain noradrenergic activity in Parkinson's disease had little effect, although the noradrenaline precursor L-threo-DOPS may reduce freezing attacks. 6 Until more specific drug molecules are available the role of brain noradrenergic and 5HT mechanisms in Parkinson's disease remains uncertain.
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PMID:Noradrenaline and 5-hydroxytryptamine modulation of brain dopamine function: implications for the treatment of Parkinson's disease. 633 12

Rats with unilateral lesions of the substantia nigra were treated with L-dopa 25 mg/kg subcutaneously 30 minutes after treatment with carbidopa 25 mg/kg intraperitoneally. In the ipsilateral striatum, dopamine levels achieved a peak of 1.57 +/- 0.63 micrograms/g (control 0.19 +/- 0.05 micrograms/g) at 20 minutes and did not differ from controls by 90 minutes after L-dopa administration. Dopamine levels peaked in the contralateral striatum at 45 minutes (11.96 +/- 0.14 micrograms/g, where control levels were 7.74 +/- 0.22 micrograms/g) and returned to control values by 180 minutes. These data suggest that in patients with advanced Parkinson's disease, L-dopa administration results in a smaller increase and a shorter duration of elevation in striatal dopamine concentration than in controls. These observations support the hypothesis that the "wearing-off" phenomenon that occurs during the treatment of patients with Parkinson's disease occurs as a consequence of a reduction in the rate of conversion of L-dopa to dopamine and perhaps diminished capacity for the storage of dopamine.
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PMID:Altered pharmacokinetics of L-dopa metabolism in rat striatum deprived of dopaminergic innervation. 654 Mar 90


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