G.U. Corsini

THERAPEUTIC EFFICACY OF APOMORPHINE COMBINED WITH AN EXTRACEREBRAL INHIBITOR OF DOPAMINE RECEPTORS IN PARKINSON'S DISEASE

Apomorphine in combination with a peripheral dopamine receptor blocker (domeperidone) was administered to four parkinsonian patients in a double-blind placebo-controlled study. The therapeutic efficacy of apomorphine was not reduced by domperidone, while nausea, drowsiness, sedation, and arterial hypotension were prevented. Combination of domperidone with dopamine agonists may result in more effective treatment of Parkinsons disease.

Linkage between X-chromosome markers and manic-depressive illness. Two Sardinian pedigrees.

ABSTRACT– Pedigrees of manic‐depressive patients in treatment at the Lithium Clinic of the Institute of Clinical Pharmacology, University of Cagliari, were evaluated for linkage between major affective illness and the protan‐deulan‐glucose‐6‐phosphatc‐dehydrogenase region of the X‐chromosome. Two informative pedigrees were found, investigated and analyzed for linkage using a multigenerational model and considering age‐dependent penetrance. The results are consistent with the hypothesis of X‐linkage in major affective illness.

1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP) NEUROTOXICITY IN MICE IS ENHANCED BY ETHANOL OR ACETALDEHYDE

Persistent neurochemical changes consistent with parkinsonism have been reported in brains of mice treated with repeated high doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now report that ethanol or acetaldehyde potentiate MPTP-induced damage to mouse striatum. One hour after the combined treatments (ethanol and MPTP or acetaldehyde and MPTP), the animals exhibited a marked and long-lasting catatonic posture and then returned gradually to apparently normal locomotion. Seven days after MPTP administration, depletion of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum were further potentiated in the group of animals treated with ethanol. This effect was more evident when the treatment was repeated twice and was dose-dependent. Acetaldehyde was more potent than ethanol in enhancing MPTP neurotoxicity. A single exposure to acetaldehyde before and during MPTP treatment produced a very consistent fall of DA, DOPAC and HVA but not serotonin (5HT) or 5-hydroxyindoleacetic acid (5HIAA) in the striatum. This suggests that ethanol effects on MPTP neurotoxicity might be related to acetaldehyde formation.

Therapeutical efficacy of a combination of apomorphine with sulpiride or metoclopramide in parkinsonism

In healthy volunteers the emetic effect of apomorphine (5–10 mg, i.m.) was prevented by haloperidol (2 mg), metoclopramide (10 mg) and sulpiride (100 mg), injected intramuscularly. In parkinsonian patients, apomorphine (1 mg) given alone ameliorated the neurological symptoms (30% improvement in the disability score), but the improvement was accompanied by nausea, vomiting, sedation or sleepiness. Haloperidol (2 mg) prevented not only the emetic effect of apomorphine (10 mg), but also its therapeutic efficacy in parkinsonism. Indeed, the disability score was worsened by the drug combination in some patients. Moreover, after haloperidol, apomorphine produced deep sedation and sleep. By contrast, in parkinsonian patients pretreated with metoclopramide (10 mg) or sulpiride (100 mg), apomorphine (10 mg) markedly diminished tremor and rigidity and failed to produce nausea, vomiting and sleepiness.

1 ‐Methyl‐4‐Phenyl‐ 1,2,3,6‐Tetrahydropyridine: Correspondence of Its Binding Sites to Monoamine Oxidase in Rat Brain, and Inhibition of Dopamine Oxidative Deamination In Vivo and In Vitro

Abstract: A saturable, specific, high‐affinity binding site for [3H] 1 ‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine was found in rat brain homogenates. The CNS regional distribution, the subcellular fractionation, and the displacement by pargyline, clorgyline, and deprenyl suggest that this binding site may correspond to monoamine oxidase. I ‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine inhibited the oxidative deamination of dopamine, both in vivo and in vitro. Striatal levels of 3,4‐dihydroxyphenylacetic acid were significantly reduced shortly after intravenous administration, and returned to normal values after a few hours. The in vitro formation of 3,4‐dihydroxyphenylacetic acid from dopamine was inhibited by concentrations of 1‐methyl‐4‐phenyl‐ 1,2,3,6‐tetrahydropyridine comparable to those of pargyline.

Evaluation of the toxicity of the dopaminergic neurotoxins MPTP and MPP+ in PC12 pheochromocytoma cells: binding and biological studies

This study was designed to investigate the toxicity of both MPTP and MPP+ using some simple cell systems, such as PC12 and C6 cultures, as models. Exposure of PC12 cells to 0.5 mM MPTP for 72 h resulted in a 50% cell loss with respect to the control cells, and clorgyline, a MAO-A inhibitor, antagonized this toxic effect. Higher concentrations of MPTP demonstrated only a weak cytostatic effect on C6 cells. Moreover, MPP+ showed a toxic effect which was 100 times more evident than MPTP toxicity in the PC12. We found a single, saturable class of [3H]MPP+ binding sites with a relatively high affinity both in PC12 and C6 cell lines. Moreover, the most susceptible cell line towards the toxic effects of both MPTP and MPP+, i.e. PC12, has the higher number of MPP+ binding sites. Our results suggest that MPTP can be toxic not only via MAO-B, but also via MAO-A activity and we propose PC12 as a model to study the intracellular mechanisms of MPTP and MPP+ toxicity.

MPTP fails to induce lipid peroxidation in vivo

It has been speculated that the conversion of MPTP to MPP+ destroys dopaminergic neurons by promoting the generation of hydroxyl radicals and causes lipid peroxidation. The results obtained in the present work indicate that the primary products of lipid peroxidation are not detectable in MPTP treated animals and thus other mechanisms besides lipid peroxidation should be considered to explain the cytotoxicity of this neurotoxin.

Therapeutic efficacy of a partial dopamine agonist in drug-free parkinsonian patients

Terguride, a mixed agonist-antagonist of central dopamine receptors, was administered to eight patients with Parkinsons Disease. The clinical symptomatology of all patients improved significantly. The maximum neurological effect of terguride was noted at the highest daily dose (1.2 mg) after 21 days of treatment in all subjects, with a statistically significant average of 50.6% neurological improvement on the Webster scale in respect to admission. All single scores of the Webster scale decreased significantly: swing of the arms, facial expression, bradikinesia, rigidity and gait, particularly. No significant adverse reactions were observed during treatment. Our study in drug-free parkinsonian patients demonstrated that terguride is able to improve the neurological symptoms similar to DA agonists, but without their typical side effects.

Characterization of a putatively vesicular binding site for [3H]MPP+ in mouse striatal membranes

[3H] N-Methyl-4-phenylpyridinium ion (MPP+) binds with a fully reversible, high affinity process to a population of sites mainly localized in the mouse striatum (Bmax = 168 +/- 15 fmol/mg protein, KD = 1.4 +/- 0.4 nM). The majority of specifically-bound radioactivity was localized in the synaptosomal fraction. Unilateral, striatal denervation with 6-hydroxydopamine (6-OHDA) markedly (by 65-70%) decreased the number of [3H]MPP+ sites. Besides dopamine, the vesicular markers tyramine, tetrabenazine and reserpine inhibited [3H]MPP+, while mazindol was a poor displacer. Adenosine triphosphate (ATP) and Mg(2+)-ions did not affect [3H]MPP+ binding. It is concluded that these sites may represent a marker of striatal storage vesicles for dopamine.

[3H]1‐Methyl‐4‐Phenyl‐2,3‐Dihydropyridinium Ion Binding Sites in Mouse Brain: Pharmacological and Biological Characterization

Abstract: Because 1‐methyl‐4‐phenyl‐2,3‐dihydropyridinium ion (MPP+) appears to damage the dopaminergic neuron and cause neuronal death, we characterized [3H]MPP+ binding sites in mouse brain membranes. Among several compounds tested, debrisoquin [3,4‐dihydro‐2(1 H)‐isoquinolinecarboxamidine] and some analogues were able to antagonize [3H]MPP+ binding. Debrisoquin is able to block adrenergic transmission and inhibit the activity of monoamine oxidase A (MAO‐A). We found a certain correlation between the ability of these agents to displace [3H]MPP+ from its binding sites and their capacity to inhibit MAO‐A activity. These data and the finding of a higher number of [3H]MPP+ binding sites in human placenta compared to mouse brain suggest that these sites may correspond to MAO‐A enzymes. Recently it has been demonstrated in human brain that neurons in regions rich in catecholamines are positive for MAO‐A. Accordingly, we suggest MAO‐A as a possible accumulation site of MPP+ within the dopaminergic neuron. We also indicate the chemical structural requirement associated with the best binding of debrisoquin analogues with [3H]MPP+ sites. It would be reasonable to test the effects of debrisoquinlike drugs able to pass the blood‐brain barrier on 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine toxicity.