Biomedical subjects
A Bocchetta
Publications and source records attributed to A Bocchetta.
Familial rates of affective illness in Sardinia with special reference to schizoaffective disorder.
Familial rates of psychiatric disorders were studied in southern Sardinia and showed an increase in relatives of probands with the following research diagnostic criteria (RDC) diagnoses: normal, unipolar depression, schizoaffective depressive, schizoaffective bipolar, bipolar with mania and bipolar with hypomania. A significantly higher risk for bipolar schizoaffective disorder was observed in relatives of bipolar schizoaffectives compared with relatives of normal probands.
Bipolar affective disorder and heterozygous beta-thalassemia.
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Covalent protein binding of a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to mouse and monkey brain in vitro and in vivo.
We have recently reported that a reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is formed in rat brain in vitro by type B monoamine oxidase (MAO). In the present study, we further characterize the irreversible binding in vitro using tissues from mice and monkeys, two species more sensitive than rats to MPTP neurotoxicity. We also report the occurrence of irreversible binding of radioactivity after administration of tritiated MPTP in the same species in vivo. Tissue homogenates were incubated at 37 degrees with 1-[methyl-3H]MPTP in in vitro experiments. Animals were injected with labeled MPTP and sacrificed at different times in in vivo experiments. The perchloric acid precipitates of tissue homogenates from either procedure were washed exhaustively with organic solvents and counted for radioactivity. The amount of recovered radioactivity in in vitro experiments was similar using brain homogenates from mice and monkeys, whereas a considerably lower amount was found in mouse liver. MAO-B inhibitors decreased the covalent binding. However, the combined MAO-B/MAO-A inhibitor pargyline had no effect if added after 2 hr of incubation. Sulfhydryl-containing compounds decreased the covalent binding in a concentration-related manner. GSH reduced the rate of the reaction throughout the incubation. The covalent binding slowly increased in time in vivo in mouse brain, not in liver. There was a two-fold variation of covalently bound radioactivity in different brain areas of 3H2-MPTP-treated monkey. This reactive metabolite may play a role in MPTP neurotoxicity.
Characterization of [3H]MPTP binding sites.
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Parkinson's disease and pesticides.
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Dopamine agonists in the treatment of schizophrenia.
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Primate-rodent 3H-MPTP binding differences, and biotransformation of MPTP to a reactive intermediate in vitro.
Specific binding of 3H-MPTP to brain homogenates is displaced predominantly by MAO-A inhibitor clorgyline in rat, and by MAO-B inhibitor deprenyl in monkey. A covalently bound metabolite is formed by MAO-B in vitro from MPTP, through a reaction almost completely inhibited by physiological concentrations of glutathione and significantly reduced by other sulfhydryl containing compounds. The difference in binding site pharmacological properties may account for the relative resistance of rat to the neurotoxic effect produced by MPTP in primates. The glutathione-prevented metabolic conversion to a reactive intermediate may be important for the mechanism of MPTP neurotoxicity and relevant to idiopathic Parkinson's disease.
A reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is formed in rat brain in vitro by type B monoamine oxidase.
The formation of a reactive intermediate in the oxidative metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that can covalently bind to monoamine oxidase or other cellular macromolecules has been postulated by several authors. We report here direct in vitro evidence that MPTP is converted by monoamine oxidase, predominantly type B, to a reactive metabolite, which binds irreversibly to proteins in rat brain. Rat brain homogenates were incubated at 37 degrees C with 1-[methyl-3H]MPTP and the perchloric acid precipitates were washed exhaustively with organic solvents and counted for radioactivity. The amount of recovered radioactivity was enzyme-related: it was time- and temperature-dependent and did not occur with preboiled tissue. This metabolic activity required oxygen; it was concentrated in the crude mitochondrial fraction and varied in different brain regions. Pargyline and deprenyl prevented the radioactivity binding, whereas clorgyline was less potent, indicating that monoamine oxidase, predominantly of type B, is the enzyme responsible for the production of the reactive metabolite. Glutathione and, to a lesser extent, cysteine and dithiothreitol, but not ascorbic acid, inhibited the irreversible protein binding, suggesting that sulfhydryl groups may react with the metabolite possibly leading to SH-conjugates. 1-Methyl-4-phenyl-2,3-dihydropyridinium increased the irreversible protein binding, indicating that the reactive metabolite of MPTP may not be identified as the dihydropyridinium compound. This chemically reactive intermediate might play a role in MPTP neurotoxicity.
Aetiology of Parkinson's disease.
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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.
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. 1-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.
Inhibition of [3H] MPTP binding to rat brain by pargyline.
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Proteolytic degradation of neuronal benzodiazepine binding sites.
The pathway of breakdown of membrane-bound benzodiazepine binding sites has been examined with proteolytic enzymes. Photoaffinity labeled benzodiazepine receptors were degraded for varying amounts of time and at varying enzyme concentrations. The properties of fractions both remaining in the membrane and released into the supernatant were examined for their apparent molecular weight by SDS gel electrophoresis. Trypsin treatment converted the 46K subunits of the GABA/BDZ complex which bind 3H-flunitrazepam into 40K and 27.5K fragments which remained in the membrane and finally a small fragment which was released into the supernatant. An endogenous trypsin-like activity in the membrane fractions has similar proteolytic effects on the membrane bound receptor.
Linkage between X-chromosome markers and manic-depressive illness. Two Sardinian pedigrees.
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-deutan-glucose-6-phosphate-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.
Properties of benzodiazepine binding sites in peripheral tissues.
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The use of dopamine agonists in the treatment of schizophrenia.
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A double-blind study of minaprine versus amitriptyline in major depression.
This study was designed to compare the antidepressant effects of minaprine and amitriptyline in a group of 60 outpatients suffering from a major depressive episode as defined by the DSM III. The 6-week study was double-blind with a random allocation of treatment. Patients were treated with flexible daily doses of 200-300 mg of minaprine and 50-75 mg of amitriptyline. Both drugs showed significant global antidepressant efficacy with no significant difference between the two treatment groups. The Hamilton item 'psychomotor retardation' improved earlier with minaprine than amitriptyline. The incidence of anticholinergic adverse effects was significantly higher in the amitriptyline treatment group.
MPTP-induced parkinsonism. Recent studies on the mechanism of toxicity.
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