Pharmacologic modulation of MPTP toxicity: MK 801 in prevention of dopaminergic cell death in monkeys and mice.
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Biomedical subjects
Publications and source records attributed to F Vaglini.
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We have previously reported that diethyldithiocarbamate and acetaldehyde enhance MPTP toxicity in mice (Corsini et al. 1986). Here we show that these drugs enhance the depletion of dopamine in the striatum and markedly increase MPTP-induced death of DA neurons in the substantia nigra. This enhancement of MPTP toxicity is specific for the nigro-striatal DA pathway and no recovery occurs, at least for four months after the treatment. Rats, although they show an MPTP-induced acute syndrome similar to the that induced in mice by the combined treatments, appear to be insensitive to both MPTP alone or to combined treatment with diethyldithiocarbamate or acetaldehyde. The selectivity of the permanent bilateral lesions of the nigro-striatal pathway make mice treated with acetaldehyde or diethyldithiocarbamate and MPTP a simple and reliable model for parkinsonism.
In cynomologus monkeys, systemic administration of MK-801, a noncompetitive antagonist for the N-methyl-D-aspartate receptor, prevented the development of the parkinsonian syndrome induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MK-801 also attenuated dopamine depletion in the caudate and putamen and protected dopaminergic neurons in the substantia nigra from the degeneration induced by the neurotoxin. Nevertheless, 7 days after MPTP administration in the caudate and putamen of monkeys also receiving MK-801, the levels of toxic 1-methyl-4-phenylpyridinium were even higher than those measured in monkeys receiving MPTP alone. This indicates that the protective action of MK-801 is not related to MPTP metabolism and strongly suggests that, in primates, the excitatory amino acids could play a crucial role in the mechanism of the selective neuronal death induced by MPTP.
The aim of this work was to evaluate the phytohaemagglutinin-induced aggregation of circulating neutrophils isolated from 25 patients affected by chronic myeloproliferative syndromes (polycythaemia vera, chronic myeloid leukaemia in chronic phase, and essential thrombocythaemia). The results showed a lesser aggregating capacity in chronic myeloid leukaemia (CML) and an opposite behaviour in polycythaemia vera and essential thrombocythaemia. Patients with polycythaemia vera whose neutrophils showed a greater aggregating capacity were shown to have had various vascular complications.
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Thiobenzamide (TB) is a thiono-containing compound endowed with liver-damaging properties and promoting ability on liver carcinogenesis. When administered in a single dose to normal as well as to adrenalectomized rats, this compound induced a striking thymus cortex involution without relevant effects on the morphological features of other lymphoid organs such as spleen and lymph nodes. The proximal TB metabolite TB-S-oxide (TBSO) shared these effects with the parent compound, whereas the terminal metabolite benzamide (BA) was ineffective. The effect of TB on thymus was found to be dose- and age-dependent. Furthermore, acute TB treatment 12h before priming with the T-dependent antigen sheep erythrocytes impaired the secondary antibody response. In addition, TB administration affected not only cell-mediated immunity (as evidenced by a decreased delayed hypersensitivity response) but also mitogen-induced proliferation of blood lymphocytes. On the contrary, the chemotactic response of polymorphonuclear leukocytes obtained from TB-treated rats was unchanged.
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A greater incidence of nasal sinus lesions is revealed in patients operated for laryngectomy than in healthy subjects. The radiographs of the paranasal sinuses of 49 patients laryngectomized for laryngeal cancer and 71 smokers, over 40, were compared. Thirty-six (73.5%) of the operated patients showed a reduction in the lucency of the sinuses (opacities, sinusitis, mucocele) and 21 (42.9%) inferior concha hypertrophy. In the control group 23 (32.4%) and 12 (16.9%) cases had the same lesions. Chi2 statistical analysis was performed on both groups. The results show a significant increase in lesions of the nasal sinuses in the group of operated patients. The reduction in the air flow through the nose and the sinus cavities during breathing seems to be the pathogenic mechanism responsible for such findings.
Rubidium ions added at 0.5 mEq to liquid cultures of human mononuclear cells stimulated the differentiation of monocyte and particularly of granulocyte cell lines.
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P-glycoprotein, the molecular marker of multidrug resistance, was investigated by means of the specific monoclonal antibody C219 in circulating lymphocytes obtained from a patient affected by B-CLL, who had undergone chemotherapy with chlorambucil and CVP. Dot-immunobinding and immunoblotting revealed the presence of P-glycoprotein in the cell lysate, but the immunoperoxidase method and indirect immunofluorescence carried out with a fluorescence microscope and a cytofluorimeter failed to detect the protein. Some methodologic problems are discussed.
The aim of this work is to evaluate the relationship between P-glycoprotein expression in circulating blasts and clinical response in patients suffering from acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and chronic myeloid leukemia in either lymphoid or myeloid blastic crisis. The results obtained show that: a) patients whose blasts express P-glycoprotein are resistant towards protocols including Doxorubicin, Daunorubicin, Etoposide, Mithramycin, Vincristine; b) P-glycoprotein can be expressed constitutively in some cases; c) P-glycoprotein does not appear to be the only mechanism responsible for resistance towards anthracyclines and Etoposide.
In the present paper the possible role of rubidium (Rb) on leukocyte differentiation is evaluated. When the metal was added to human mononuclear bone marrow cells cultured for 14 days in soft agar, it was able to increase the number of clusters and to reduce the number of colonies. This activity depended upon the presence of conditioned medium. Rb induced a faster differentiation of HL 60 cells cultured in a medium able to promote granulocyte differentiation. The metal did not show any activity on continuously cultured HL 60. These data suggest that Rb is a supporting element for cell differentiation. Toxicity tests on rats are also reported.
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