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1.
J Neural Transm (Vienna) ; 111(8): 1017-30, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15254790

ABSTRACT

In this study, we investigated whether changes in the regulatory mechanisms of apoptosis and oxidative stress may be detected, peripherally, in patients with Parkinson's disease (PD). For this purpose, we measured caspase-3 activity, Bcl-2 concentrations, peripheral benzodiazepine receptor (PBR) expression and Cu/Zn superoxide dismutase (SOD) concentrations in lymphocytes of untreated PD patients, patients treated only with L-Dopa or with L-Dopa and dopamine agonists and healthy volunteers. Caspase-3 activity was significantly increased in all PD patient groups. Patients treated with L-Dopa and dopamine agonists showed the lowest values of Bcl-2, coupled with the highest density of PBRs, while increased levels of Cu/Zn SOD were found in the group under monotherapy with L-Dopa. We also found, in PD patients, clear, negative correlations between Bcl-2 levels and both duration and severity of the disease. Our findings point to the existence of changes in the regulatory mechanisms of apoptosis in PD patients -- observable outside the central nervous system -- which seem to be modulated by the pharmacological treatment with dopaminergic agents.


Subject(s)
Antiparkinson Agents/therapeutic use , Apoptosis/physiology , Caspases/metabolism , Dopamine Agents/therapeutic use , Lymphocytes/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Aged , Apoptosis/drug effects , Caspase 3 , Cell Survival/drug effects , Disease Progression , Dopamine Agonists/pharmacology , Female , Humans , Levodopa/pharmacology , Lymphocytes/drug effects , Lymphocytes/enzymology , Male , Middle Aged , Peripheral Nervous System/drug effects , Peripheral Nervous System/metabolism , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Superoxide Dismutase/metabolism
2.
Neurol Sci ; 24(3): 157-8, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14598064

ABSTRACT

We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apoptotic enzyme caspase- 3, and anti-oxidant/anti-apoptotic enzyme Cu/Zn superoxide dismutase (SOD) in human lymphocytes exposed to dopamine (DA). The same determinations were also carried out in parkinsonian patients treated with L-dopa. Caspase-3 activity and Cu/Zn SOD levels tended to increase when lymphocytes were exposed to low or intermediate doses of DA, while a decrease was observed, particularly in caspase-3 activity, with the higher DA dose. Bcl-2 levels were unaffected. In patients, we observed a negative correlation between Cu/Zn SOD levels and daily intake of L-dopa, which also tended to be negatively correlated with caspase-3 activity, but not with Bcl- 2. Our results show that dopaminergic stimulation is associated with complex changes in regulatory proteins of apoptosis.


Subject(s)
Apoptosis/drug effects , Dopamine/pharmacology , Lymphocytes/drug effects , Parkinson Disease/metabolism , Adult , Aged , Cardiotonic Agents , Case-Control Studies , Caspase 3 , Caspases/metabolism , Dopamine Agents/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , In Vitro Techniques , Levodopa/therapeutic use , Lymphocytes/metabolism , Male , Middle Aged , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Proto-Oncogene Proteins c-bcl-2/metabolism , Superoxide Dismutase/metabolism
3.
Ann N Y Acad Sci ; 1010: 675-8, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15033810

ABSTRACT

In this study, we measured the lymphocyte levels of proteins involved in apoptosis regulation, such as Bcl-2, the peripheral benzodiazepine receptor (PBR), caspase-3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with Parkinson's disease (PD), either untreated or under therapy with dopaminergic agents (l-Dopa alone or l-dopa + dopamine agonists) and in healthy volunteers. All PD groups showed increased activity of caspase-3, compared to controls, particularly those under treatment only with l-Dopa. In this latter group, the increase in caspase-3 activity was also paralleled by an increase in the concentration of Cu/Zn SOD. In addition, patients taking l-Dopa + dopamine agonists showed marked decrease in Bcl-2 levels and increased PBR expression, which seems in keeping with the hypothesis that PBR may be functionally related to Bcl-2. In conclusion, we found clear modifications in the levels of proteins involved in the control of apoptosis in lymphocytes of PD patients. These changes were disease related but also modulated by the pharmacological treatment, which confirms the potential role of apoptosis in PD pathogenesis and the modulatory influence of dopaminergic agents.


Subject(s)
Antiparkinson Agents/therapeutic use , Apoptosis , Biomarkers/analysis , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Analysis of Variance , Caspase 3 , Caspases/analysis , Dopamine Agonists/therapeutic use , Humans , Levodopa/therapeutic use , Reference Values , Superoxide Dismutase/analysis
4.
Pharmacology ; 63(1): 42-9, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11408831

ABSTRACT

In isolated human neutrophils, diazepam (10 nmol/l to 10 micromol/l) concentration-dependently increased migration and phagocytosis. Diazepam-induced migration and phagocytosis were inhibited by the peripheral benzodiazepine receptor (PBR) antagonist PK11195 (10 micromol/l). The PBR agonist Ro5-4864 (10 nmol/l to 10 micromol/l) did not affect migration but slightly enhanced phagocytosis, while clonazepam, which binds to the central-type benzodiazepine receptors but has no affinity for PBRs, was ineffective on both parameters up to 10 micromol/l. Phagocytosis induced by diazepam or Ro5-4864 was inhibited by the Ca2+ channel blocker L-verapamil (10 micromol/l), which however did not affect the action of diazepam on migration. Competition binding experiments performed by fluorescent staining of PBRs showed that diazepam directly interacts with PBRs on human neutrophils. Both diazepam and Ro5-4864 (10 nmol/l to 10 micromol/l) induced a rise of intracellular free Ca2+ concentrations ([Ca2+]i), which was inhibited by PK11195 (10 micromol/l) and L-verapamil (10 micromol/l) and prevented by extracellular Ca2+ chelation with EGTA (5 mmol/l). In conclusion, experimental evidence indicates that in human neutrophils diazepam stimulates both migration and phagocytosis through activation of PBRs. Diazepam-induced [Ca2+]i changes depend on a PBR-operated, L-verapamil-sensitive increase in the plasma membrane permeability and subsequent extracellular Ca2+ entry, and contribute to diazepam-induced phagocytosis. On the contrary, the effect of diazepam on migration seems to occur through Ca2+ -independent mechanisms.


Subject(s)
Calcium/metabolism , Chemotaxis, Leukocyte/drug effects , Diazepam/pharmacology , Neutrophils/drug effects , Phagocytosis/drug effects , Receptors, GABA-A/metabolism , Calcium Channel Blockers/pharmacology , Cells, Cultured , Flow Cytometry , GABA-A Receptor Agonists , GABA-A Receptor Antagonists , Humans , In Vitro Techniques , Isoquinolines/pharmacology , Neutrophils/physiology , Verapamil/pharmacology
5.
Life Sci ; 68(3): 283-95, 2000 Dec 08.
Article in English | MEDLINE | ID: mdl-11191644

ABSTRACT

A rapid and simple HPLC-ED method is described to identify and measure catecholamines (CTs) and their major metabolites in immune cells. Using this method, intracellular CTs were quantified in human peripheral blood mononuclear cells (PBMCs), T and B lymphocytes, monocytes and granulocytes. Immune cell subsets were separated by density gradient centrifugation and immunomagnetic cell sorting. CTs were also found in the human hematopoietic cell lines NALM-6 (pre-B) and (in smaller amounts) in Jurkat (T lymphoblastoid) and U937 (promonocytic). In cultured PBMCs, intracellular CTs were reduced by both the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine and the chromaffin granule depletant reserpine. In NALM-6 cells, both alpha-methyl-p-tyrosine and the dopamine-beta-hydroxylase inhibitor disulfiram reduced intracellular CTs, supporting the presence of active synthetic pathways in these cells. Since sympathoadrenergic mechanisms play a key role in the interactions between the immune system and the nervous system, these findings may be relevant for a better understanding of the neuro-immune network.


Subject(s)
Catecholamines/analysis , Chromatography, High Pressure Liquid/methods , Electrochemistry/methods , Hematopoietic Stem Cells/chemistry , Leukocytes, Mononuclear/chemistry , B-Lymphocytes/chemistry , Cell Separation , Disulfiram/pharmacology , Granulocytes/chemistry , Humans , Jurkat Cells , Monocytes/chemistry , Reserpine/pharmacology , T-Lymphocytes/chemistry , Time Factors , U937 Cells , alpha-Methyltyrosine/pharmacology
6.
Pharmacol Res ; 40(2): 153-8, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10433874

ABSTRACT

We report that neutrophil function was impaired in former heroin addicts on chronic naltrexone maintenance. Of the subjects, 62.5% had elevated plasma ACTH, 25% had elevated plasma cortisol and one subject had increased urinary cortisol. All subjects showed enhanced expression of opioid receptors on monocytes, neutrophils and lymphocytes. In vitro, incubation with therapeutically relevant concentrations of naltrexone induced a slow increase of neutrophil cytoplasmatic free Ca(2+)concentrations ([Ca(2+)]()E2>i) and slowed down the [Ca(2+)]()E2>i rise induced by N-formyl-methionyl-leucyl-phenylalanine. Neither naltrexone nor its metabolite beta-naltrexol affected human neutrophil function in vitro. We conclude that impairment of neutrophil function during chronic naltrexone may be related to opioid receptor overexpression. With this regard, the possible role of naltrexone-induced [Ca(2+)]()E2>i changes deserves further investigation. 1999 Academic Press.


Subject(s)
Leukocytes/drug effects , Naltrexone/therapeutic use , Narcotic Antagonists/therapeutic use , Neutrophils/drug effects , Receptors, Opioid/drug effects , Adolescent , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/drug effects , Adult , Calcium/metabolism , Female , Heroin Dependence/drug therapy , Humans , Hydrocortisone/blood , Hydrocortisone/urine , Leukocytes/cytology , Leukocytes/metabolism , Male , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Neutrophils/metabolism , Neutrophils/physiology , Receptors, Opioid/biosynthesis
8.
Neurosci Lett ; 222(2): 75-8, 1997 Jan 31.
Article in English | MEDLINE | ID: mdl-9111732

ABSTRACT

We have studied the effect of [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO, opioid mu-receptor agonist) and ICI-204,448 (kappa-receptor agonist) on endogenous noradrenaline release in the guinea-pig isolated distal colon. DAMGO enhances noradrenaline over-flow and this effect is antagonized by naloxone (pIC50 = 10.27) and nor-binaltorphimine (pIC50 = 7.97), and concentration-dependently turned into inhibition by yohimbine. ICI-204,448 inhibits noradrenaline overflow and is antagonized by naloxone (pIC50 = 9.38) and nor-binaltorphimine (pIC50 = 10.48), but is not affected by yohimbine. Evidence is thus given that mu- and kappa-opioid receptors modulate noradrenaline release in the guinea-pig colon. Modifications by yohimbine of the effect of DAMGO indicate the existence of a functional relationship between mu-receptors and alpha(2)-autoreceptors in this model.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Myenteric Plexus/chemistry , Receptors, Adrenergic, alpha-2/metabolism , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Adrenergic alpha-2 Receptor Antagonists , Adrenergic alpha-Agonists/metabolism , Adrenergic alpha-Agonists/pharmacology , Analgesics/pharmacology , Animals , Colon/innervation , Dose-Response Relationship, Drug , Electric Stimulation , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/pharmacology , Guinea Pigs , Myenteric Plexus/drug effects , Myenteric Plexus/metabolism , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Neurotransmitter Agents/metabolism , Norepinephrine/metabolism , Norepinephrine/pharmacology , Pyrrolidines/pharmacology , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/antagonists & inhibitors , Yohimbine/pharmacology
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