Biomedical subjects

G Racagni

Publications and source records attributed to G Racagni.

At least 37 records · Page 2Linked to original sources

PubMed2001

Posttraumatic stress disorder: diagnosis and epidemiology, comorbidity and social consequences, biology and treatment.

Epidemiological studies clearly indicate that posttraumatic stress disorder (PTSD) is becoming a major health concern worldwide even if still poorly recognized and not well treated. PTSD commonly co-occurs with other psychiatric disorders, and several symptoms overlap with major depressive disorders, anxiety disorders and substance abuse; this may contribute to diagnostic confusion and underdiagnosis. This anxiety disorder provokes significant occupational, psychiatric, medical and psychosocial disability, and its consequences are enormously costly, not only to the survivors and their families, but also to the health care system and society. Work impairment associated with PTSD is very similar to the amount of work impairment associated with major depression. The pathophysiology of PTSD is multifactorial and involves dysregulation of the serotonergic as well as the noradrenergic system. A rational therapeutic approach should normalize the specific psychobiological alterations associated with PTSD. This can be achieved through the use of antidepressant drugs, mainly of those that potentiate serotonergic mechanisms. Recent double-blind placebo-controlled studies report the efficacy of selective serotonin reuptake inhibitors. Several cognitive-behavioral and psychosocial treatments have also been reported to be efficacious and could be considered when treating PTSD patients.

Antidepressive Agents↗

PubMed2001

Changes in enzymatic activities involved in glucose metabolism by acyl-CoAs in Trypanosoma cruzi.

This study describes the effect of some saturated and unsaturated free fatty acids and acyl-CoA thioesters on Trypanosoma cruzi glucose 6-phosphate dehydrogenase and hexokinase activities. Glucose 6-phosphate dehydrogenase was sensitive to the destabilizing effect provoked by free fatty acids, while hexokinase remained unaltered. Glucose 6-phosphate dehydrogenase inhibition by free fatty acids was dependent on acid concentration and chain length. Both enzymes were inhibited when they were incubated with acyl-CoA thioesters. The acyl-CoA thioesters inhibited glucose 6-phosphate dehydrogenase at a lower concentration than the free fatty acids; the ligands glucose 6-phosphate and NADP+ afforded protection. The inhibition of hexokinase by acyl-CoAs was not reverted when the enzyme was incubated with ATP. The type of inhibition found with acyl-CoAs in relation to glucose 6-phosphate dehydrogenase and hexokinase suggests that this type inhibition may produce an in vivo modulation of these enzymatic activities.

Acyl Coenzyme A↗

PubMed2000

Calcium-dependent modulation of FGF-2 expression in cultured cerebellar granule neurons.

We investigated the expression for fibroblast growth factor-2 (FGF-2), in cultured rat cerebellar granule cells and its modulation by Ca2+ regulating agents. There were no significant differences in the levels of FGF-2 mRNA in cells cultured in high vs low K+. The expression of the trophic factor is induced by Ca2+ entry through the plasma membrane only in mature neurons but not at an early stage of maturation. Conversely the release of Ca2+ from intracellular stores increased the expression for FGF-2 at 2 or 7 days in culture. suggesting that is not dependent upon cellular maturation. These results suggest that specialized mechanisms can operate to regulate FGF-2 expression and that the integration of electrical and receptor-mediated signals for its modulation within cerebellar granule neurons may depend upon the maturational stage of the cells.

Animals↗

PubMed2000

Modification of presynaptic CaM kinase II affinity for ATP in hippocampus after long term blockade of serotonin reuptake.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is markedly enriched at synapses, where it is involved in the control of synaptic transmission, transmitter release and synaptic plasticity. CaMKII has also been found to be involved in the long-term action of antidepressants on post-receptor signaling mechanisms, because monoamine reuptake inhibitors induced an increase in autophosphorylation and activity of the kinase in nerve terminals of hippocampus. To study whether changes in the amount of enzyme or kinetic changes, due to posttranslational modifications, are responsible for kinase activation in nerve terminals, alpha-CaMKII level and kinetic constants of the autophosphorylation reaction as a function of ATP concentration were measured in presynaptic cytosol from hippocampus. Treatment with two serotonin reuptake inhibitors did not change the level of presynaptic kinase or the Vmax of autophosphorylation reaction. Instead the Km of the kinase for ATP was decreased 2.8-fold with fluvoxamine and 3.5-fold with paroxetine, implying an increase in the affinity for ATP. This result represents the first finding of changes in kinetic constants of a major brain enzyme after treatment with antidepressant drugs.

Adenosine Triphosphate↗

PubMed2000

Apoptosis induced by 2-chloro-adenosine and 2-chloro-2'-deoxy-adenosine in a human astrocytoma cell line: differential mechanisms and possible clinical relevance.

We have previously demonstrated that 2-chloro-adenosine (2-CA) can induce apoptosis of rat astroglial cells (Abbracchio et al. [1995] Biochem. Biophys. Res. Commun. 213:908-915). In the present study, we have characterized, for the first time, the effects induced on a human astrocytoma cell line (ADF cells) by both 2-CA and its related analog 2-chloro-2'-deoxy-adenosine (2-CdA, that is employed as anti-cancer agent in chronic lymphoid malignancies). Exposure of these cells to either adenosine analog resulted in time- and concentration-dependent apoptosis. Experiments with pharmacological agents known to interfere with adenosine receptors, its membrane transporter, and intracellular nucleoside kinases showed that: (i) cell death induced by either adenosine analog did not depend on extracellular adenosine receptors, but on a direct intracellular action; however, only in the case of 2-CA, was entry into cells mediated by the specific nitrobenzyl-tioinosine-sensitive transporter; (ii) for both adenosine analogs, induction of apoptosis required the phosphorylation/activation by specific intracellular nucleoside kinases, i.e., adenosine kinase for 2-CA, and deoxycytidine kinase for 2-CdA. In addition, only in the case of 2-CdA, was induction of apoptosis preceded by a block of cells at the G2/M phase of the cell cycle. Finally, at concentrations of either analog that killed about 80-90% of astrocytoma cells, a significantly lower effect on the viability of primary cortical neurons was observed. In conclusion, both adenosine analogs can trigger apoptosis of human astrocytoma cells, albeit with different mechanisms. This effect together with the relative sparing of neuronal cells, may have potential clinical implications for the therapy of tumors of glial origin.

2-Chloroadenosine↗

PubMed2000

cAMP cascade leads to Ras activation in cortical neurons.

Monoaminergic G protein-coupled receptors (GPCRs) are highly expressed in the CNS at the cerebrocortical level, where they support a variety of behavioural responses. To elucidate possible intracellular signalling pathways coupled to these receptors, we have studied their ability to activate extracellular signal-regulated kinases (ERKs) in cultured cortical neurons. An increase in ERK activity was observed after stimulation of neurons with dopamine or serotonin, and with agonists selective for various GPCRs. In addition, ERK activation was also observed following treatment with phorbol dibutyrate (PdBu) and forskolin, activators of protein kinase C (PKC) and protein kinase A (PKA), respectively. Concomitant with ERK activation, all the monoaminergic agonists tested also increased the level of active Ras (Ras-GTP). Surprisingly, Ras activation was also observed after activation of cAMP pathway, and this effect was at least in part mediated by PKA. Ras activation by cAMP was unique for neurons, since in PC12 cells forskolin caused activation of ERK but did not increase Ras-GTP level. These results highlight the relevance of Ras as a target for multiple signalling cascades leading to activation of the ERK pathway in neurons.

Animals↗

PubMed2000

Changes in Trypanosoma cruzi phospholipid turnover induced by parasite contact with cell membranes.

To investigate the possibility that cell contact could initiate a series of signals in both the host cell and the flagellate protozoan Trypanosoma cruzi, we studied [32P]-phospholipid turnover during parasite interaction with cellular membranes in vitro. Lipid alterations were produced in the parasite during the initial period of contact with the plasma membranes of human erythrocytes. In the presence of calcium an increment in phosphatidylethanolamine was observed with a concomitant decrease in phosphatidic acid fractions, whereas these modifications were not observed in the absence of calcium. There was an evident decrease in phosphatidylcholine and a shift in the phosphatidylinositol/lysophosphatidylethanolamine fraction among the phospholipids of major turnover in the absence or presence of calcium. Among the minor labeled species, lysophosphatidylcholine reached levels that duplicated control values, whereas the amounts of lysophosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate diminished by over 50%. All of these variations indicate that the parasite's contact with plasma membranes induces changes involving T. cruzi phospholipids and suggest the participation of these compounds in the activation of intracellular mechanisms that might be important during the life cycle of this parasite.

Animals↗

PubMed2000

Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Adrenergic beta-Antagonists↗

PubMed2000

Direct and indirect costs of schizophrenia in community psychiatric services in Italy. The GISIES study. Interdisciplinary Study Group on the Economic Impact of Schizophrenia.

BACKGROUND: The present work is a cost-of-illness (COI) study that aims at assessing total direct and indirect costs of schizophrenic patients in community psychiatric services in Italy and identifying the variables that influence costs. METHODS: A retrospective prevalence-based multi-centre COI study, was designed. Ten community mental health centres (CMHC) were involved and 100 patients were recruited. Data on patients' costs were gathered through specifically designed instruments. RESULTS: More than half total direct costs were attributed to CMHC interventions. The yearly average costs of schizophrenia per patient amounted to nearly ITL 50 million: 30% for direct costs and 70% for indirect costs. CONCLUSION: CMHCs tend to manage long-term ill patients by adopting a strong community-based system of care. Schizophrenia is correlated to loss of working days and lack of well-being. From the results of this study, it might be argued that the de-institutionalisation programme has produced 'spillovers' in terms of families' greater involvement in patients management.

Adolescent↗

PubMed2000

Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from schizophrenic patients.

Abnormalities in the cAMP-dependent protein kinase (PKA), a central component of cAMP signaling, have been reported in several psychiatric disorders. Previous studies showed cAMP signaling alterations in schizophrenic patients but less is known about the involvement of PKA in such disorder. Therefore, we investigated the PKA subunits by Western blot analysis in platelets from 12 patients with schizophrenia and 13 controls. The results showed that the immunolabeling of the PKA regulatory subunits type I (RI) and type II (RII) was significantly reduced in patients compared with controls whereas no differences were observed in the catalytic (C) subunit of the enzyme. These preliminary data suggest that schizophrenic patients have altered PKA levels, thus supporting that dysfunctions in the components of cAMP signaling may contribute to the pathophysiology of schizophrenia.

Actins↗

PubMed2000

Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics.

There is now some evidence that schizophrenia may be accompanied by an activation of the inflammatory response system (IRS) and that typical antipsychotics may suppress some signs of IRS activation in that illness. This study was carried out to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and Clara Cell protein (CC16), an endogenous anticytokine, in nonresponders to treatment with typical neuroleptics and (ii) the effects of atypical antipsychotics on the above IRS variables. The above parameters were determined in 17 patients with treatment-resistant schizophrenia (TRS) to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. Patients with TRS had repeated measurements of the IRS variables before and 2 and 4 months after treatment with atypical antipsychotics. Serum IL-6 was significantly higher in schizophrenic patients, irrespective of their response to typical antipsychotics, than in normal controls. Serum IL-1RA was significantly higher in the TRS patients than in controls, whereas responders took up an intermediate position. The serum concentrations of CC16 were significantly lower after treatment with atypical antipsychotics during 4 months than before treatment. It is concluded that (i) schizophrenia and, in particular, TRS is characterized by an activation of the monocytic arm of cell-mediated immunity and (ii) atypical antipsychotics may decrease the anti-inflammatory capacity of the serum in TRS patients.

Adult↗

PubMed2000

Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment.

OBJECTIVE: During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders. METHODS: Among the components of cAMP signaling, this review focuses on the cAMP-dependent phosphorylation system. We analyzed the basic components of the cAMP-dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP-dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed. RESULTS: The studies herein presented demonstrated that the levels and the activity of cAMP-dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore. these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP-dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP-dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders. CONCLUSIONS: Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.

Antidepressive Agents↗

PubMed2000

Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs.

Depression has been treated pharmacologically for over three decades, but the views regarding the mechanism of action of antidepressant drugs have registered recently a major change. It was increasingly appreciated that adaptive changes in postreceptor signaling pathways, rather than primary action of drugs on monoamine transporters, metabolic enzymes, and receptors, are connected to therapeutic effect. For some of the various signaling pathways affected by antidepressant treatment, it was shown that protein phosphorylation, which represents an obligate step for most pathways, is markedly affected by long-term treatment. Changes were reported to be induced in the function of protein kinase C, cyclic AMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase. For two of these kinases (cyclic AMP- and calcium/calmodulin-dependent), the changes have been studied in isolated neuronal compartments (microtubules and presynaptic terminals). Antidepressant treatment activates the two kinases and increases the endogenous phosphorylation of selected substrates (microtubule-associated protein 2 and synaptotagmin). These modifications may be partly responsible for the changes induced by antidepressants in neurotransmission. The changes in protein phosphorylation induced by long-term antidepressant treatment may contribute to explain the therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.

Animals↗

PubMed2000

Changes of synaptotagmin interaction with t-SNARE proteins in vitro after calcium/calmodulin-dependent phosphorylation.

The regulation of multiple phases of the life cycle of synaptic vesicles is carried out by a complex series of protein-protein interactions. According to the SNARE hypothesis the core of these interactions is a heterotrimeric complex formed by syntaxin, SNAP-25, and VAMP-synaptobrevin. Other proteins interacting with the core of the SNARE complex, such as voltage-activated calcium channels and synaptotagmin (a putative calcium sensor), are considered crucial for the calcium dependence of release and also molecular mediators of synaptic plasticity. Here the interaction of synaptotagmin with SNARE proteins was studied in immunoprecipitated native complexes, and the effects of previous phosphorylation-dephosphorylation on this interaction were analyzed. It is surprising that the interaction of synaptotagmin with syntaxin and SNAP-25 in native complexes was not found to be calcium-dependent. However, previous incubation under dephosphorylating conditions decreased the synaptotagmin-syntaxin interaction. Stimulation of Ca2+/calmodulin-dependent protein kinase II, which endogenously phosphorylates synaptotagmin in synaptic vesicles, increased the interaction of syntaxin and SNAP-25 with synaptotagmin (particularly when measured in the presence of calcium), as well as increasing the binding of the kinase itself. These results suggest that calcium decreases synaptotagmin-t-SNARE interactions after dephosphorylation and increases them after phosphorylation. Overall, these results imply a phosphorylation-dephosphorylation balance in regulation of the synaptotagmin-t-SNARE interaction and suggest a role for protein phosphorylation in the modulation of calcium sensitivity in transmitter release.

Animals↗

PubMed2000

Depression and sleep disorders: clinical relevance, economic burden and pharmacological treatment.

A wide range of studies have been published over the past two decades that involve the intersection of sleep EEG, insomnia, psychiatric illness (especially depressive disorders) and psychopharmacology. Much of value has been discovered, but there have also been false starts and contradictory results. There is in fact strong evidence that insomnia is associated with medical and psychiatric illness and that the sleepiness associated with insomnia is the cause of many accidents. Thus, the direct (visits to doctors, cost of sleeping medication, complications from use of these medications) and indirect (accidents, quality of life) costs of insomnia are enormous and constitute a major public health problem in the industrialized countries. Believing that it is now timely to assess the state of this important research area, a consensus conference was convened on June 26-28, 1998, in Porto Cervo (Italy) to attempt to clarify the important issues and findings on the clinical effect of the different classes of antidepressant drugs on sleep quality in depression. The participants' consensus on some of the main topics is presented with the hope that this discussion and analysis will contribute to productive research in this important field.

Antidepressive Agents↗

PubMed2000

Altered cAMP-dependent protein kinase A in platelets of patients with obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to assess cAMP-dependent protein kinase A in patients with obsessive-compulsive disorder (OCD). METHOD: The levels and the activity of protein kinase A were evaluated in whole platelets obtained from 12 unmedicated patients with OCD and 15 healthy comparison subjects. RESULTS: The immunolabeling of protein kinase A regulatory subunits type I and II were significantly greater but that of the catalytic subunit significantly lower in patients with OCD than in healthy subjects. The cAMP-stimulated activity in patients with OCD was significantly lower than that in healthy subjects. CONCLUSIONS: These data suggest a possible role of protein kinase A in the pathophysiology of OCD.

Actins↗

PubMed1999

Inhibitory effect of the neuroprotective agent idebenone on arachidonic acid metabolism in astrocytes.

Idebenone, a compound with protective efficacy against neurotoxicity both in in vitro and in in vivo models, exists in two different oxidative states: the ubiquinol-derivative (reduced idebenone) and the ubiquinone-derivative (oxidised idebenone). In the present study, we have observed that both the redox forms of idebenone have a dose-dependent inhibitory effect on the enzymatic metabolism of arachidonic acid in astroglial homogenates (IC50 reduced idebenone: 1.76 +/- 0.86 microM; IC50 oxidised idebenone: 16.65 +/- 3.48 microM), while in platelets, they are apparently less effective (IC50 reduced idebenone: 18.28 +/- 4.70 microM; IC50 oxidised idebenone: > 1 mM). We have also observed that the oxidised form preferentially inhibited cyclooxygenase vs. lipoxygenase metabolism (IC50 ratio lipoxygenase/cyclooxygenase: 3.22), while the reduced form did not discriminate between the two pathways (IC50 ratio lipoxygenase/cyclooxygenase: 1.38). In this respect, the inhibitory action of reduced idebenone resembled that of the antioxidant nordihydroguaiaretic acid, while oxidised idebenone behaved similarly as indomethacin and piroxicam--two typical anti-inflammatory agents. Our results suggest the existence of two distinct mechanisms of action for the two redox forms of idebenone and a preferential action of the drug on arachidonic acid metabolism in the central nervous system.

Animals↗

PubMed1999

Abnormalities of cyclic adenosine monophosphate signaling in platelets from untreated patients with bipolar disorder.

BACKGROUND: Abnormalities in the cyclic adenosine monophosphate (cAMP)-dependent phosphorylation system have been recently reported in patients with bipolar disorder. We evaluated the immunoreactivity of the regulatory and catalytic subunits of cAMP-dependent protein kinase (protein kinase A) and 1 of its substrates, Rap1, in platelets from untreated euthymic, manic, and depressed patients with bipolar disorder and healthy subjects. METHODS: Platelets were collected from 112 drug-free patients with bipolar disorder (52 euthymic, 29 depressed, and 31 manic) and 62 healthy subjects. The levels of cAMP-dependent protein kinase and Rap1 were assessed by Western blot analysis, immunostaining, and computer-assisted imaging. RESULTS: The immunolabeling of the catalytic subunit of cAMP-dependent protein kinase was significantly different among groups (P<.001), with higher values in untreated depressed and manic patients with bipolar disorder compared with untreated euthymic patients with bipolar disorder and healthy subjects. No significant differences were found in the immunolabeling of the regulatory subunits (type I and type II) of cAMP-dependent protein kinase. The immunolabeling of Rap1 was significantly higher (P<.001) in untreated euthymic, depressed, and manic patients than in healthy persons. CONCLUSIONS: Levels of Rap1 and the catalytic subunit of cAMP-dependent protein kinase are altered in the platelets of bipolar patients. These findings may provide clues toward understanding the involvement of cAMP signaling in the pathogenesis of bipolar disorder.

Adult↗