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Biomedical subjects

G Racagni

Publications and source records attributed to G Racagni.

At least 55 records · Page 3Linked to original sources
PubMed1999

Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine.

In the present paper we investigated, in the rat brain, the expression of basic fibroblast growth factor (FGF-2) in response to the atypical antipsychotic clozapine. We found that acute or chronic administration of this compound produced a selective increase of FGF-2 mRNA and protein in the striatum. Although acute injection of clozapine did increase FGF-2 expression in parietal cortex and nucleus accumbens we found that, following repeated administration, the induction of the trophic molecule was taking place only at striatal level. The analysis of other antipsychotic drugs did not provide conclusive evidence for the molecular mechanisms involved in clozapine-induced elevation of FGF-2. In fact, chronic administration of classical neuroleptics, haloperidol and chlorpromazine, did not alter the expression of FGF-2. Furthermore the novel drugs quetiapine and olanzapine, despite some similarities in their receptor profiles, were similarly ineffective. Hence these data suggest that, among antipsychotic drugs, the induction of FGF-2 is unique to clozapine. On the basis of the neuroprotective activity of this trophic molecule, our data might be relevant for the potential use of clozapine in tardive dyskinesia and parkinsonism, which develop during long term administration of classical neuroleptic drugs.

Animals↗
PubMed1999

Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate).

The interplay between dopamine and glutamate appears to be relevant in the etiopathology of schizophrenia. Although currently used antipsychotics do not interact with glutamatergic receptors, previous results have demonstrated that the expression profile of ionotropic glutamate receptors can be regulated by drugs such as haloperidol or clozapine. In the present investigation, the mRNA levels for NMDA and AMPA receptor subunits were measured after chronic treatment with the novel antipsychotic agent Seroquel (quetiapine fumarate, quetiapine) as compared to haloperidol and clozapine. Similarly to the prototype atypical clozapine, quetiapine reduced the mRNA expression for NR-1 and NR-2C, two NMDA forming subunits, in the nucleus accumbens. Furthermore, quetiapine, but not haloperidol or clozapine, increased the hippocampal expression for the AMPA subunits GluR-B and GluR-C. The differences between classical and atypical antipsychotics, as well as among the novel agents, might be relevant for specific aspects of their therapeutic activity and could provide valuable information for the role of glutamate in specific symptoms of schizophrenia.

Animals↗
PubMed1999

Treatment resistant depression: methodological overview and operational criteria.

A wide variety of definitions are used for Treatment Resistant Depression (TRD), considering various criteria and different concepts. Some of the key issues are: the diagnosis, the treatment adequacy in terms of dose and duration, the treatment response assessment and the number of failed therapeutic trials required. Systematic research has been characterizing the concept and criteria to define the different variables involved. Lack of consensus on these issues limits comparison across clinical trials and interpretation of treatment efficacy in the management of treatment resistant patients. Through reanalyzes of available data, we point out the limits of TRD definitions and propose conceptual and operational criteria for a collaborative research project on TRD. It appears that a number of variables commonly associated to treatment resistance are independent of patients characteristics and mainly refer to misdiagnosis and inadequate treatment. The proposed criteria are intended for therapeutic trials in TRD, combining the evaluation of treatment efficiency and the validation of the concept of TRD itself. Major depression with poor response to two adequate trials of different classes of antidepressants is proposed for an operational definition of TRD. Rationale for this definition is discussed in contrast to alternative definitions.

Antidepressive Agents↗
PubMed1999

Physiology to functionality: the brain and neurotransmitter activity.

The monoamine hypothesis of depression proposes that the biological basis for depression is a deficiency in the neurotransmitters serotonin or noradrenaline, or both. Over the past 30 years this hypothesis has been refined as more experimental and clinical evidence has emerged. The selective serotonin reuptake inhibitors in particular have made a significant contribution to our understanding of the role of serotonin in depression. Our knowledge of the noradrenergic system is less complete, mainly because, until recently, no equivalent agents were available for this system. With the advent of reboxetine, the first selective noradrenaline reuptake inhibitor, attention is again focusing on the role of noradrenaline in depression. To an extent, the action of the selective inhibitors can be predicted through knowledge of the neuroanatomy of the central and peripheral nervous systems. With regard to depression, the most important pathways are those of the serotonergic and noradrenergic neurones projecting to the prefrontal cortex, from the raphe nucleus and locus coeruleus, respectively. However, increasing the levels of the monoamines in the central nervous system affects many other pathways and a wide range of serotonin and adrenergic receptors, leading to a multiplicity of potential beneficial and adverse events. In addition, the complex intracellular responses are beginning to be examined, again with the aid of the selective antidepressants.

Animals↗
PubMed1998

Differential regulation of FGF-2 and FGFR-1 in rat cortical astrocytes by dexamethasone and isoproterenol.

We have used rat cortical astrocytes in culture to investigate the signaling pathways involved in the regulation of fibroblast growth factor-2 (FGF-2) and one of its high affinity receptor FGF receptor-1 (FGFR-1). These cells represent a source of different neurotrophic factors and play important roles in physiological and pathological conditions of the central nervous system. FGF-2 mRNA levels are increased by stimulation of beta-adrenergic receptors or exposure to glucocorticoid hormones and these effects are additive to each other. The regulation of FGFR-1, highly expressed in cultured astroglial cells, appears to be different. Isoproterenol produced an elevation of FGFR-1 mRNA levels, whereas dexamethasone decreased its expression alone or in the presence of isoproterenol, suggesting that the glucocorticoid pathway may predominate over the cAMP-induced up-regulation of the receptor. FGF-2 over-expression may produce different cellular responses depending on the concomitant regulation of its receptor and the cell phenotype where these changes do occur. These mechanisms can contribute to adaptive changes taking place in the CNS in different physiological and pathological situations.

Adrenergic beta-Agonists↗
PubMed1998

Modifications in brain cAMP- and calcium/calmodulin-dependent protein kinases induced by treatment with S-adenosylmethionine.

Several lines of evidence suggest that the mechanism of action of antidepressant drugs (AD) involves adaptive changes occurring in intraneuronal post-receptor signal transduction cascades. Protein phosphorylation has a key role in signal transduction and was previously found to be a target in the action of AD (5-HT and/or NA reuptake blockers). Several studies showed that cAMP- and type II Ca2+/calmodulin-dependent protein kinases (PKA and CaMKII) are markedly affected by typical AD in two different and complementary cellular districts, respectively microtubules (a somatodendritic compartment) and synaptic vesicles (a presynaptic terminal compartment). In order to investigate whether the effect on protein kinases may be involved in the therapeutic action of drugs it is interesting to compare the effect of atypical AD with that of typical drugs. In this study the effect of the atypical AD S-adenosylmethionine (SAMe) was tested. Repeated (12 days) SAMe treatment induced in cerebrocortical microtubules an increase in the binding of cAMP to the RII PKA regulatory subunit and an increase in the endogenous phosphorylation of microtubule-associated protein 2, an effect resembling that of typical AD. In synaptic terminals the treatment induced an increase in the activity of CaMKII and in the endogenous phosphorylation of vesicular substrates. However, this modification was found in the cerebral cortex rather than in the hippocampus, where typical AD affect CaMKII. In addition the synapsin I level was decreased in the hippocampus and increased in the cerebral cortex, an effect not detected with typical AD.

Animals↗
PubMed1998

Effects of lithium on cAMP-dependent protein kinase in rat brain.

We have investigated the effects of lithium treatment on cAMP-dependent protein kinase in discrete brain areas of rat by using photoaffinity labeling as well as western blotting. Lithium administered for 5 weeks resulted in a significant increase of the cAMP binding to the 52 kDa cAMP-receptor in the soluble, but not in the particulate, fractions of both hippocampus and frontal cortex. Moreover, immunoblotting experiments revealed that chronic lithium treatment significantly increased the immunoreactivity against the regulatory and the catalytic subunits of the cAMP-dependent protein kinase in the soluble fraction of both brain areas. In contrast, no appreciable effect was observed in the particulate fractions. Short-term lithium treatment induced a significant increase in the immunolabeling of the catalytic subunits in the soluble fraction of both areas; whereas, the regulatory subunits and the actin were unchanged. In the particulate fractions, short-term lithium treatment did not elicit any substantial modification. Taken together, the results of the present study add to the growing evidence indicating that components of the cAMP signalling could play a crucial role in the biochemical action of lithium.

Animals↗
PubMed1998

Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy.

These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two-day consensus conference held on July 29 and 30, 1995 in Siena, Italy. Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from shorter acting intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose. The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitalizations, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these medications. The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs. In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response (both therapeutic and adverse effects) and pharmacokinetic properties. In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the latter.

Antipsychotic Agents↗
PubMed1998

Different patterns of induction of FGF-2, FGF-1 and BDNF mRNAs during kindling epileptogenesis in the rat.

Neurotrophic factors (NTF) play important roles in the developing and in the adult brain. NTF involvement in neuronal plasticity is suggested by the modulation of NTF expression patterns in different physiological and pathological situations and by the effects they produce in the adult brain (e.g. axonal sprouting induction and neuroprotection). We used the RNAase protection assay to investigate the expression patterns of some NTFs during amygdala kindling, an animal model of epilepsy in which 'pathological' neuronal plasticity appears to occur. After a single kindling stimulation, fibroblast growth factor-2 (FGF-2) mRNA levels were increased in the hippocampus, the cortex and the hypothalamus, whereas they were not significantly altered in the thalamus and the striatum. A single stimulation did not alter fibroblast growth factor-1 (FGF-1) and brain-derived neurotrophic factor (BDNF) gene expression. Fully kindled animals, left unstimulated for a week, did not exhibit any alteration in the mRNA levels for any of the NTFs examined. However, in contrast with the effect of a single stimulation, amygdala stimulation of kindled animals (evoking a generalized tonic-clonic seizure) produced a great increase in hippocampal and cortical BDNF mRNA levels, but FGF-1 mRNA levels were not altered, and FGF-2 mRNA levels were significantly increased only in the cortex. These results suggest that different NTFs can be recruited at different stages of kindling epileptogenesis and, accordingly, may play different parts in the adaptive changes taking place in this experimental paradigm.

Amygdala↗
PubMed1998

Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors.

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the numerous substances that originate from tobacco smoke, nicotine is by far the most widely studied. Nicotine is a natural alkaloid that has considerable stimulatory effects on the CNS. Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChRs, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)-nicotine in two animal models of parkinsonism: diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice and methamphetamine-induced neurotoxicity in rats and mice. The neuroprotective effect of (-)-nicotine was very similar to that of the noncompetitive NMDA receptor antagonist (+)-MK-801. In parallel experiments, we found that (-)-nicotine induces the basic fibroblast growth factor-2 (FGF-2) and the brain-derived neurotrophic factor in rat striatum. The effect of (-)-nicotine on the induction of FGF-2 was prevented by the nAChR antagonist mecamylamine. We also found that (+)-MK-801 was able to induce FGF-2 in the striatum. As trophic factors have been reported to be neuroprotective for dopaminergic cells, our data suggest that the increase in neurotrophic factors is a possible mechanism by which (-)-nicotine protects from experimental parkinsonisms.

Animals↗
PubMed1997

Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs.

Based on anatomical and biochemical observations a role of glutamate in schizophrenia has been postulated. In the present work we have investigated the gene expression for two families of NMDA receptor subunits (NR-1 and NR-2) following acute and chronic treatment with typical (haloperidol) and atypical (clozapine) antipsychotic drug (APD) in rats. A single injection of the two drugs elicited a significant increase in the mRNA levels of NR-2B in the nucleus accumbens, whereas only haloperidol was able to elevate NR-2A and NR-2B in the hippocampus. Following a 21 day treatment, significant differences in the regulatory pattern of NMDA-R subunits were observed. Haloperidol increased their mRNA levels in striatum whereas clozapine, consistent with its relatively weaker influence on nigro-striatal dopamine function, did not change the expression of NR subunits in this region. Both APD's were able to decrease the expression of NR-2 subunits in the hypothalamus, but only clozapine was capable of reducing NR-2C in frontal cortex and accumbens. The regulation of NMDA-R subunits in specific brain regions may represent a novel and important mechanism through which APD's exert some of their effects on brain function.

Animals↗
PubMed1997

Changes in nitric oxide metabolite levels in stimulated substantia nigra neurons.

Simultaneous quantification of the two major nitric oxide (NO) metabolites, nitrite and nitrate, was performed on mouse mesencephalic neurons in vitro, in basal conditions or after excitatory stimuli. Measurements were made using both extracellular medium and cytosolic extracts. Basal metabolite levels were stable up to 5 min. Depolarization by high levels of potassium promptly increased extracellular nitrite (270% of basal, peak at 10s) leaving intracellular levels unchanged. Glutamate receptor agonists caused a rapid increase in intracellular, but not extracellular, nitrite levels (240% of basal, peak at 30s). Intracellular nitrate levels raised slowly after addition of potassium (215% of basal at 1 min) or N-methyl-D-aspartate (230% of basal at 5 min), but not after quisqualate. The different dynamic variations of the two NO metabolites point to the specificity of the activated metabolism according to the type of excitatory stimulus.

Animals↗
PubMed1997

L-deprenyl potentiates cAMP-induced elevation of FGF-2 mRNA levels in rat cortical astrocytes.

The expression of fibroblast growth factor-2 (FGF-2, basic FGF) is up-regulated in astroglial cells by different stimuli, including glucocorticoid hormones and agents that cause an increase in cyclic AMP (cAMP) levels. In the present study we showed that L-deprenyl, a drug able to rescue neurons from potentially lethal damage, can potentiate FGF-2 induction by 8Br-cAMP in cultured astrocytes. This effect appears to be independent from its well known inhibitory activity on monoamine oxidase (MAO) type B. As astrocyte activation is an important step in response to neuronal injury, our data suggest that potentiation of neurotrophic factor expression may exert neuroprotection and therefore limit the progression of neuronal damage in several pathological situations.

Animals↗
PubMed1997

Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism.

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (-)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (-)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects.

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated 32P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder.

Adult↗
PubMed1997

Ca2+/phospholipid-binding and syntaxin-binding of native synaptotagmin I.

Synaptotagmin, a synaptic vesicle protein endowed with multiple properties, is the putative calcium sensor in neuroexocytosis. Ca2+/phospholipid binding and syntaxin binding activity of synaptotagmin were previously investigated using recombinant fusion proteins. In phospholipid binding the EC50 for calcium obtained was different when fusion proteins containing one (C2A) or both (C2A+C2B) binding domains were used. It was alternatively proposed that one or both synaptotagmin binding domains are important for calcium-sensing and triggering of transmitter release. In this study the binding activity of native full-length synaptotagmin, immobilized on beads, was investigated. We found the kinetic parameters of Ca2+/phospholipid binding to be compatible with the role of calcium sensor for synaptotagmin (EC50 for calcium = 72 +/- 7 microM), with the two C2 domains supporting separate and complementary calcium sensing properties. The binding of native syntaxin to synaptotagmin was measurable in the absence of calcium, but was markedly stimulated (2.2-fold) in the presence of mM calcium. It may be speculated that the two domains have a synergistic action in fast synchronous transmitter release, whereas C2B domain alone may support slow asynchronous release, working as a high affinity calcium sensor.

Animals↗
PubMed1997

Neuronal and glial glutamate transporters possess an SH-based redox regulatory mechanism.

Glutamate uptake into nerve cells and astrocytes via high-affinity transporters controls the extracellular glutamate concentration in the brain, with major implications for physiological excitatory neurotransmission and the prevention of excitotoxicity. We report here that three recently cloned rat glutamate transporter subtypes, viz. EAAC1 (neuronal), GLT1 and GLAST (glial), possess a redox-sensing property, undergoing opposite functional changes in response to oxidation or reduction of reactive sulphydryls present in their structure. In particular, thiol oxidation with 5,5'-dithio-bis(2-nitrobenzoic) acid (DTNB) and disulphide reduction with dithiothreitol (DTT) result, respectively, in reduced and increased uptake capacity by a preparation of partially purified brain transporters as well as by the three recombinant proteins reconstituted into liposomes. In this model system, EAAC1, GLT1 and GLAST react similarly to DTT/DTNB exposures despite their different contents of cysteines, suggesting that only the conserved residues might be involved in redox modulation. Redox sensitivity is a property of the glutamate transporters also when present in their native cell environment. Thus, by using cultured cortical astrocytes and the whole-cell patch-clamp technique we were able to observe dynamic increase and decrease of the glutamate uptake current in response to application of DTT and DTNB in sequence. Moreover, in the same paradigm, DDT-reversible current inhibition was observed with hydrogen peroxide instead of DTNB, indicating that the SH-based redox modulatory site is targeted by endogenous oxidants and might constitute an important physiological or pathophysiological regulatory mechanism of glutamate uptake in vivo.

ATP-Binding Cassette Transporters↗