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Biomedical subjects

F Angelucci

Publications and source records attributed to F Angelucci.

At least 19 recordsLinked to original sources
PubMed2005

BDNF in schizophrenia, depression and corresponding animal models.

Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.

Animals↗
PubMed2005

Clinical characteristics, course and prognosis of spinal multiple sclerosis.

STUDY DESIGN: Retrospective examination. OBJECTIVE: To define the clinical characteristics and response to therapy of spinal multiple sclerosis (MS). SETTING: Italy. METHODS: Retrospective review was performed on 563 patients with clinical definite MS. Selection criteria were two or more spinal cord lesions in the presence of normal magnetic resonance imaging of the brain. RESULTS: Spinal MS was diagnosed in 13 patients (2.3%) out of 563 with clinical definite MS. There were seven female and six male patients; nine had a relapsing-remitting (RR) and four, a primary progressive (PP) course. All patients were treated with immunosoppressive or immunomodulatory therapy. Mean disease duration in patients with RR-MS was 13.1+/-10.1 years with a mean age at onset of 29.5+/-14.3 years; the mean Expanded Disability Status Scale (EDSS) at the time of the study was 3.5+/-2.5 with a progression index of 0.28. Mean disease duration in patients with PP course was 7+/-6.2 years with a mean age at onset of 56.7+/-10.4 years; the mean EDSS at the time of the study was 6.2+/-2.0 with a progression index of 1.48. CONCLUSIONS: Patients with spinal RR-MS are characterised by an early disease onset with minimal or moderate disability progression; patients with spinal PP-MS show a late disease onset and more rapid disability progression. In our series of spinal MS patients, disability progression seems to be mainly due to the disease course and age at onset rather than to the site of lesion.

Adolescent↗
PubMed2005

Neurotrophic factors and clinical recovery in relapsing-remitting multiple sclerosis.

Pathogenic autoimmune cells are demonstrated to be able to produce neurotrophic factors during acute phase of multiple sclerosis (MS). In this study, we determined the production of various neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4)] and some pro-inflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] by unstimulated peripheral blood mononuclear cells (PBMC) in 21 relapsing-remitting MS patients during different phases of disease (stable, relapse and post-relapse). During acute phase of disease, we detected a considerable increase of BDNF, TNF-alpha and IFN-gamma production, while significantly higher levels of GDNF, NGF, NT3 and NT4 were found in post-relapse phase. When neurotrophin production was correlated with clinical outcome (complete or partial recovery from new symptoms), we found a significantly higher BDNF production in relapse phase followed by increased GDNF, NGF, NT3 and NT4 levels during post-relapse phase in subjects with complete remission only. During relapse phase, we detected a significant increase of pro-inflammatory cytokines, that was more evident in patients with partial recovery. The neuroprotective potential of immune cells seems to be inversely correlated with disease duration and with the age of patients.

Adult↗
PubMed2003

Identification of the bioactive peptide PEC-60 in brain.

PEC-60 is a 60-residue peptide originally isolated from pig intestine. It inhibits glucose-induced insulin secretion from perfused pancreas in a hormonal manner and also has biological activity in the immune system. PEC-60-like immunoreactive material has been reported in catecholamine neurons of the central and peripheral nervous systems, but the peptide has not been identified from that material. We have now isolated PEC-60 from pig and rat brains with a method that combines column purification procedures with the specificity of a radioimmunoassay and the sensitivity of mass spectrometry to directly identify the peptide. The results show that PEC-60, like many other peptides, is expressed in the gastrointestinal tract and the central nervous system. The specific regional brain distribution and interaction with classical neurotransmitters raise the possibility that PEC-60 may play a role in the central nervous system disorders involving dopamine dysregulation.

Animals↗
PubMed2001

NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome.

While multiple growth factor, cytokines, and immune cells are identified in atherosclerotic lesions, as well as an essential nonneuronal function of neurotrophins implicated in cardiovascular tissue development and in lipid and glucose metabolism, the role of the neurotrophins NGF and BDNF and also the adipokine leptin in human coronary atherosclerosis and related disorders, such as metabolic syndrome, remains unclear. Here we report that (i) both the amount and the immunoreactivity of NGF was reduced and the expression of p75NGF receptor and the number of mast cell increased in human atherosclerotic coronary arteries (n = 12) compared with control specimens (n = 9) obtained from autopsy cases, and (ii) NGF and BDNF plasma levels were reduced in patients with metabolic syndrome (n = 23) compared with control subjects (n = 10). Also, in metabolic syndrome patients, a positive correlation between the plasma leptin levels and the number of adipose tissue mast cells was found, suggesting that leptin may be a novel adipoimmune mediator. Altogether, the results provide the first correlative evidence for the potential involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders.

Brain-Derived Neurotrophic Factor↗
PubMed2000

Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration.

The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders.

Animals↗
PubMed2000

Mapping the differences in the brain concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression.

Antidepressant drugs as well as electroconvulsive stimuli can significantly influence brain concentrations of neurotrophic factors. However, it is not known whether the baseline brain concentrations of neurotrophic factors are altered in human subjects suffering from affective disorders or whether there are sex differences in concentrations of neurotrophins in human brain. In order to elucidate some of these questions, we measured by ELISA brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL). Altered BDNF and NGF concentrations were found in frontal cortex, occipital cortex, and hypothalamus of depressed FSL compared to FRL control rats. Furthermore, different levels of these neurotrophins were also found in the male and female brain. Cumulatively these observations suggest that BDNF and NGF may play a role in depression and, hypothetically, different brain regional concentrations of BDNF and NGF in male and female animals may be relevant to gender differences in vulnerability to depression.

Animals↗
PubMed2000

Polymer-bound camptothecin: initial biodistribution and antitumour activity studies.

Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0. 4% free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were approximately 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v. injection of [3H]CPT-conjugate and free [3H]CPT. Radioactivity uptake in tumour was evident only after [3H]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug.

Animals↗
PubMed2000

Learning performances, brain NGF distribution and NPY levels in transgenic mice expressing TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in a variety of neurobiological activities including changing behavior and regulation of both neurotrophin and neuropeptide levels. In this study we used two lines of transgenic mice overexpressing brain TNF-alpha characterized by neurological deficits (line Tg6074) or phenotypically normal (line TgK3). We analyzed whether or not impairments in learning and memory processes due to TNF-alpha overexpression were associated with changes in endogenous brain NGF, NPY and beta-amyloid. The results indicate that full TNF-alpha transgene expression disrupted the learning capabilities of transgenic mice (both Tg6074 and TgK3). NGF decreased in the hippocampus of both transgenic mice whereas hippocampal NPY slightly potentiated in Tg6074. The decrease in NGF is correlated with deficits in spatial learning and memory whereas inflammation in the brain of Tg6074 could be responsible of the hippocampal increase in NPY. As a whole, these results show that transgenic mice overexpressing TNF-alpha in the brain represent a useful model for studying neuronal degeneration and brain inflammatory processes.

Amyloid beta-Peptides↗
PubMed2000

Data and hypotheses on the role of nerve growth factor and other neurotrophins in psychiatric disorders.

Nerve growth factor (NGF) was discovered and characterized for its role on the growth, differentiation and maintenance of specific neurons of the peripheral nervous system. Subsequent studies revealed that NGF is synthesized and released within the central nervous system and exerts a trophic and functional role on basal forebrain cholinergic neurons; it is involved in a protective role following brain insults induced by an epileptic status, seizure, as well as surgical and chemical lesions.More recently our collaborative studies provided evidence that NGF is implicated in neurobehavioral response including cerebral alterations associated with psychiatric disorders. In this brief review, ongoing and emerging data are presented and discussed.

Animals↗
PubMed2000

Studies in animal models and humans suggesting a role of nerve growth factor in schizophrenia-like disorders.

Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are known to play a crucial role in growth, differentiation and function in a variety of brain neurons during development and in adult life. We have recently shown that environmental changes, aggressive behavior and anxiety-like responses alter both circulating and brain basal NGF levels. In the present review, we present data obtained using animal models which suggest that neurotrophic factors, particularly NGF and BDNF, might be implicated in mechanism(s) leading to a condition associated with schizophrenic-like behaviors. The hypothesis that neurotrophins of the NGF family can be implicated in some maldevelopmental aspects of schizophrenia is supported by findings indicating that the constitutive levels of NGF and BDNF are affected in schizophrenic patients.

Aggression↗
PubMed1999

Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits.

It has been hypothesized that a deleterious key contribution to schizophrenia (SZ) development is a failure of migration and setting of young neurons into their appropriate cortical target sites, particularly in the entorhinal cortex (EC). To test this hypothesis in an animal model, we injected, in pregnant rats, on gestational day (GD) 9, or 10, or 11, or 12, the antimitotic compound methylazoxymethanolacetate (MAM) known to cause EC neuronal loss. We investigated whether or not EC disruption during prenatal development is able to affect behavior, including memory and learning, and brain nerve growth factor (NGF). Prenatally MAM treated young rats didn't display gross behavioral changes in social interaction, open-field and novel object investigation tests. By contrast, GD11 and GD12 MAM treated rats had a retardation in passive avoidance acquisition, while, in GD12 animals, pain sensitivity was reduced. GD12 animals also showed increased NGF in the EC and remaining cortex. MAM treated animals showed no changes in paw NGF or substance P levels suggesting that the altered nociceptive response is not related to local downregulation of these two molecules. The possibility that these behavioral and biochemical alterations might be associated with the onset of SZ is discussed.

Analysis of Variance↗
PubMed1999

Song behavior, NGF level and NPY distribution in the brain of adult male zebra finches.

The aim of the present study was to investigate the role of nerve growth factor (NGF) and neuropeptide Y (NPY) in the higher vocal center (HVC) on singing behavior of adult male zebra finches. The results of our studies show: (a) that NGF is present in the brain of these birds and it is higher in the HVC than in the other neostriatal tissues; (b) that exogenous administration of NGF or NGF-antibody had no discernible effect on singing behavior; and (c) that NGF enhances the NPY immunoreactivity in neurons and fibers localized in HVC and other areas of the neostriatum and hippocampus whereas anti-NGF decreased NPY stained cells in the hippocampus. These studies indicate that NGF is produced in the brain of zebra finch and that it plays a role in the regulation of NPY.

Animals↗
PubMed1999

Ring-B modified anthracyclines.

One of the most investigated classes of antitumor drugs is represented by anthracyclines. Over thirty years since the original discovery of daunorubicin and doxorubicin thousands of anthracycline analogues have been synthesized and tested to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. Previous structure-activity studies had shown that minor modifications of the anthracycline structure can result not only in active agents, but, more importantly, analogues with reduced cardiotoxicity and activity on multi drug resistance. The fact that 4-demethoxydaunorubicin showed higher potency than daunorubicin and a reduced cardiotoxicity, prompted us to explore novel analogues with altered substitution patterns on the anthraquinone system, particularly ring-B. In this review we will describe total synthesis and antitumor activity of three classes of derivatives: whereby one hydroxyl group in ring-B was either removed or replaced with nitro or amino groups. While these modifications yielded anthracyclines with a promising pharmacological activity, they did not modify activity on multidrug resistant (MDR) tumors. On the other hand, introduction of morpholino group in the sugar part of these new molecules, dramatically increased activity on MDR tumors. We conclude that activity on MDR tumors is not bound to modifications in the aglycone moiety of anthracyclines.

Animals↗
PubMed1998

Exploratory and displacement behavior in transgenic mice expressing high levels of brain TNF-alpha.

Studies reported recently have shown that tumor necrosis factor-alpha (TNF-alpha) a cytokine released by macrophages and monocytes plays a key role in inflammatory processes and immune and neuro-endocrine regulation. TNF-alpha is also produced in the central nervous system (CNS). However, the role of this cytokine in the CNS is largely unknown, although evidence indicates that it is involved in various neurobehavioral manifestations. Using transgenic mice expressing high amounts of murine TNF-alpha transgene in the neurons of the CNS, we investigated the stereotyped, exploratory, and displacement activities in the hole-board and black/white box. Transgenic mice and their normal control littermates were hybrids of the CBA x C57BL/6 genetic backgrounds and were obtained by backcrossing the CBA x C57BL/6 founder female and her progeny with F1 hybrid mates. Transgenic mice did not show changes in the stereotyped behavior on the hole-board, but they displayed several alterations in the exploratory activities both in the hole-board and black/white box. Transgenic mice also exhibited an increase in grooming when exposed to a highly unfamiliar environmental stimuli in the black/white box. The study suggests that supranormal endogenous TNF-alpha in the brain affects the behavioral responses to stressful conditions.

Animals↗
PubMed1997

Role of TNF-alpha but not NGF in murine hyperalgesia induced by parasitic infection.

Using adult mice infected with the trematode Schistosoma mansoni, we observed that this infection induces both thermal hyperalgesia and an increase in the levels of nerve growth factor in the paws. To explore the mechanism involved in peripheral hypersensitivity during chronic infection, mice were infected with 60 cercariae of S. mansoni and injected 17 weeks later with nerve growth factor, anti-nerve growth factor or with other molecules known to be associated with hyperalgesic processes. The results of these studies showed that antibodies against tumor necrosis factor-alpha, but not against nerve growth factor, reduce thermal sensitivity in schistosome infected mice, suggesting that this cytokine but not NGF plays a crucial role in schistosome-induced thermal hyperalgesia. Treatments with anti-inflammatory drugs support this hypothesis.

Animals↗
PubMed1997

Haloperidol administration in humans lowers plasma nerve growth factor level: evidence that sedation induces opposite effects to arousal.

Studies reported in recent years have indicated that the level of nerve growth factor (NGF), in both the brain and in the bloodstream, increases following stressful events and anxiety-associated behaviour. These observations prompted us to investigate whether an anti-arousal drug would induce an opposite effect. We have reported that the administration of haloperidol (HA), a neuroleptic drug clinically used for psychiatric disorders, decreases NGF levels in the hypothalamus of adult male mice. In the present study, we showed that HA reduced the basal NGF plasma levels in 8 neuroleptic-free schizophrenic patients. These observations strengthen the hypothesis that NGF may play a functional role in stress-coping responses.

Adolescent↗