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Biomedical subjects

M Ferrucci

Publications and source records attributed to M Ferrucci.

At least 19 recordsLinked to original sources
PubMed2006

Abnormal involuntary movements (AIMs) following pulsatile dopaminergic stimulation: severe deterioration and morphological correlates following the loss of locus coeruleus neurons.

Parkinsonian patients are treated with dopamine replacement therapy (typically, intermittent administration of the dopamine precursor L-DOPA); however, this is associated with the onset of abnormal involuntary movements, which seriously impair the quality of life. The molecular mechanisms underlying abnormal involuntary movements represent an intense field of investigation in the area of neurobiology of disease, although their aetiology remains unclear. Apart from the fine cellular mechanisms, the pathways responsible for the generation of abnormal involuntary movements may involve changes in neurotransmitter systems. A potential candidate is noradrenaline, since a severe loss of this neurotransmitter characterizes Parkinson's disease, and noradrenergic drugs produce a symptomatic relief of L-DOPA-induced dyskinesia. In previous studies we found that pulsatile dopamine release, in the absence of the physiological noradrenaline innervation, produces motor alterations and ultrastructural changes within striatal neurons. In the present study we demonstrate that a unilateral damage to the noradrenaline system anticipates the onset and worsens the severity of L-DOPA-induced contralateral abnormal involuntary movements in hemi-parkinsonian rats. Similarly, ubiquitin-positive striatal ultrastructural changes occur in unilaterally dopamine-depleted, noradrenaline-deficient rats following chronic L-DOPA administration. This study confirms a significant impact of the noradrenergic system in the natural history of Parkinson's disease and extends its role to the behavioural and morphological effects taking place during pulsatile dopamine replacement therapy.

Adrenergic Uptake Inhibitors↗
PubMed2006

A hypothesis on prion disorders: are infectious, inherited, and sporadic causes so distinct?

Prion diseases include a group of either sporadic, inherited or infectious disorders characterized by spongiform neurodegeneration and reactive glyosis in several brain regions. Whatever the origin, the neuropathological hallmark of prion diseases is the presence of brain aggregates containing an altered isoform of a cellular protein, named prion protein. Recent findings show the potential toxicity of the normal cellular prion protein, which occurs when its physiological metabolism is altered. In particular, several studies demonstrate that accumulation of the prion protein in the cytosol can be a consequence of an increased amount of misfolded prion proteins, a derangement of the correct protein trafficking or a reduced activity of the ubiquitin-proteasome system. The same effects can be a consequence of a mutation in the gene coding for the prion protein. In all these conditions, one assists to accumulation and self-replication of insoluble prion proteins which leads to a severe disease resembling what observed following typical "prion infections". This article provides an opinion aimed at reconciling the classic Prusiner's theory concerning the "prion concepts" with the present knowledge arising from experimental studies on neurodegenerative disorders, suggesting a few overlapping steps in the pathogenesis of these diseases.

Brain↗
PubMed2005

Previous exposure to (+/-) 3,4-methylenedioxymethamphetamine produces long-lasting alteration in limbic brain excitability measured by electroencephalogram spectrum analysis, brain metabolism and seizure susceptibility.

Seizures represent the most common neurological emergency in ecstasy abusers; however, no study addressed whether (+/-) 3,4-methylenedioxymethamphetamine ("ecstasy") per se might produce long-lasting alterations in brain excitability related to a pro-convulsant effect. C57 Black mice were treated with three regimens of (+/-) 3,4-methylenedioxymethamphetamine (5mg/kg x 2 for 1, 2 or three consecutive days). Following the last dose of (+/-) 3,4-methylenedioxymethamphetamine, during a time interval of 8 weeks, the following procedures were carried out: 1) cortical electroencephalographic recordings, including power-spectrum analysis; 2) administration of sub-threshold doses of kainate; 3) measurement of regional [(14)C]2-deoxyglucose uptake; 4) monoamine assay. We demonstrate that all mice pre-treated with (+/-) 3,4-methylenedioxymethamphetamine showed long-lasting encephalographic changes with frequencies peaking at 3-4.5 Hz at the power-spectrum analysis. This is concomitant with latent brain hyperexcitability within selected limbic brain regions, as shown by seizure facilitation and long-lasting latent metabolic hyperactivity which can be unraveled by phasic glutamate stimulation. This study sheds new light into the brain targets of (+/-) 3,4-methylenedioxymethamphetamine and discloses the occurrence of (+/-) 3,4-methylenedioxymethamphetamine-induced latent hyperexcitability within limbic areas, while it might provide a model to study in controlled experimental conditions limbic seizures and status epilepticus in C57 Black mice. Persistent changes produced by (+/-) 3,4-methylenedioxymethamphetamine in limbic brain excitability might be responsible for seizures and limbic-related disorders in chronic (+/-) 3,4-methylenedioxymethamphetamine abusers.

Animals↗
PubMed2004

Similarities between methamphetamine toxicity and proteasome inhibition.

The monoamine neurotoxin methamphetamine (METH) is commonly used as an experimental model for Parkinson's disease (PD). In fact, METH-induced striatal dopamine (DA) loss is accompanied by damage to striatal nerve endings arising from the substantia nigra. On the other hand, PD is characterized by neuronal inclusions within nigral DA neurons. These inclusions contain alpha-synuclein, ubiquitin, and various components of a metabolic pathway named the ubiquitin-proteasome (UP) system, while mutation of genes coding for various components of the UP system is responsible for inherited forms of PD. In this presentation we demonstrate for the first time the occurrence of neuronal inclusions in vivo in the nigrostriatal system of the mouse following administration of METH. We analyzed, in vivo and in vitro, the shape and the fine structure of these neuronal bodies by using transmission electron microscopy. Immunocytochemical investigation showed that these METH-induced cytosolic inclusions stain for ubiquitin, alpha-synuclein, and UP-related molecules, thus sharing similar components with Lewy bodies occurring in PD, with an emphasis on enzymes belonging to the UP system. In line with this, blockade of this multicatalytic pathway by the selective inhibitor epoxomycin produced cell inclusions with similar features. Moreover, using a multifaceted pharmacological approach, we could demonstrate the need for endogenous DA in order to form neuronal inclusions.

Animals↗
PubMed2004

Effects of repeated low doses of MDMA on EEG activity and fluoro-jade B histochemistry.

The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine derivative that is widely abused. In previous studies, depending on the animal species, neurotoxicity has been demonstrated for either serotonin (5-HT) or/and dopamine (DA) nerve endings. These studies focused on the basal ganglia circuitry; however, in humans chronic abuse of MDMA often results in neurological symptoms that last after MDMA withdrawal and are not related to the extrapyramidal system such as electroencephalographic (EEG) abnormalities and cognitive impairment. These alterations might be due to the concomitant intake of other illicit compounds, the consequence of MDMA-induced hyperthermia, or to a primary neurotoxicity directed to extrastriatal regions. These observations call for a more in-depth analysis on the potential involvement of brain areas outside the basal ganglia in the toxic effects induced primarily by MDMA. In the present study, we treated C57Black mice chronically (25 days) with daily injections of MDMA (2.5 mg/kg). During treatments, mice were monitored in order to detect behavioral modifications, and epidural electrodes were installed to perform EEG recording. Behavioral data showed a sensitization as measured by locomotor activity, which related to progressive and long-lasting EEG changes and neuronal degeneration within the hippocampus.

Animals↗
PubMed2003

DNA damage and ubiquitinated neuronal inclusions in the substantia nigra and striatum of mice following MDMA (ecstasy).

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, which is neurotoxic to both serotonin (5HT) and dopamine (DA) nerve terminals. Previous reports, carried out in rodents and non-human primates, demonstrated neurotoxicity to monoamine axon terminals, although no study has analyzed nigral and striatal cell bodies at the sub-cellular level. OBJECTIVE: In this study, we examined intrinsic nigral and striatal cells, and PC12 cell cultures to evaluate whether, in mice, MDMA might affect nigral and striatal cell bodies. METHODS: After administering MDMA, we analyzed effects induced in vivo and in vitro using high-performance liquid chromatography (HPLC) analysis, light- and electron microscopy with immunocytochemistry, and DNA comet assay. RESULTS: We found that MDMA (5 mg/kg x4, 2 h apart), besides a decrease of nigrostriatal DA innervation and 5HT loss, produces neuronal inclusions within nigral and intrinsic striatal neurons consisting of multi-layer ubiquitin-positive whorls extending to the nucleus of the cell. These fine morphological changes are associated with clustering of heat shock protein (HSP)-70 in the nucleus, very close to chromatin filaments. In the same experimental conditions, we could detect oxidation of DNA bases followed by DNA damage. The nature of inclusions was further investigated using PC12 cell cultures. CONCLUSIONS: The present findings lead to re-consideration of the neurotoxic consequences of MDMA administration. In fact, occurrence of ubiquitin-positive neuronal inclusions and DNA damage both in nigral and striatal cells sheds new light into the fine alterations induced by MDMA, also suggesting the involvement of nuclear and cytoplasmic components of the ubiquitin-proteasome pathway in MDMA toxicity.

Animals↗
PubMed2003

Presence of beta-arrestin in cellular inclusions in metamphetamine-treated PC12 cells.

Cellular inclusions containing ubiquitin and alpha-synuclein were observed in PC12 cells treated with metamphetamine (MA). To study the possible involvement of beta-arrestin in inclusion formation, we treated PC12 cells with MA for different times and analyzed the ubiquitin proteosome pathway (UPP). We found that beta-arrestin is ubiquitinated in the MA-treated PC12 cell line. The involvement of beta-arrestin in UPP was further supported by electron microscopy and by confocal microscopy, which documented the presence of beta-arrestin in these Lewy body-like inclusions. Our experiments reveal an interesting and previously unappreciated connection between beta-arrestin and ubiquitination and suggest that beta-arrestin could be involved in the development of the inclusion bodies.

Animals↗
PubMed2003

Amphetamines induce ubiquitin-positive inclusions within striatal cells.

The present study explores whether effects induced by amphetamine derivatives on striatal GABA cells might be connected with effects on dopamine (DA) metabolism. Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were administered to C57Black mice following a dosage regimen in which various doses of both drugs were injected i.p. at 2-h intervals. Neuronal inclusions produced under these experimental conditions were examined under electron microscopy. Drugs reducing DA availability prevented inclusion formation; conversely we observed that increasing DA synthesis or impairing physiological DA degradation enhanced the number of inclusions. The present study indicates that the presence of extracellular striatal DA is essential for the production of subcellular alterations induced by amphetamine derivatives. This is in line with a recent hypothesis connecting striatal DA release with degeneration of striatal GABA neurons.

Adrenergic Uptake Inhibitors↗
PubMed2003

Recent knowledge on molecular components of Lewy bodies discloses future therapeutic strategies in Parkinson's disease.

Lewy bodies (LB) were first described by Lewy in 1912 [1] as neuronal pale eosinophilic inclusions which became a pathological hallmark of Parkinson s disease (PD). In his original study, Lewy defined these inclusions as pale eosinophilic cytoplasmic structures, and studies since then have revealed LB to be ubiquitin-, alpha-synuclein-, and parkin-containing inclusions. This suggests that knowledge of the biochemical steps involved in the genesis of LB might disclose a final common pathway which might be responsible for different types of inherited and sporadic parkinsonism. This would lead to the identification of new therapeutic targets for interfering with disease progression. Although LB were originally described solely in PD, in the last decade these inclusions were described in a spectrum of degenerative disorders ranging from pure movement disorders to dementia. This suggests that common biochemical alterations leading to the formation of intracellular inclusions might underlie various pathological conditions. Consequently, the knowledge of the biochemical steps involved in the formation of neuronal inclusions could represent a key to develop new therapeutic strategies. In recent years it has been possible to develop both in vitro and in vivo neuronal inclusions resembling Lewy bodies. These experimental approaches have ranged from the use of alpha-synuclein transgenic mice to the continuous exposure to a mitochondrial complex I inhibitor. The aim of the present paper is to review briefly, recent advances on Lewy body research to achieve new insight into the etiology of PD and the molecular events leading to neurodegeneration.

Animals↗
PubMed2003

Differential distribution of transforming growth factor-alpha immunohistochemistry within whole gastric mucosa in rats.

Transforming growth factor-alpha (TGF-alpha) plays an important role in both proliferation and differentiation of mucosal cells at the gastrointestinal level, including stomach, where it is constitutively produced. This study evaluated the immunohistochemical distribution of TGF-alpha within whole gastric mucosa in rats, through the examination of seriate sections. Each stomach was opened along the greater curvature, pinned upon a cork plate, fixed in formalin and cut in 2-mm parallel strips which were sequentially superimposed on a glass slide. Sections were immunostained for TGF-alpha and pictures were taken from three areas: greater and lesser curvature; mucosa lying between the two curvatures. The sections were graded on the basis of the intensity of TGF-alpha staining, which was scored as follows: 0) no staining; 1) weakly positive; 2) intensely positive. The percent number of immunopositive cells and a mean intensity were calculated. Gastric mucosa showed a marked immunopositivity to TGF-alpha, mainly in parietal cells whose cytoplasm displayed moderate to intense staining. Positive cells (and the mean intensity) of total mucosa were 15.7+/-6.1% (1.13+/-0.42). However, they were not uniformly distributed, being 26.3+/-1.9% (1.67+/-0.24) in the mucosa lying between the two curvatures, 12.4+/-2.5% (1.52+/-0.22) along the lesser curvature and 8.3+/-2.1% (0.31+/-0.17) along the greater curvature. These results show that parietal cells of rat gastric mucosa exhibit immunoreactivity to TGF-alpha. Considering the gastroprotective effects of this factor, its non-homogeneous distribution within different areas may be of importance in understanding the lesion pattern of gastric damage after the administration of noxious agents.

Animals↗
PubMed2002

Noradrenergic loss enhances MDMA toxicity and induces ubiquitin-positive striatal whorls.

Movement disorders involve a number of neurodegenerative conditions, mostly affecting basal ganglia. Parkinson's disease (PD) is classically defined by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Administration of specific neurotoxins represents a common tool to reproduce this lesion. Among these, amphetamine derivatives act as powerful monoamine neurotoxins, impairing striatal dopamine (DA) axons in mice. Despite the well-investigated effects on striatal DA terminals, only sporadic studies have focused on the potential toxicity of amphetamines towards post-synaptic neurons within the striatum. In the present work we found that 3,4-methylenedioxymethamphetamine (MDMA) produces ultrastructural alterations in striatal cells, featuring as membraneous whorls, positive for ubiquitin and heat shock protein 70. These morphological alterations were enhanced in locus coeruleus-lesioned mice.

Adrenergic Uptake Inhibitors↗
PubMed2002

Striatal postsynaptic ultrastructural alterations following methylenedioxymethamphetamine administration.

Amphetamine derivatives, such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), act as monoaminergic neurotoxins in the central nervous system. Although there are slight differences in their mechanism of action, these compounds share a final common pathway, which involves dopamine release and oxidative stress. Apart from striatal toxicity involving monoamine axons, no previous report evidenced any alteration at the striatal level concerning postsynaptic sites. Given the potential toxicity for extracellular dopamine at the striatal level, and the hypothesis for neurotoxic effects of dopamine on striatal medium-sized neurons in Huntington's disease, we evaluated at an ultrastructural level the effects of MDMA on intrinsic striatal neurons of the mouse. In this study, administering MDMA, we noted ultrastructural alterations of striatal postsynaptic GABAergic cells consisting of neuronal inclusions shaped as whorls of concentric membranes. These whorls stained for ubiquitin but not for synuclein and represent the first morphologic correlate of striatal postsynaptic effects induced by MDMA.

Animals↗
PubMed2001

Immunohistochemical evidence and ultrastructural compartmentalization of a new antioxidant enzyme in the rat substantia nigra.

We previously described in the rat the presence of dehydroascorbate reductase, an enzyme regenerating ascorbic acid, which is constantly lost during oxidative processes occurring at a fast rate within the central nervous system. In the present study, we specifically evaluate the occurrence of this enzyme in the rat substantia nigra by using immunohistochemistry, and by analyzing the neuronal compartmentalization of dehydroascorbate reductase within nigral neurons by immunoblotting and transmission electron microscopy coupled with immunocytochemistry. The enzyme occurs in various portions of the substantia nigra, but it is more abundant in the ventromedial part extending through the ventral tegmental area, and the dorsal portion, involving the pars compacta. Within nigral neurons, the cytosolic enzyme is present in a perinuclear position, close to mitochondria, and in the nuclear membrane; we also found the enzyme in nigral axons close to the myelin sheath. In addition, dehydroascorbate reductase was present in the nucleus of nigral neurons. The nuclear occurrence of the enzyme was confirmed by immunocytochemical labelling and immunoblotting of isolated nuclei. The nuclear enzyme was constantly evident as clusters of immunogold particles on chromatin. This localization suggests new roles for dehydroascorbate reductase (eg. prevention of DNA oxidative damage and regulation of gene transcription).

Animals↗
PubMed2000

Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment.

We recently identified the direct product of dopamine (DA) by monoamine-oxidase (MAO) activity, dihydroxyphenylacetaldehyde (DOPALD) in the trans-striatal dialysate. Based on these findings, in this work, we directly measured the variations in DOPALD levels after various kinds of pharmacological treatment in rat striatal extracellular fluid. Using both reversible and irreversible MAO inhibitors, we found that MAO-A inhibition suppressed, whereas MAO-B inhibition did not modify DOPALD levels in the dialysate. The vesicular DA uptake blocker Ro 4-1284 led to an increase in extracellular DA and DOPALD, whereas the increase in extracellular DA obtained after administration of the plasma membrane DA uptake blocker GBR-12909 occurred without concomitant changes in DOPALD extracellular levels. Microinfusions of DA through the dialysis probe or systemic administration of L-DOPA increased striatal DOPALD to a greater extent compared with other DA metabolites, both in intact and in 6-hydroxydopamine (6-OHDA)-lesioned striatum. This study indicates that the direct product of MAO activity within the rat striatum derives from the activity of the isoenzyme MAO-A. The assay of DOPALD, together with DOPAC, represents a reliable tool to measure directly, in freely moving animals, DA oxidative metabolism. As recent studies have shown that microinfusions of exogenous DOPALD might induce cell death, pharmacological modulation of DOPALD levels might also be relevant for an understanding of the mechanisms involved in DA neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Ultrastructural localization of calcium deposits in rat myocardium after loud noise exposure.

In previous studies we demonstrated that loud noise exposure induces ultrastructural alterations in the rat myocardium together with an increase in noradrenergic activity and in mitochondrial calcium influx. To verify the causal relationship between myocardial calcium entry and ultrastructural alterations induced by loud noise, in the present study we coupled routine electron microscopy with cytochemistry specifically dedicated to visualize calcium accumulation (revealed as antimonate deposits). We observed that the ultrastructural alterations occurring in both atrium and ventricle after 12 h of noise exposure, were densely packed with antimonate deposits. In particular, enlargements of the sarcoplasmic reticulum and dilution of the mitochondrial matrix, observed during routine electron microscopy, were markedly positive for calcium accumulation when observed by using antimonate. The present data strongly suggest that calcium entry results in accumulation of this ion at myocardial subcellular level. Moreover, the present results joined with previous evidence indicate that calcium accumulation is the final common pathway responsible for noise-induced myocardial morphological alterations.

Animals↗
PubMed1985

Antibodies to HTLV-III and the lymphadenopathy syndrome in multitransfused beta-thalassemia patients.

Antibodies to HTLV-III have been investigated in 118 multitransfused beta-thalassemia patients. Thirteen patients (11.01%) were found to be positive; 3 of these 13 showed clinical and immunological signs of the lymphadenopathy syndrome. A retrospective study carried out on 65 sera has shown that at least 6 patients were negative 3 years before the present investigation. This is the first extensive study on HTLV-III infection in multitransfused beta-thalassemics. It suggests that these patients are at risk for the acquired immune deficiency syndrome and related diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1980

[Serology of toxoplasmosis: review of tests currently in use for diagnosis and prevention].

Toxoplasma infection stimulates a very rich answer in circulating antibodies, which are easily detected by many serological tests. Many years elapsed since 1948, when Sabin and Feldmann [28] carried out for the first time a dye test which is, still at present, the chief reference test for the numerous techniques which have been subsequently available. The aim of the present review, which is largely based on personal experiences, is to draw some conclusions on the meaning and usefulness of these tests, and on the best way to express their results. Though a special attention has been allowed to techniques using a whole cellular antigen (dye test, immunofluorescence, direct agglutination test) some useful hints are also given on CF, IHA and ELISA, which employ an extractive antigen. A special stress is layed on the usefulness, or, rather, the need to express results, whenever possible, in IU (International Units), in order to attribute a standard comparable meaning to the tests.

Agglutination Tests↗