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1.
Arq Bras Cardiol ; 75(6): 471-80, 2000 Dec.
Article in English, Portuguese | MEDLINE | ID: mdl-11175472

ABSTRACT

OBJECTIVE: To assess the relation between coronary artery disease and the calcification index on helical computed tomography. METHOD: We studied 22 patients (ages ranging from 40 to 70 years) who underwent coronary angiography because of chest pain suggestive of angina pectoris. Findings on coronary angiography were classified as follows: significant obstructive disease (stenosis > or = 50 %), nonobstructive disease (stenosis <50 %), and no disease. With no previous knowledge of the results of the coronary angiography and within 7 days, helical computed tomography of the chest was performed. Then, data of the coronary angiography were correlated with the calcification index obtained by helical computed tomography. RESULTS: The sensitivity of helical computed tomography to the presence of significant obstructive lesions on coronary angiography was 87.5 %, specificity was 100 %, and negative and positive predictive values were 75 % and 100 %, respectively. The mean calcification index was greater in patients with severe coronary lesions, mainly when involvement of 2 or 3 vessels occurred, than that in patients with no coronary artery disease or with nonobstructive coronary artery lesions (p<0.05). CONCLUSION: Helical computed tomography is an effective method for detecting and quantifying coronary artery calcification, and it has proved to be sensitive to and specific for the noninvasive diagnosis of coronary artery stenosis.


Subject(s)
Calcinosis/diagnostic imaging , Coronary Angiography/methods , Coronary Disease/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Sensitivity and Specificity
3.
FASEB J ; 10(8): 891-6, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8666166

ABSTRACT

In this study, we injected 10 mg/kg kainate i.p. into rats. This resulted in a brain injury, which we quantified in the hippocampus, the amygdala, and the pyriform cortex. Neuronal damage was preceded by a set of typical behavioral signs and by biochemical changes (noradrenaline decrease and 5-hydroxyindoleacetic acid increase) in the affected brain areas. Melatonin (2.5 mg/kg) was injected i.p. four times: 20 min before kainate, immediately after, and 1 and 2 h after the kainate. The cumulative dose of 10 mg/kg melatonin prevented kainate-induced neuronal death as well as behavioral and biochemical disturbances. A possible mechanism of melatonin-provided neuroprotection lies in its antioxidant action. Our results suggest that melatonin holds potential for the treatment of pathologies such as epilepsy-associated brain damage, stroke, and brain trauma.


Subject(s)
Antioxidants/pharmacology , Brain/drug effects , Kainic Acid/pharmacology , Melatonin/pharmacology , Animals , Behavior, Animal/drug effects , Brain/metabolism , Brain/pathology , Kainic Acid/antagonists & inhibitors , Male , Rats , Rats, Wistar
4.
J Cell Biol ; 132(1-2): 167-79, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8567721

ABSTRACT

VAMP/synaptobrevin is part of the synaptic vesicle docking and fusion complex and plays a central role in neuroexocytosis. Two VAMP (vesicle-associated membrane protein) isoforms are expressed in the nervous system and are differently distributed among the specialized parts of the tissue. Here, VAMP-1 and -2 are shown to be present in all rat tissues tested, including kidney, adrenal gland, liver, pancreas, thyroid, heart, and smooth muscle. The two isoforms are differentially expressed in various tissues and their level may depend on differentiation. VAMP-1 is restricted to exocrine pancreas and to kidney tubular cells, whereas VAMP-2 is the predominant isoform present in Langerhans islets and in glomerular cells. Both isoforms show a patchy vesicular intracellular distribution in confocal microscopy. The present results provide evidence for the importance of neuronal VAMP proteins in the physiology of all cells.


Subject(s)
Membrane Proteins/biosynthesis , Animals , Blotting, Northern , Blotting, Western , Cell Compartmentation , Fluorescent Antibody Technique , Gene Expression , In Situ Hybridization , Male , Membrane Proteins/genetics , Membrane Proteins/isolation & purification , R-SNARE Proteins , RNA, Messenger/isolation & purification , Rats , Rats, Wistar , Tissue Distribution
5.
Exp Neurol ; 125(2): 278-85, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8313942

ABSTRACT

The efficacy of monosialoganglioside GM1 treatment was evaluated in a model of experimental stroke. Cerebral ischemia was induced by permanent occlusion of left middle cerebral artery. GM1 was administered intravenously soon after the occlusion of the artery and then intramuscularly daily for 7 days. Results indicate that GM1 can reduce the extent of infarct volume and neurochemical deficits associated with the ischemic event. The protection was more evident in the cortex than in the caudate-putamen. These observations confirm and extend the evidence of the GM1 efficacy in experimental models of stroke and further support the usefulness of gangliosides in the treatment of these pathologies.


Subject(s)
Brain Ischemia/drug therapy , Cerebral Infarction/drug therapy , G(M1) Ganglioside/therapeutic use , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Brain Edema/drug therapy , Brain Edema/etiology , Brain Ischemia/complications , Brain Ischemia/metabolism , Brain Ischemia/pathology , Caudate Nucleus/pathology , Cerebral Infarction/metabolism , Cerebral Infarction/pathology , Choline O-Acetyltransferase/metabolism , Dopamine/metabolism , Isoquinolines/metabolism , Male , Putamen/pathology , Rats , Rats, Sprague-Dawley
6.
Neurochem Int ; 24(1): 57-65, 1994 Jan.
Article in English | MEDLINE | ID: mdl-8130736

ABSTRACT

The repeated intracerebroventricular administration of nerve growth factor (5 micrograms/2.5 microliters) to neonatal rats induced the activation of choline acetyltransferase in forebrain cholinergic neurons that was paralleled by a concomitant change in the density of muscarinic cholinergic receptors in the cerebral cortex. The administration of nerve growth factor altered muscarinic binding sites in a biphasic fashion during postnatal development. A significant stimulation of the developmental increase in the density of muscarinic binding sites occurred in nerve growth factor-treated animals at days 2 and 3 after birth. Conversely, nerve growth factor induced a significant decrease in the receptor number at postnatal days 8 and 14. Muscarinic receptor number returned to control values after treatment, suggesting that nerve growth factor-induced changes to muscarinic cholinergic receptors are reversible. Nerve growth factor administration did not affect muscarinic cholinergic receptor density in striatal membranes and did not alter the relative content of cortical messenger RNAs encoding m1 and m3 muscarinic cholinergic receptor subtypes at postnatal day 14, as determined by reverse transcriptase-polymerase chain reaction. The up- and down-regulation of muscarinic cholinergic receptors induced by nerve growth factor during postnatal development may be temporally related events associated with concomitant changes in the activity of choline acetyltransferase.


Subject(s)
Animals, Newborn/metabolism , Cerebral Cortex/metabolism , Nerve Growth Factors/pharmacology , Receptors, Muscarinic/metabolism , Animals , Choline O-Acetyltransferase/metabolism , Enzyme Activation , Female , Injections, Intraventricular , Male , Mice , Nerve Growth Factors/administration & dosage , Polymerase Chain Reaction , Quinuclidinyl Benzilate/metabolism , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Receptors, Muscarinic/genetics , Tritium
7.
Ann N Y Acad Sci ; 695: 314-7, 1993 Sep 24.
Article in English | MEDLINE | ID: mdl-8239303

ABSTRACT

A large body of experimental data suggests that neurotrophic molecules and/or substances that facilitate their action could be pharmaceutical agents for neurodegenerative pathologies. In particular, it has been demonstrated that nerve growth factor (NGF) exerts a physiological role for forebrain cholinergic neurons, while brain-derived neurotrophic factor (BDNF) seems to play a relevant role in rescuing dopaminergic neurons following damage. In addition, gangliosides are reported to potentiate neurotrophic factor effects in vitro as well as in vivo. In this study we examined the effects of the monosialoganglioside GM1 in different experimental models. The responsiveness of forebrain cholinergic neurons following NGF +/- GM1 was evaluated by assessing choline acetyltransferase (ChAT) activity in hippocampus, septal area and striatum of behaviorally impaired 24-month-old rats. NGF was intracerebroventricularly (i.c.v.) infused for 2 weeks while GM1 was given systemically for 3 weeks, starting from the beginning of NGF infusion. Moreover, the possible protective effects of GM1 were assessed following exposure of cultured cerebellar granule cells and dopaminergic mesencephalic neurons to different doses of 6-OH-DOPA, a metabolite of the dopamine pathway which has excitotoxic properties and has been hypothesized to participate in the pathology of Parkinson's disease. GM1 treatment to aged rats was seen to potentiate the NGF-induced increase of ChAT activity in the striatum ipsilateral to the NGF infusion. Moreover, in the striatum contralateral to the NGF infusion, GM1 increased ChAT activity above the control values, whereas NGF treatment alone did not affect enzymatic activity. GM1 treatment of cerebellar granule cells and mesencephalic neurons counteracted the dose- and time-dependent neurotoxicity of 6-OH-DOPA. These data support the notion that GM1 might prove useful in treating those pathological conditions where trophic factor deficits and/or excitotoxin-related toxicity play an important role.


Subject(s)
Brain/enzymology , Choline O-Acetyltransferase/metabolism , G(M1) Ganglioside/pharmacology , Nerve Growth Factors/pharmacology , Aging/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Animals , Brain/drug effects , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiology , G(M1) Ganglioside/administration & dosage , G(M1) Ganglioside/therapeutic use , Humans , Injections, Intraventricular , Nerve Growth Factors/administration & dosage , Nerve Growth Factors/therapeutic use , Organ Specificity , Parkinson Disease/drug therapy , Parkinson Disease/pathology
8.
J Pharmacol Exp Ther ; 263(3): 1440-6, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1361575

ABSTRACT

The neurotoxic properties of 2,4,5-trihydroxyphenylalanine (TOPA; the 6-hydroxylated derivative of dopa) was investigated in cultures of central neurons. Application of solutions of TOPA to cerebellar granule cells resulted in a concentration- and time-dependent neuronal death, with prolonged (24 hr) exposure producing a clear left-handed shift in the dose-response relationship from the one observed with a 60-min exposure (LD50: 4 and 29 microM, respectively). This toxicity was largely blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Solutions of TOPA were also toxic to mesencephalic neurons after acute or chronic exposure, displaying the same leftward shift in LD50. This latter preparation contained a minor population of dopaminergic, tyrosine hydroxylase immunopositive cells which were likewise sensitive to the excitotoxic effects of TOPA. Neurotoxic activity of TOPA appeared to depend upon its oxidation in solution, as judged using chemical analysis and reducing agents. The monosialoganglioside GM1 was effective in protecting against neurodegeneration induced by brief or prolonged exposure to solutions of TOPA. These results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation proposes their use as chemoprophylactic agents for preventing or arresting the neuronal losses accompanying such situations.


Subject(s)
Cerebellum/drug effects , Dihydroxyphenylalanine/analogs & derivatives , G(M1) Ganglioside/pharmacology , Mesencephalon/drug effects , Parkinson Disease/drug therapy , 6-Cyano-7-nitroquinoxaline-2,3-dione , Animals , Cells, Cultured , Cerebellum/chemistry , Dihydroxyphenylalanine/chemistry , Dihydroxyphenylalanine/toxicity , G(M1) Ganglioside/therapeutic use , MPTP Poisoning , Oxidation-Reduction , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley
9.
Vis Neurosci ; 8(6): 567-73, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1586655

ABSTRACT

The present study provides evidence that the adult mammalian retina is highly sensitive to the excitotoxic action of NMDA. In particular, we have investigated the effects of a single intravitreal injection of different doses of N-methyl-D-aspartate (NMDA) (2-200 nmoles) on the adult rat retina. Morphological evaluation of transverse sections of retinae demonstrated a dose-dependent loss of cells in the ganglion cell layer (GCL) and a reduction in the thickness of the inner plexiform layer. No obvious alterations were noted in the more distal retinal layers. Quantitative analyses of Nissl-stained whole-mounted retinae revealed that administration of 20 nmoles of NMDA resulted in a 70% loss of cells with a soma diameter greater than 8 microns (presumed retinal ganglion cells); a 20% loss of cells with a soma diameter smaller than 8 microns (presumed displaced amacrine cells) was also observed. In addition, NMDA produced a dose-dependent decrease of retinal choline acetyltransferase (ChAT) activity, suggesting that NMDA affects cholinergic amacrine cells as well. MK-801, a non-competitive NMDA antagonist, completely prevented the NMDA-induced loss of cells in the GCL and blocked, in a dose-dependent manner, the NMDA-induced decrease of ChAT activity. The excitotoxic action of NMDA observed in these experiments is thus likely mediated through the NMDA receptor subtype. This "in vivo" model may be utilized to identify potential drugs that antagonize or limit the deleterious effects consequent to NMDA receptor overstimulation in the central nervous system.


Subject(s)
N-Methylaspartate/toxicity , Retina/drug effects , Animals , Choline O-Acetyltransferase/metabolism , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Injections , Male , N-Methylaspartate/antagonists & inhibitors , Rats , Rats, Inbred Strains , Retina/enzymology , Retina/pathology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/enzymology , Retinal Ganglion Cells/pathology
10.
J Mol Recognit ; 3(5-6): 187-91, 1990.
Article in English | MEDLINE | ID: mdl-2096885

ABSTRACT

A functional role for Nerve Growth Factor (NGF) in the peripheral nervous system is well-documented, but a similar case for NGF in the central nervous system remains to be established. One approach to answering this question would be the availability of high-affinity monospecific Fab fragments obtained against NGF. In the present studies we describe the preparation and characterization of such Fab fragments from anti-mouse NGF polyclonal antibodies. Following their purification by the use of a NGF Sepharose-coupled affinity column, the Fab fragments were examined for biological competence in several ways. In vitro, the anti-Fab fragments blocked the neuronotrophic activity of NGF, as measured by the survival of chicken embryonic day 8 dorsal root ganglion neurons. In vivo, these Fab fragments, when administered systemically to neonatal rats, produced a decrease of noradrenaline levels in two sympathetically innervated organs, the heart and the spleen. These findings suggest that affinity purified Fab fragments of anti-NGF antibodies can be a useful tool for studying the physiological function of NGF in the nervous system.


Subject(s)
Immunoglobulin Fab Fragments/isolation & purification , Nerve Growth Factors/immunology , Animals , Chick Embryo , Female , Immunoblotting , Immunoglobulin Fab Fragments/administration & dosage , Immunoglobulin Fab Fragments/immunology , Male , Mice , Nerve Growth Factors/isolation & purification , Norepinephrine/metabolism , Rats , Rats, Inbred Strains
11.
Acta Neurobiol Exp (Wars) ; 50(4-5): 323-31, 1990.
Article in English | MEDLINE | ID: mdl-2130652

ABSTRACT

The effect of nerve growth factor (NGF) on the intact septohippocampal cholinergic system of adult rats was studied. Nerve growth factor was continuously infused at different doses (5-100 micrograms) for two weeks into the lateral ventricle of adult rats. Controls received intracerebroventricular infusion of equal amounts of cytochrome c. Nerve growth factor treatment was capable of inducing a dose-dependent increase of choline acetyltransferase activity (ChAT) in septal area and ventral hippocampus. In both areas, the NGF-induced rise of ChAT activity was sustained for at least one week after infusion, then it progressively declined towards control values. By three and five weeks, using NGF at 25 and 100 micrograms respectively, ChAT increase was still significant in both septum and ventral hippocampus. The present findings corroborate a role for NGF in adult septohippocampal cholinergic system and indicate that the "pharmacological" modulation of these neurons by NGF may last several weeks following withdrawal of this trophic factor.


Subject(s)
Brain/enzymology , Cerebral Ventricles/physiology , Choline O-Acetyltransferase/metabolism , Hippocampus/enzymology , Nerve Growth Factors/pharmacology , Animals , Brain/drug effects , Cerebral Ventricles/drug effects , Hippocampus/drug effects , Injections, Intraventricular , Male , Nerve Growth Factors/administration & dosage , Rats , Rats, Inbred Strains
12.
Neuron ; 3(3): 267-73, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2484338

ABSTRACT

Forebrain cholinergic neurons have been shown to respond in vivo to administration of nerve growth factor (NGF) with a prominent and selective increase of choline acetyltransferase (ChAT) activity. This has suggested that NGF can act as a trophic factor for these neurons. To test this hypothesis directly, anti-NGF antibodies (and their Fab fragments) were intracerebroventricularly injected into neonatal rats to neutralize endogenously occurring NGF. The anti-NGF antibody administration produced a decrease of ChAT activity in the hippocampus, septal area, cortex, and striatum of rat pups. This finding was substantiated by a concomitant decrease of immunopositive staining for ChAT in the septal area. These effects indicate that the occurrence of endogenous NGF in the CNS is physiologically relevant for regulating the function of forebrain cholinergic neurons.


Subject(s)
Brain/physiology , Nerve Growth Factors/physiology , Animals , Animals, Newborn/metabolism , Antibodies/immunology , Antibodies/physiology , Antibody Specificity , Brain/enzymology , Choline O-Acetyltransferase/metabolism , Female , Histocytochemistry , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/physiology , Immunoglobulin G/immunology , Immunoglobulin G/physiology , Immunologic Techniques , Male , Nerve Growth Factors/immunology , Neurons/enzymology , Rats , Septum Pellucidum/enzymology , Staining and Labeling
13.
Neuroscience ; 33(1): 47-52, 1989.
Article in English | MEDLINE | ID: mdl-2601860

ABSTRACT

The effect of nerve growth factor on the intact versus injured septohippocampal cholinergic system of adult rats was studied. Nerve growth factor was continuously infused into the lateral ventricle of adult uninjured rats or rats that had received unilateral partial transection of the fimbria. Controls (operated and unoperated) received intraventricular infusion of cytochrome c. After 2 weeks of nerve growth factor or cytochrome c treatments, choline acetyltransferase and acetylcholinesterase activities were measured in the septal area and in the hippocampus (divided into dorsal, medial and ventral parts). The continuous infusion of nerve growth factor resulted in a marked dose-dependent increase of choline acetyltransferase activity in both septum and hippocampus of adult unlesioned rats. In lesioned rats the nerve growth factor treatment was capable of inducing choline acetyltransferase activity in the hippocampus of not only the lesioned but also the unlesioned side, as well as in the septal area. In addition, nerve growth factor affected choline acetyltransferase activity differently in the hippocampus of the operated side with respect to the contralateral side or in unoperated animals. The chronic infusion of nerve growth factor did not affect acetylcholinesterase activity in the septum or in the hippocampus of either lesioned or unlesioned rats. The present findings indicate that nerve growth factor is capable of modulating the function of not only damaged but also normal adult forebrain cholinergic neurons. This suggests that nerve growth factor may modulate the function of these neurons in adulthood.


Subject(s)
Cholinergic Fibers/metabolism , Hippocampus/metabolism , Nerve Growth Factors/pharmacology , Septal Nuclei/metabolism , Acetylcholinesterase/metabolism , Animals , Choline O-Acetyltransferase/metabolism , Cholinergic Fibers/drug effects , Hippocampus/cytology , Hippocampus/drug effects , Male , Rats , Rats, Inbred Strains , Septal Nuclei/cytology , Septal Nuclei/drug effects
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