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G Sancesario

Publications and source records attributed to G Sancesario.

At least 19 recordsLinked to original sources
PubMed1995

Vulnerability of medium spiny striatal neurons to glutamate: role of Na+/K+ ATPase.

In Huntington's disease neuronal degeneration mainly involves medium-sized spiny neurons. It has been postulated that both excitotoxic mechanisms and energy metabolism failure are implicated in the neuronal degeneration observed in Huntington's disease. In central neurons, > 40% of the energy released by respiration is used by Na+/K+ ATPase to maintain ionic gradients. Considering that impairment of Na+/K+ ATPase activity might alter postsynaptic responsivity to excitatory amino acids (EAAs), we investigated the effects of the Na+/K+ ATPase inhibitors, ouabain and strophanthidin, on the responses to different agonists of EAA receptors in identified medium-sized spiny neurons electrophysiologically recorded in the current- and voltage-clamp modes. In most of the cells both ouabain and strophanthidin (1-3 microM) did not cause significant change in the membrane properties of the recorded neurons. Higher doses of either ouabain (30 microM) or strophanthidin (30 microM) induced, per se, an irreversible inward current coupled to an increase in conductance, leading to cell deterioration. Moreover, both ouabain (1-10 microM) and strophanthidin (1-10 microM) dramatically increased the membrane depolarization and the inward current produced by subcritical concentrations of glutamate, AMPA and NMDA. These concentrations of Na+/K+ ATPase inhibitors also increased the membrane responses induced by repetitive cortical activation. In addition, since it had previously been proposed that dopamine mimics the effects of Na+/K+ ATPase inhibitors and that dopamine agonists differentially regulate the postsynaptic responses to EAAs, we tested the possible modulation of EAA-induced membrane depolarization and inward current by dopamine agonists. Neither dopamine nor selective dopamine agonists or antagonists affected the postsynaptic responses to EAAs. Our experiments show that impairment of the activity of Na+/K+ ATPase may render striatal neurons more sensitive to the action of glutamate, lowering the threshold for the excitotoxic events. Our data support neither the role of dopamine as an ouabain-like agent nor the differential modulatory action of dopamine receptors on the EAA-induced responses in the striatum.

Animals↗
PubMed1995

Immunocytochemical localization of vinculin in muscle and nerve.

A complete survey of the immunofluorescence distribution of the cytoskeletal protein vinculin in the normal skeletal muscle and peripheral nerve of humans and of different rodent species was performed. Our results enable us to localize vinculin in different types of adhesion plaques such as sarcolemmal costameres and neuromuscular and myotendinous junctions, but also in a fine intermyofibrillar lattice, possibly associated with intermediate filaments and/or with the triads. Moreover, we describe the presence of vinculin in junctional domains of several, previously unrecognized, specialized cells such as: the outer sheath of the muscle spindle capsule, the multilayered flat cells of the perineurium, the smooth muscle cells of epineurial blood vessels, and the endothelial cells in the endoneurium. These data call for a major role of vinculin in mechanisms of adhesion between cells, between cell and substrate and between intermyofibrillar components in the neuromuscular system. Such knowledge provides an anatomical background for studies on the possible pathological effects induced by an impairment in vinculin function.

Adult↗
PubMed1995

Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission.

Oxcarbazepine (OCBZ) is the keto-analogue of carbamazepine (CBZ). In humans, OCBZ is rapidly and almost completely metabolized to 10, 11-dihydro-10-hydroxy-CBZ (GP 47779), the main metabolite responsible for the drug's antiepileptic activity. The corticostriatal pathway is involved in the propagation of epileptic discharges. We characterized the electrophysiological effects of GP 47779 on striatal neurons by making intracellular recordings from corticostriatal slices. GP 47779 (3-100 microM) produced a dose-dependent inhibition of glutamatergic excitatory postsynaptic potentials (EPSPs). This effect was not coupled either with changes of the membrane potential of these cells or with alterations of their postsynaptic sensitivity to excitatory amino acids (EAA) suggesting a presynaptic site of action. GP 47779 reduced the current-evoked firing discharge only at concentrations > 100 microM. GP 47779 did not affect the presynaptic inhibitory action of adenosine, showing that presynaptic adenosine receptors were not implicated in the GP 47779-mediated reduction of corticostriatal EPSPs. Our data indicate that GP 47779 apparently acts directly on corticostriatal terminals to reduce the release of EAA, probably by inhibiting high-voltage-activated (HVA) calcium (Ca2+) currents (described in the accompanying article). The inhibitory action of GP 47779 on corticostriatal transmission may contribute to the antiepileptic effects of this drug.

Adenosine↗
PubMed1994

Dystrophin is not essential for the integrity of the cytoskeleton.

Dystrophin is localized, in normal muscle fibers, on the cytoplasmic surface of the sarcolemma. The function of this protein is not known but, according to its structure and intracellular distribution, it seems likely that dystrophin interacts with other cytoskeletal proteins to form a complex linkage between myofibrils, sarcolemma and extracellular matrix. To evaluate the possibility that dystrophin deficiency induces, per se, a disarray in the cytoskeleton, we studied three components of this structure in muscle fibers of the dystrophic mdx mouse in a phase preceding the onset of necrosis. Vinculin, abundant in sarcolemmal structures called costameres, desmin, the principal component of intermediate filaments and nebulin, constituent of the so-called "third filament" within the sarcomere, were stained with the indirect immunofluorescence technique in cryostat sections. The same monoclonal antibodies were used in Western blots of proteins extracted from the same muscles. No difference was observed in the distribution or in the relative abundance of the three proteins, comparing muscles from 18 day-old mdx and control mice. Our results indicate that the lack of dystrophin does not induce, per se, alterations in the structures linking the sarcolemma to the contractile apparatus. It is likely that the structural damage in dystrophin-less muscle fibers is initially confined to limited portions of the plasma membrane. These focal lesions, impairing intracellular calcium homeostasis, can lead to muscle fiber necrosis.

Animals↗
PubMed1994

Nitric oxide inhibition aggravates ischemic damage of hippocampal but not of NADPH neurons in gerbils.

BACKGROUND AND PURPOSE: Nitric oxide may influence pathophysiology of brain ischemia in a complex way depending on the sources of its production either from neurons or endothelial cells. We investigated whether inhibition of nitric oxide synthesis affects postischemic neuronal death in hippocampus. Moreover, we evaluated whether the presence of nitric oxide synthase activity in specific neurons protects these against ischemia in the hippocampus, striatum, and sensorimotor cortex. METHODS: To inhibit nitric oxide synthase, several dosing regimens of NG-nitro-L-arginine methyl ester (L-NAME) were used (5 or 50 mg/kg IP, twice a day for 4 days, or 30 mg/kg IV) in gerbils. Control animals received either the isomer NG-nitro-D-arginine methyl ester or the vehicle. The gerbils underwent 10-minute occlusion of carotid arteries under ether anesthesia and controlled body temperature while physiological parameters were monitored. Neuronal damage was assessed 5 days after ischemia using Nissl-stained sections of hippocampus. Nitric oxide synthase neurons were histochemically stained for reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity. RESULTS: L-NAME treatments, but not the chronic one at 5 mg/kg, induced elevation of blood pressure (30% to 80% greater than the control level, P < .01), as observed shortly before and after bilateral carotid occlusion. Postischemic neuronal loss in the CA1 through CA4 sectors was worsened by chronic pretreatment with L-NAME at 50 mg/kg (eg, CA1 neuronal counts per 100-microns length: 3.2 +/- 2.74, mean +/- SD; n = 19; P < .01). After the acute (30 mg/kg) or chronic pretreatment at lower dosage (5 mg/kg) with L-NAME, neuronal loss was comparable to that of animals treated with the D-isomer or the vehicle (CA1 counts in vehicle-treated animals: 7.65 +/- 6.51, mean +/- SD; n = 14). None of the L-NAME treatments affected postischemic survival of NADPH diaphorase-positive neurons in hippocampus, striatum, and sensorimotor cortex. CONCLUSIONS: These observations demonstrate that inhibition of endothelial and neuronal nitric oxide synthase activity does not modify resistance of nitric oxide-producing neurons to transient ischemia. The severe inhibition of nitric oxide production aggravates postischemic neuronal death in the hippocampus, whereas the mild inhibition is ineffective.

Amino Acid Oxidoreductases↗
PubMed1993

NADPH diaphorase activity is inhibited by EDTA in neurons but not in choroid plexus epithelium.

NADPH diaphorase histochemical staining was investigated in rat brain and choroid plexuses. All epithelial cells of the latter as well as some sparse neurons in striatum and cerebral cortex showed strong NADPH reaction product. While staining was homogeneous in neuronal cytoplasm, it was particulate in epithelial cells. Preincubation with EDTA (0.1 mM, 2h) prevented appearance of NADPH diaphorase reaction in neurons but not in choroid plexuses. These data show that in rat brain two forms of NADPH diaphorase are present; they are specifically localized in neurons and choroidal cells, respectively.

Animals↗
PubMed1993

Sudomotor skin responses to brain stimulation do not depend on nerve sensory fiber functionality.

Evaluation of sudomotor innervation to the limbs was performed via electrical stimulation of the median nerve at the wrist and transcranial magnetic stimulation of the brain. Sympathetic skin responses (SSRs) from the palms and the soles were recorded in a patient suffering from a form of predominantly sensory neuropathy. Motor responses to nerve stimulation were present, even if with slower than normal conduction velocity. However, median, ulnar and sural nerve sensory potentials were absent. SSRs to median nerve stimulation at the wrist were missing on palms and soles. By contrast, during brain stimulation of the hand motor area with magnetic impulses, SSRs were reliably identifiable at all recording sites. It is hypothesized that SSRs to mixed nerve stimulation need normal functionality of afferent fibers, while those to brain stimulation can be elicited without any sensory information from the limbs.

Brain↗
PubMed1993

Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson's disease.

Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson's disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also alters the physiological responses to dopamine receptor stimulation. Nigral lesions induce supersensitivity of D2 dopamine receptors controlling the release of glutamate and reduce the inhibitory influence of D1 receptors at postsynaptic level. These functional changes of the striatal neurons may alter the output signals from the striatum to the other structures of the basal ganglia and then produce most of the physiopathological changes observed in Parkinson's disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Active muscle length reduction progressively damages soleus in hindlimb-suspended rabbits.

This study describes the morphologic changes in rabbit soleus muscle following hindlimb suspension (HS) for 1 to 4 weeks (group A); or following HS with hindfeet passively dorsiflexed, by means of an elastic band, for 1 to 2 weeks (group B). In the latter, elastic band use allowed phasic contractions of foot extensor muscles against resistance and prevented 35% chronic soleus shortening, which occurred in group A animals. In group A, the soleus revealed progressive muscle atrophy and myofibrillar damage. Myofibrils underwent dissolution, muscle regeneration was ineffective, and adipose tissue developed from about 2-week suspension onward. Conversely, passive dorsiflexion of unloaded hindfeet was essential in maintaining mass and structural muscle integrity in the soleus of group B. It is hereby demonstrated that HS-induced soleus damage in the rabbit is progressive, and can be prevented, avoiding long-term shortening of soleus and its phasic unloaded contractions. Soleus sensitivity to unloading conditions, such as HS, tenotomy, and hypogravity, may depend on the particular physiology of this tonic antigravity muscle, engaged mainly in developing long-lasting isometric contractions in a stretched length.

Animals↗
PubMed1992

Design and baseline results of the monosialoganglioside early stroke trial. The EST Study Group.

BACKGROUND AND PURPOSE: The Early Stroke Trial is a randomized, placebo-controlled, double-masked, multicenter study to assess the safety and efficacy of monosialoganglioside in patients who have suffered an ischemic stroke of the cerebral hemispheres. METHODS: Only patients who could be evaluated and treated within 5 hours after the onset of stroke were considered; within each center, subjects were stratified by age, sex, and clinical severity. Patients were randomly allocated to receive a specified sequence of intravenous and intramuscular doses of either monosialoganglioside or identical-appearing placebo for 21 days. Patients were followed up for 4 months after randomization. Neurological status was measured primarily by using the Canadian Neurological Scale. After assessing the effect of treatment on survival, the principal measure of efficacy will be the change in neurological status between baseline and the 4-month follow-up among survivors. RESULTS: Sixteen clinical centers, 15 in Europe and one in North America, entered a total of 792 eligible patients during a 36-month recruitment period (from May 1987 to April 1990). In our series there were more men than women, and the relative frequency of patients increased with advancing age. The most frequently associated cardiovascular conditions were hypertension, atrial fibrillation, and peripheral vascular disease. Approximately 46% of the patients were admitted to a hospital within 1 hour and 81%, within 2 hours after the onset of stroke. About 22% first received the study treatment within 3 hours and 57%, within 4 hours. CONCLUSIONS: This study demonstrates the feasibility of large-scale trials with the onset of treatment within 5 hours after an ischemic stroke.

Adult↗
PubMed1991

Epileptic activity following cerebral ischemia in Mongolian gerbils is depressed by CPP, a competitive antagonist of the N-methyl-D-aspartate receptor.

A 10-min bilateral carotid occlusion (BCO) in Mongolian gerbils induces transient generalized epileptic discharges in the hippocampal and cortical regions, which are followed by long lasting interictal spiking activity. An initial peak of this activity occurs within 18-36 h after BCO, then it decreases slowly and completely disappears by the 6th-7th day. On the 7th day, morphological evidence shows a selective loss of CA1 hippocampal neurons. 4-(3-Phosphonopropyl)-2-piperazine-carboxylic acid (CPP), a competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor was administered (7 or 15 mg/kg i.p.) immediately after clamping, and again every 12 h for 3 consecutive days. It induced a dose-related depression of epileptic activity, while, on the other hand, at both dosages, it always prevented the loss of CA1 neurons. The results are discussed in view of the different mechanisms mediating cell damage and epileptic activity.

Animals↗
PubMed1991

Increase of dopamine beta-hydroxylase immunoreactivity in non-noradrenergic nerves of rat cerebral arteries following long-term sympathectomy.

The expression of dopamine beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) immunoreactivity (IR) after short-term (2 days) and long-term (3 weeks) sympathectomy was investigated in rat cerebral vessels, dura mater and pterygopalatine ganglion neurones (which are known to project to cerebral arteries) by immunohistochemistry at both the light and electron microscopical levels. TH-IR, like glyoxylic acid-induced fluorescence, was completely abolished by sympathectomy. By contrast, DBH-IR was localized in nerve fibres, lacking 5-hydroxydopamine (5-OHDA)-labelled vesicles, along cerebral vessels of long-term sympathectomized rats, but not in the dura mater, and in pterygopalatine ganglia, where the number of DBH-IR neurons increased from 27.87% to 54.11%. Since virtually all the pterygopalatine neurons displayed choline acetyltransferase (ChAT)-IR, both in control and sympathectomized rats, it is concluded that long-term sympathectomy caused an increase of the expression of DBH-IR in cholinergic neurones of the pterygopalatine ganglion, without these neurons producing or storing noradrenaline.

Animals↗
PubMed1991

Myofibrillar disruption in the rabbit soleus muscle after one-week hindlimb suspension.

Relevant muscle- and species-specific differences may be found in the reaction of muscles to hindlimb suspension. This problem has been studied in 5 rabbits following a one-week hindlimb suspension, and in 5 ground-based controls. The soleus and the tibialis were prepared for light and transmission electron microscopy. In suspension the animals occasionally extended and flexed the hindlimbs, but, when standing still, their hindfeet were plantar-flexed to an angle of 180 degrees. In this position the length of the soleus was determined to be 35% less than in controls, whereas that of the tibialis was 30% more. Histologically, the tibialis fibers usually exhibited a preserved sarcomeric pattern, whereas soleus fibers displayed a regular sequence of areas of shortened sarcomeres, alternating with areas of myofibrillar disruption. These findings demonstrated that hindlimb suspension induces a focal breakdown of the soleus myofibrils, probably dependent on the reduced longitudinal tension of the suspended soleus and its phasic contractions against no load. It is conceivable that similar factors could also be responsible for soleus muscle atrophy induced by hypogravity as well as by other clinical conditions during which a stressful plantar flexion of the feet occurs against no load.

Animals↗
PubMed1991

Cerebrospinal fluid estrone in pseudotumor cerebri: a change in cerebral steroid hormone metabolism?

Estrogen and androgen hormones were studied in the plasma and cerebrospinal fluid (CSF) of five patients affected by pseudotumor cerebri (PTC). Six men and six women without cerebral or endocrine diseases were selected as controls. Androstenedione (A), testosterone (T), 17-hydroxyprogesterone (17OH-P), E1 and E2 were measured in plasma and CSF in baseline conditions and following 1 month prednisone therapy (2 mg/die, per os) using RIA following chromatographic separation on celite microcolumns. Men and women affected by PTC show increased CSF E1 levels and marked decreased CSF A levels, with respect to controls. In plasma, on the contrary, normal values of these parameters were observed in PTC. In normal subjects A/E1 ratio shows the same values in plasma and CSF, suggesting for the two hormones analogous feasibility to cross the blood brain barrier. In PTC patients A/E1 ratio is comparable to controls in plasma, but lower in CSF as a result of decreased A and increased E1 contents. The CSF imbalance between A and E1 attenuates but does not disappear after treatment. No correlation is found between pressure levels and steroid pattern both in baseline condition or after one month of treatment. In conclusion, our results demonstrate that PTC is not only associated with increased CSF E1 levels, as previously suggested, but, above all, with decreased CSF A levels and this hormonal impairement seems to be confined to the CSF compartment and not observed in plasma. These data do not lead to any definitive conclusion about the role of altered CSF estrogen and androgen levels in PTC pathogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Bilateral carotid occlusion in normotensive rats: olds facts and new observations.

This work describes that prolonged mild cerebral ischemia may lead to either general or regional derangement of brain morphofunctional integrity. Normotensive adult Wistar rats were used. Under anesthesia with volatile agents or thiopental, the common carotid arteries were ligated permanently. In one group of animals local cerebral blood flow (1CBF) was measured two hours after carotid occlusion using the [14C]iodoantipyrine method. The other carotid-occluded animals were used for clinical rating and histological evaluation, which was performed two days to 4 weeks after surgical operation. The [14C]iodoantipyrine method showed widespread reduction in the cerebral circulation of carotid-occluded animals. Several hours after carotid occlusion, 40% of the animals showed dramatic neurological signs and died on the day of operation. In 35% of surviving animals, brain infarctions were observed in one and exceptionally two areas of the sensorimotor cortex, thalamus, hippocampus or cerebellum. The evolutionary sequence of the histopathological changes seems to date the induction of the infarcts to the early period of carotid occlusion. In conclusion, reduction of cerebral blood flow causes, in a high percentage of animals, various degrees of acute brain damage after an apparent symptom-free interval.

Animals↗
PubMed1990

Epileptic activity following 10 minute cerebral ischemia in Mongolian gerbils: an electrophysiological study.

The effects of bilateral carotid occlusion (BCO) on electroencephalographic (EEG) activity and hippocampal structural integrity was studied in 25 Mongolian gerbils. During BCO EEG became flat in frontal cortex and hippocampus but bilateral spikes and motor signs were recorded during this period. Following release of clamping EEG gradually recovered within 36 h but interictal activity persisted disappearing on the 6th-7th day. At the end of 7 days a selective necrosis of CA1 hippocampal neurons was observed. The results indicate that 10 min cerebral ischemia induces a transient epileptic activity followed by the CA1 neuronal loss. Mechanisms underlying ischemic damage are complex and probably they involve an altered synaptic transmission.

Animals↗
PubMed1990

Spontaneous subarachnoid hemorrhage in an HIV patient.

In an HIV-seropositive patient presenting generalized tonic-clonic seizures, magnetic resonance imaging and cerebrospinal fluid examination disclosed the signs of a previous subarachnoid bleed. No vascular malformation was observed with cerebral angiography. Laboratory tests revealed an autoimmune thrombocytopenia. A spontaneous subarachnoid hemorrhage induced by thrombocytopenia should be considered when investigating HIV patients presenting even non-specific neurological symptoms.

Adult↗