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A Stefani

Publications and source records attributed to A Stefani.

At least 19 recordsLinked to original sources
PubMed1998

Group I mGluRs modulate calcium currents in rat GP: functional implications.

The modulation of voltage-dependent calcium currents strongly affects the firing pattern of central neurons. Changes in the intrinsic firing properties of mammalian globus pallidus cells (external pallidus in humans) are indicated as underlying the development of movement disorders. Pallidal neurons receive an excitatory input from the subthalamus, supposed to activate both ionotropic and metabotropic glutamate receptors. Since the activation of glutamate metabotropic receptors in rodent basal ganglia affects dopamine-mediated motor behaviors, we examined whether agonists at metabotropic sites modulate high-threshold calcium currents in pallidus. The broad agonist 1S,3R-ACPD produced a 22% reduction of calcium currents, which was mimicked by the group I agonist DHPG. These two responses were not additive; furthermore, the ACPD- and DHPG-mediated inhibition of high-threshold calcium currents were prevented by the cycloglycine MCPG, suggesting the involvement of a group I mGluR. The modulation was fast, saturating in less than 3 sec, partially voltage-dependent, in that about one-third was relieved by facilitation, and G-protein-mediated, since it was largely suppressed by NEM. Finally, the response was antagonized by omega-conotoxin-GVIA and omega-agatoxin-IVA, supporting the involvement of N- and P-type channels. The observed reduction of calcium signals might shape pallidal excitability, influencing the physiological balancing between globus pallidus and subthalamus. In pathological conditions such as parkinsonism, characterized by the putative increase of the endogenous release of glutamate from subthalamic neurons, the inhibition of high-threshold calcium currents in pallidus might modify the firing pattern of pallidal neurons and partially counteract the excitatory drive from STN. Nevertheless, the putative mGluR-induced reduction of intrinsic excitability might turn out to decrease the transmitter release from pallidal axon terminals, leading to further disinhibition of the output stations of the basal ganglia.

Animals↗
PubMed1998

Group III metabotropic glutamate receptor agonists modulate high voltage-activated Ca2+ currents in pyramidal neurons of the adult rat.

In pyramidal neurons of the rat sensorimotor cortex, we have investigated the modulation of high voltage-activated calcium currents by agonists at group III metabotropic glutamate receptors (mGluRs). l-2-Amino-4-phosphonobutyrate (l-AP4) and l-serine-O-phosphate (l-SOP) reduced calcium currents in the vast majority of cells isolated from the adult animal. Interestingly, this modulation was negligible in the young animals (2-14 postnatal days), becoming prominent only after full development (more than 21 days). The efficacy of l-SOP mimicked l-AP4 in reducing calcium currents. Yet, l-SOP produced saturating responses at about 3 microM and significant modulation at nanomolar concentrations (EC50=923 nM). The voltage-dependence of the group III mGluR-mediated responses was evaluated by comparing the inhibition of "standard" and "facilitated" conductances. On the calcium currents facilitated by depolarizing prepulse, 3 microM l-SOP produced a mean 13.4% inhibition compared with 19.6% in control condition, supporting the proposition that part of the inodulation was voltage-dependent. The calcium current inhibition caused by the activation of group III metabotropic glutamate receptors was only partially sensitive to omega-conotoxin GVIA, but largely inhibited by omega-agatoxin IVA, at concentrations (100 nM) known to block P- and Q-type channels. Conversely, the dihydropyridine antagonists nifedipine and nimodipine (50-500 nM) failed to prevent the group III mGluR-mediated response in the majority of tested cells (more than 65%). Furthermore, the long-lasting tail promoted by the inclusion of the dihydropyridine agonist Bay K 8644 was not consistently affected by l-SOP and l-AP4. These findings imply that the observed modulation involves different channel subtypes, namely N- and P- or Q-type channels, and suggests that group III mGluRs play an important role in the intrinsic and synaptic functions of adult cortical pyramidal neurons.

Aging↗
PubMed1998

Gabapentin inhibits calcium currents in isolated rat brain neurons.

Gabapentin (1(aminomethyl) cyclohexane acetic acid; GBP) is a recently developed anticonvulsant, for which the mechanism of action remains quite elusive. Besides its possible interaction with glutamate synthesis and/or GABA release, in cerebral membranes gabapentin has been shown to bind directly to the alpha2delta subunit of the calcium channel. Therefore, we have tested the possibility that gabapentin affects high threshold calcium currents in central neurons. Calcium currents were recorded in whole-cell patch-clamp mode in neurons isolated from neocortex, striatum and external globus pallidus of the adult rat brain. A large inhibition of calcium currents by gabapentin was observed in pyramidal neocortical cells (up to 34%). Significantly, the gabapentin-mediated inhibition of calcium currents saturated at particularly low concentrations (around 10 microM), at least in neocortical neurons (IC50 about 4 microM). A less significant inhibition was seen in medium spiny neurons isolated from striatum (-12.4%) and in large globus pallidus cells (-10.4%). In all these areas, however, the GBP-induced block was fast and largely voltage-independent. Dihydropyridines (nimodipine, nifedipine) prevented the gabapentin response. Omega-conotoxin GVIA and omega-conotoxin MVIIC, known to interfere with the currents driven by alpha1b and alpha1a calcium channels, did not prevent but partially reduced the response. These findings imply that voltage-gated calcium channels, predominately the L-type channel, are a direct target of gabapentin and may support its use in different clinical conditions, in which intracellular calcium accumulation plays a central role in neuronal excitability and the development of cellular damage.

Acetates↗
PubMed1998

Migration of pectus excavatum correction metal support into the abdomen.

The authors describe a case of migration of a metal support, used to fix a corrected pectus excavatum deformity, into the peritoneal cavity. The migrated wire caused abdominal pain. A video laparoscopic removal of the wire was undertaken and the patient made a full recovery. A review of the literature shows that this has not been reported before and that serious complications related to metal struts are very uncommon. We do not believe that a revision of this surgical technique is needed; anyway, foreign body migration should always be considered as a cause for unusual symptoms in patients undergoing this operation.

Abdomen↗
PubMed1998

On the inhibition of voltage activated calcium currents in rat cortical neurones by the neuroprotective agent 619C89.

1. The lamotrigine analogue 619C89, utilised to reduce postischaemic and posttraumatic neuronal injury, has been shown to inhibit sodium channels and cloned N-type calcium channels. To verify whether this neuroprotective agent also blocked native calcium channels, we have tested its action in cortical pyramidal neurones, acutely isolated from the adult rat brain. 2. 619C89 inhibited more than 90% of the high voltage-activated calcium currents recorded in the whole-cell configuration. The response was relatively slow in onset (30-60 s), recovered incompletely (96%), but showed no consistent desensitization. 3. This inhibitory effect was not selective for any calcium channel subtype, being largely unaffected by omega-conotoxin-GVIA, omega-agatoxin-IVA, omega-conotoxin-MVIIC and dihydropyridine antagonists. 4. Saturating responses to 619C89 were detected for concentrations > or = 50 microM. Dose-response curves revealed that 619C89 have an approximately 8 microM binding site. 5. The effect of 619C89 was dependent on the divalent concentrations in that its potency was reduced on increase of the charge carrier up to 20 mM barium. Since the lamotrigine analogue shifted to the right the dose-dependence of the cadmium block, the 619C89-mediated inhibition of calcium currents seemed to rely on a direct interaction with the channel pore. Functional implications are discussed.

Animals↗
PubMed1998

Helicobacter pylori cytotoxic genotype is associated with peptic ulcer and influences serology.

OBJECTIVE: We studied 146 patients with peptic ulcer disease (n = 72), antral gastritis (n = 58), or duodenitis (n = 16) to ascertain whether the cytotoxic genotype of Helicobacter pylori (Hp) is associated with peptic ulcer disease and/or antral gastritis and whether it influences the circulating levels of total anti-Hp antibodies, anti-cagA antibodies, and pepsinogens. METHODS: A gastric juice sample was obtained from each patient. After DNA extraction, polymerase chain reaction was used to amplify the genes urease A (ureA), cagA, and vacA of Hp. RESULTS: A significant association was found between peptic ulcer disease and the cytotoxic genotypes, characterized by the presence of s1 and m1 alleles of vacA and by cagA. Patients with a cagA-positive genotype showed a significant increase in anti-cagA antibodies and also had significantly increased circulating levels of pepsinogen C. CONCLUSIONS: Cytotoxic Hp strains are mainly involved in determining peptic ulcer disease, but not antral gastritis. The higher levels of circulating pepsinogen C found in patients infected with cytotoxic genotypes may reflect the higher degree of inflammation sustained by these strains.

Adult↗
PubMed1998

Physiological and molecular properties of AMPA/Kainate receptors expressed by striatal medium spiny neurons.

The mechanisms by which glutamate shapes the activity of striatal medium spiny neurons are of fundamental importance to our understanding of normative and pathological striatal physiology. Non-N-Methyl-D-aspartate (non-NMDA) glutamate receptor expression and function were studied in medium spiny neurons with a combination of single cell RT-PCR, immunocytochemistry and whole-cell voltage-clamp techniques. Reverse transcription polymerase chain reaction analysis found that GluR2 mRNA appeared to be the most abundant and widely distributed AMPA receptor mRNA. GluR1 was also commonly detected. However, GluR3 mRNA was preferentially expressed by neurons coexpressing substance P and enkephalin and GluR4 mRNA was not detected in identified medium spiny neurons. All neuronal classes appeared to express GluR5 or GluR6 and/or GluR7 mRNA in addition to kainate (KA) subunit mRNA. Immunocytochemical studies confirmed the mRNA distributions and also revealed that GluR1 protein was largely restricted to dendritic spines. Although the mRNA and protein for both alpha-amino-3-hydroxy-5-methyl-ioxyzole-4-proprionic acid (AMPA) and KA class subunits was detected, the physiological response to glutamatergic ligands and the benzothiadizine cyclothiazide was characteristic of AMPA, not KA receptors. The AMPA receptor antagonist GYKI 52466 blocked the response to AMPA and all but a small transient component of the response to KA. The current-voltage relationship of the AMPA-evoked currents was relatively linear but Ca2+ fluorometry revealed that substantial changes in intracellular Ca2+ concentration accompanied exposure to either agonist. These results argue that somatodendritic non-NMDA glutamate receptors in medium spiny neurons are primarily GluR2-containing receptors of the AMPA class but that activation of these receptors as a group nevertheless results in a significant Ca2+ influx.

Animals↗
PubMed1998

Cardiac rhabdomyosarcoma: a clinicopathologic and electron microscopy study.

A 66-year-old woman was admitted to the hospital with a neurological syndrome characterized by ataxia and diplopia. Magnetic resonance of the brain documented an ischemic medullary lesion. Examination of the heart revealed a grade 2/6 systolic murmur at the left sternal border and apex that radiated towards the axilla. The echocardiography study showed a mild mitral regurgitation, and an abnormally enlarged posterior papillary muscle was found in the left ventricle. Two weeks after admission, the patient died suddenly due to a stroke. At autopsy, a recent vast swollen ischemic cerebral infraction was found. Furthermore, two old infarcts were observed in the spleen. A cardiac examination showed a white-gray ulcered mass in the left ventricle and histological analysis revealed a rhabdomyosarcoma.

Aged↗
PubMed1997

Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies.

Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamate in situ, yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller; use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1-10 microM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by < 12% at 10 microM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.

Animals↗
PubMed1997

Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson's disease: clinical score and internal globus pallidus activity. Short communication.

We analysed the firing activity of internal globus pallidus cells in two Parkinson's disease patients undergoing stereotaxic surgery. Both patients showed an advanced rigid-akinetic syndrome with disabling levodopa induced dyskinesias. Apomorphine, intraoperatively administered at doses (1-2 mg) inducing a short but clear clinical improvement without involuntary movements, reduced the pallidal discharge rate by > 50% in both patients. An higher apomorphine dose (2.5 mg), tested in one hemisphere, blocked the firing activity with a time course independent from the occurrence of dyskinesias. These finding suggest that the reduction of internal pallidus excitability is one of the mechanisms underlying the efficacy of dopaminergic therapy, but also that changes in other basal ganglia stations are likely to be involved in dyskinesias.

Antiparkinson Agents↗
PubMed1997

Results of surgical resection in patients over the age of 70 years with non small-cell lung cancer.

METHODS: From January 1989 to October 1993, at the Department of Cardio-Thoracic Surgery of the University of Modena, 806 patients underwent thoracotomy and curative pulmonary resection for non small-cell lung cancer. Eighty five patients were 70 years old or older (mean 73.4 years, range 70-88). There were 78 males (91.7%) and 7 females (8.3%). This population was compared to 130 younger patients (under 70 years old), treated during the same period and with similar features with respect to the type of resection, sex, histology, grading and staging. Lobectomy was the procedure of preference in both groups. RESULTS: As regards postoperative mortality and overall complications, no significant differences were noted between the two groups of patients (two younger patients died and 43.8% had postoperative complications; one patient of the older group died and 55.2% had postoperative complications), but in the older ones a higher incidence of cardiovascular complications was found (P < 0.01). With respect to the long-term survival (follow-up 12-70 months), no significant difference was found between the two groups. CONCLUSION: Such findings show that pulmonary resection for bronchogenic cancer is feasible and justified in patients more than 70 years old, even if a higher incidence of cardiovascular complications may occur: a careful preoperative selection ought to be performed and lobectomy should be preferred.

Adult↗
PubMed1997

Voltage-activated calcium channels: targets of antiepileptic drug therapy?

Voltage-gated calcium currents play important roles in controlling neuronal excitability. They also contribute to the epileptogenic discharge, including seizure maintenance and propagation. In the past decade, selective calcium channel blockers have been synthesized, aiding in the analysis of calcium channel subtypes by patch-clamp recordings. It is still a matter of debate whether whether any of the currently available antiepileptic drugs (AEDs) inhibit these conductances as part of their mechanism of action. We tested oxcarbazepine, lamotrigine, and felbamate and found that they consistently inhibited voltage-activated calcium currents in cortical and striatal neurons at clinically relevant concentrations. Low micromolar concentrations of GP 47779 (the active metabolite of oxcarbazepine) and lamotrigine reduced calcium conductances involved in the regulation of transmitter release. In contrast, felbamate blocked nifedipine-sensitive conductances at concentrations significantly lower than those required to modify N-methyl-D-aspartate (NMDA) responses or sodium currents. Aside from contributing to AED efficacy, this mechanism of action may have profound implications for preventing fast-developing cellular damage related to ischemic and traumatic brain injuries. Moreover, the effects of AEDs on voltage-gated calcium signals may lead to new therapeutic strategies for the treatment of neurodegenerative disorders.

Animals↗
PubMed1996

Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications.

In pyramidal cortical cells, high-voltage-activated Ca2+ currents affect seizure propagation and the release of excitatory amino acids at the corticostriatal axon terminals. The new antiepileptic drug lamotrigine (Lamictal) produced a large and dose-dependent inhibition of high-voltage-activated Ca2+ currents (IC50 = 12.3 microM) in rat cortical neurons. This action was not blocked by the dihydropyridine receptor antagonist nifedipine; instead, the response was blocked by the concomitant application of the N-type Ca2+ channel blocker, omega-conotoxin GVIA (1-3 microM) and the P-type Ca2+ channel blocker, omega-agatoxin-IVA (20-100 nM). These findings demonstrate that lamotrigine, at therapeutic doses, is capable of modulating the Ca2+ conductances involved in excitatory amino acid release in the corticostriatal pathway, partially explaining lamotrigine usefulness in the therapy of epilepsy as well as in the treatment of excitatory amino acid-induced neurotoxicity.

Animals↗
PubMed1996

L-AP4 inhibits high voltage-activated Ca2+ currents in pyramidal cortical neurones.

We tested the ability of L-AP4 to modulate high voltage-activated (HVA) calcium (Ca2+) currents in pyramidal neurones acutely isolated from the adult rat (4-8 weeks). Whole cell recordings, with barium (Ba2+) ions as the charge carrier, were performed. L-AP4 reduced HVA Ca2+ conductances in 86% of the recorded cells. Saturating concentrations of L-AP4 inhibited about 21% of the current (+/- 8.3%, n = 8), although great variability was observed. Interestingly, low micromolar concentrations of (1S,3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4R)-alpha-(carboxy-cyclopropyl)-glycine (1-CCGI) had weaker effects than L-AP4. MAP4 fully antagonized the L-AP4-mediated reduction of HVA Ca2+ currents. These findings suggest the involvement of the AP4-sensitive receptor in the control of both cellular excitability and transmitter release in rat neocortical neurones.

Amino Acids, Dicarboxylic↗
PubMed1996

The modulation of calcium currents by the activation of mGluRs. Functional implications.

Glutamatergic transmission in the central nervous system (CNS) is mediated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory proteins (G-proteins) and modulate different second messenger pathways. Multiple effects have been described following their activation; among others, regulation of fast synaptic transmission, changes in synaptic plasticity, and modification of the threshold for seizure generation. Some of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca2+) currents. Some HVA Ca2+ channels (N-, P-, and Q-type channels) are signaling components at most presynaptic active zones. Their mGluR-mediated inhibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal firing behavior and the integration of complex events at the somatic level. In addition, the mGluR-mediated effects on voltage-gated Ca2+ signals have been suggested to strongly influence neurotoxicity. Rather different coupling mechanisms underlie the relation between mGluRs and Ca2+ currents: Together with a fast, membrane-delimited mechanism of action, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity of selective agonists and antagonists for the different subclasses of mGluRs had hampered the clear definition of the roles of mGluRs in brain function. However, the recent availability of new pharmacological tools is promising to provide a better understanding of the neuronal functions related to different mGluR subtypes. The analysis of the mGluR-mediated modulation of Ca2+ conductances will probably offer new insights into the characterization of synaptic transmission and the development of neuroprotective agents.

Animals↗
PubMed1996

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

Animals↗
PubMed1996

A field potential analysis on the effects of lamotrigine, GP 47779, and felbamate in neocortical slices.

We studied the action of the new antiepileptic drugs lamotrigine (LTG), GP 47779 (the active metabolite of oxcarbazepine), and felbamate (FBM) on stimulus-evoked field potentials recorded from rat prefrontal and frontal cortical slices. In the presence of physiologic concentrations of extracellular magnesium (1.2 mM) the field potential amplitude was not affected by the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, 2-amino-5-phosphonovalerate (APV), while it was blocked by the non-NMDA glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). When magnesium was removed from the bathing medium, there was a significant NMDA-mediated component of the field potential. LTG and GP 47779 decreased, in a dose-dependent manner, the field potential amplitude under both experimental conditions. FBM caused a dose-related decrease of the field potential amplitude only in the absence of external magnesium, suggesting a selective interaction with an NMDA-mediated component of this potential. These findings indicate that the reduction of cortical excitatory transmission might represent a common target for new antiepileptic drugs.

Animals↗