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Biomedical subjects

P Calabresi

Publications and source records attributed to P Calabresi.

At least 163 records · Page 9Linked to original sources
PubMed1992

Activation of quisqualate metabotropic receptors reduces glutamate and GABA-mediated synaptic potentials in the rat striatum.

The role of quisqualate (QUIS) metabotropic receptors in the synaptic transmission in the striatum was investigated using the cortico-striatal slice preparation. Low concentrations (1-30 microM) of trans-1-amino-cyclopentyl-1,3- dicarboxylic acid (t-ACPD), a selective agonist of QUIS metabotropic receptors, decreased glutamate-mediated synaptic potentials (EPSPs) evoked in the striatum by the stimulation of cortico-striatal fibers. This agonist decreased also GABA-mediated depolarizing synaptic potentials evoked by intrastriatal stimulation in the presence of 6-cyano-7-nitro-quinoxaline-2,3- dione (CNQX); this effect was less potent than the action of t-ACPD on glutamate-mediated potentials. Low concentrations of t-ACPD did not affect the intrinsic membrane properties of striatal neurons and their postsynaptic responses to exogenous glutamate and GABA. Higher concentrations (50-100 microM) to t-ACPD caused membrane depolarizations and inward currents in several neurons. Our data suggest that low concentrations of t-ACPD selectively reduce synaptic transmission while higher concentrations of this agonist may cause a direct excitatory action on striatal neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

In vivo selection of a highly metastatic cell line from a human pancreatic carcinoma in the nude mouse.

A cell line with high metastatic capacity to the liver was established by sequential passages of a human pancreatic cancer cell line through the nude mouse liver. A subline, L3.5, established after five passages of the fast-growing variant (FG) of the human pancreatic cancer COLO 357 through the nude mouse liver produced extensive hepatic metastases in 100% of experimental animals when injected into the spleen. The incidence of pulmonary metastases decreased from 43% for FG to 9% for L3.5. The L3.5 cell line showed aggressive growth with almost complete replacement of the hepatic parenchyma in one third of the mean time required for the development of macroscopic metastases of FG in the liver after splenic injections of tumor cells. This study indicates that the nude mouse provides a good model for in vivo selection of metastatic cells from human pancreatic cancer. The L3.5 cell line will be valuable in the study of human pancreatic cancer metastasis, particularly in the area of survival and growth of metastatic cells in the microenvironment of the liver.

Adenocarcinoma↗
PubMed1992

Antitumor activity of basic fibroblast growth factor-saporin mitotoxin in vitro and in vivo.

Many cancer cell lines express basic fibroblast growth factor (FGF) receptors, making them potential targets for the delivery of FGF-based cytotoxic compounds. To this end, we have investigated the antitumor activity of a novel mitotoxin, Fibroblast Growth Factor-saporin (FGF-SAP), a conjugate of FGF and the ribosome-inactivating protein, saporin. In vitro, FGF-SAP is cytotoxic for human melanoma, teratocarcinoma, and neuroblastoma cells expressing FGF-receptors. Mice treated with FGF-SAP i.v., on a variety of schedules, showed dramatic tumor growth inhibition with minimal toxicity. Thus, FGF-SAP appears to be a well-tolerated and potent antitumor agent. The potential of FGF-targeted cytotoxicity is discussed.

Animals↗
PubMed1992

Chronic neuroleptic treatment: D2 dopamine receptor supersensitivity and striatal glutamatergic transmission.

We studied the in vitro electrical activity of rat neostriatal neurons following chronic neuroleptic treatment. In haloperidol-treated rats, unlike naive animals, activation of neostriatal D2 dopamine receptors induced a potent presynaptic inhibition of glutamate-mediated excitatory synaptic potentials. Haloperidol treatment did not affect the intrinsic membrane properties of the neostriatal neurons. Pre- and postsynaptic physiological responses to direct and indirect gamma-aminobutyric acid (GABA)-ergic and cholinergic agonists were not affected by chronic haloperidol treatment. These findings suggest that movement disorders induced by chronic neuroleptic treatment may result, at least in part, from a hypersensitivity of presynaptic D2 dopamine receptors regulating the release of glutamate.

Aging↗
PubMed1992

Receptors for platelet-derived growth factor on microvascular endothelial cells.

Endothelial cells are widely thought to be unresponsive to platelet-derived growth factor (PDGF) and devoid of PDGF receptors. However, in examining the growth factor responses of microvascular endothelial cells isolated from human omental adipose tissue, we detected PDGF-induced tyrosine phosphorylation of an 180-kD glycoprotein, subsequently identified as the cellular receptor for PDGF by specific immunoprecipitation. Scatchard analysis of 125I-PDGF binding to human microvascular endothelial cells revealed 30,000 PDGF receptors/cell with a kD of 0.14 nM. PDGF stimulated tyrosine phosphorylation of PDGF and other cellular proteins in a dose- and time-dependent manner, with half-maximal receptor phosphorylation occurring at 0.3 nM recombinant human PDGF-BB within 1 min of PDGF exposure. Normal cellular consequences of receptor activation were also observed, including tyrosine phosphorylation of a 42-kD protein and serine phosphorylation of ribosomal protein S6. Furthermore, PDGF was mitogenic for these cells. The finding of functional PDGF receptors on human microvascular endothelial cells suggests an important direct role for PDGF in neovascularization.

Adipose Tissue↗
PubMed1992

The electrophysiological actions of dopamine and dopaminergic drugs on neurons of the substantia nigra pars compacta and ventral tegmental area.

The dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area play a crucial role in regulating movement and cognition respectively. Several lines of evidence suggest that a degeneration of dopaminergic cells in the substantia nigra produces the symptoms of Parkinson's disease. On the other hand, a hyperactivity of the dopaminergic transmission in the brain induces dyskinesia, dystonia and psychosis. It is also well established that the euphoric and rewarding responses evoked by drugs of addiction, such as amphetamine and cocaine, are mediated by central dopamine systems. Electrophysiological experiments which study the activity of single dopaminergic neurons in the ventral mesencephalon have shown that dopamine and dopaminergic drugs reduce the firing frequency of these cells. This is due to the stimulation of D2-D3 autoreceptors and to a hyperpolarization of the membrane produced by an increase in potassium conductance. In addition, substances which increase the release (amphetamine), the synthesis (levodopa) or block the uptake (cocaine, nomifensine, amineptine) of dopamine in the brain inhibit the firing activity of the dopaminergic cells throughout dopamine-mediated mechanisms. In this review, we will briefly examine the literature concerning the physiological and behavioural responses caused by dopamine and dopaminergic agents on the dopaminergic neurons of the ventral mesencephalon. Our conclusion suggests that the electrophysiological actions of dopamine and dopamine-related drugs on dopaminergic cells in the ventral mesencephalon might be indicative of the pharmacological effects of these agents on the brain.

Animals↗
PubMed1992

Migraine with aura-like syndrome due to arteriovenous malformation. The clinical value of transcranial Doppler in early diagnosis.

Arteriovenous malformations are an acknowledged cause of migraine that can long constitute the only clinical manifestation before bleeding. We describe two cases of patients suffering from symptoms like migraine with aura in whom arteriovenous malformations were detected by transcranial Doppler examination. We suggest that a screening of migraine patients to prevent bleeding from a possible underlying unruptured arteriovenous malformation could be performed by using transcranial Doppler, a non-invasive and low cost examination.

Adult↗
PubMed1992

Basic fibroblast growth factor production and growth factor receptors as potential targets for melanoma therapy.

A number of growth factors can stimulate the proliferation of human malignant melanoma cell lines. We investigated the effects of exogenous growth factors including basic fibroblast growth factor (bFGF), epidermal growth factor, transforming growth factor-alpha, insulin, insulin-like growth factor-I (IGF-I), acidic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta and nerve growth factor on six human metastatic melanoma cell lines. The mitogenic activity of each growth factor was tested using the [3H]thymidine incorporation assay. There was a variable response of the different cell lines to most growth factors. All of the melanoma cell lines tested responded to IGF-I. Furthermore, the effects of growth factors were additive, a combination of bFGF and IGF-I having the greatest effect on three melanoma cell lines tested. The quantitative radioimmunoassay for bFGF and [125I]bFGF binding assay revealed that all of these melanoma cell lines produced bFGF and expressed high affinity receptors for bFGF. A 20-mer antisense oligodeoxynucleotide against the AUG initiation site of the bFGF coding region inhibited the proliferation of Mel-Tang by 40% (p less than 0.0001) and that of SK-MEL-5 by 20% (p less than 0.005), suggesting that these cell lines are at least under partial autocrine control of proliferation by bFGF. The presence of bFGF receptors on a high percentage of melanoma cell lines makes these a potential target for melanoma therapy.

Base Sequence↗
PubMed1992

Long-term synaptic depression in the striatum: physiological and pharmacological characterization.

The effect of tetanic activation of corticostriatal glutamatergic fibers was studied in striatal slices by utilizing extracellular and intracellular recording techniques. Tetanic stimulation produced a long-term synaptic depression (LTD) (> 2 h) of both extracellularly recorded field potentials and intracellularly recorded EPSPs. LTD was not coupled with changes of intrinsic membrane properties of the recorded neurons. In some neurons, repetitive cortical activation produced a short-term posttetanic potentiation (1-3 min). Subthreshold tetanic stimulation, which under control condition did not cause LTD, induced LTD when associated with membrane depolarization. Moreover, LTD was not expressed in cells in which the conditioning tetanus was coupled with hyperpolarization of the membrane. Bath application of aminophosphonovalerate (30-50 microM), an antagonist of NMDA receptors, did not affect the amplitude of the synaptic potentials and the expression of LTD. Striatal LTD was significantly reduced by the pretreatment of the slices with 30 microM 2-amino-3-phosphonopropionic acid, an antagonist of glutamate metabotropic receptors. LTD was not blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. Scopolamine (3 microM), an antagonist of muscarinic receptors, induced a slight, but significant, increase of the amplitude of LTD. Both SCH 23390 (3 microM), an antagonist of D1 dopamine (DA) receptors, and I-sulpiride (1 microM), an antagonist of D2 DA receptors, blocked LTD. LTD was also absent in slices obtained from rats in which the nigrostriatal DA system was lesioned by unilateral nigral injection of 6-hydroxydopamine. In DA-depleted slices, LTD could be restored by applying exogenous DA (30 microM) before the conditioning tetanus. In DA-depleted slices, LTD could also be restored by coadministration of SKF 38393 (3-10 microM), a D1 receptor agonist, and of LY 171555 (1-3 microM), a D2 receptor agonist. Application of a single class of DA receptor agonists failed to restore LTD. These data show that striatal LTD requires three main physiological and pharmacological conditions: (1) membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, (2) activation of glutamate metabotropic receptors, and (3) coactivation of D1 and D2 DA receptors. Striatal LTD may alter the output signals from the striatum to the other structures of the basal ganglia. This form of synaptic plasticity can influence the striatal control of motor activity.

2-Amino-5-phosphonovalerate↗
PubMed1991

Nomifensine but not amantadine increases dopamine-induced responses on rat substantia nigra zona compacta neurons.

Responses of substantia nigra zona compacta neurons to nomifensine and amantadine were studied with intracellular recording techniques (current and voltage clamp) in in vitro slice preparation of rat mesencephalon. The application of nomifensine (1-10 microM) slightly hyperpolarized the cells and inhibited action potential discharge that occurs spontaneously. In voltage-clamp experiments (-50, -60 mV, holding potential) an outward current was observed. The membrane responses to exogenously-applied dopamine were potentiated by the concomitant superfusion of nomifensine. The effects of nomifensine were antagonized by (-)-sulpiride (1 microM), a D2 receptor antagonist. By contrast, the superfusion of amantadine (1-30 microM) on substantia nigra zona compacta cells was ineffective on firing rate, membrane potential or on sensitivity to exogenous dopamine. In the presence of high doses (300 microM to 1 mM) of amantadine a depolarization and an increase in firing activity was observed. While our results provide electrophysiological evidence for an inhibition of the dopamine uptake system by nomifensine, they do not support a dopaminergic mechanism for the actions of amantadine in the substantia nigra zona compacta.

Amantadine↗
PubMed1991

Tissue-specific expansion of uridine pools in mice. Effects of benzylacyclouridine, dipyridamole and exogenous uridine.

The concentration of uridine (Urd) in murine tissues appears to be controlled by Urd catabolism, concentrative Urd transport, and the non-concentrative, facilitated diffusion of Urd. Previous reports document the tissue-specific disruption of these processes, and subsequently intracellular pools of free Urd in mice, by the administration of exogenous Urd (250 mg/kg) or the Urd phosphorylase (EC 2.4.2.3; uracil:ribose-1-phosphate phosphotransferase) inhibitor 5-benzylacyclouridine (BAU) (240 mg/kg). We now report the effect of combinations of BAU (120 mg/kg, p.o.), the nucleoside transport inhibitor dipyridamole (DP) (25 mg/kg, i.p.), and exogenous Urd (250 mg/kg, i.v.) on Urd pools in mice. This dose of BAU increased Urd pools 2- to 6-fold, in a tissue-specific manner, for up to 5 hr. DP increased Urd pools 3-fold in spleen, over a 4-hr period, but did not affect other tissues. Administration of BAU 1 hr prior to exogenous Urd resulted in a 50- to 100-fold expansion of tissue normal after 6 hr. Administration of DP 1 hr prior to exogenous Urd caused a tissue-specific 40- to 100-fold increase in Urd pools which, except in spleen, returned to normal within 2 hr. The marked additive effects of these combinations were in contrast to those obtained following the administration of BAU 1 hr prior to DP. This regimen increased Urd pools from 4- to 9-fold, in a tissue-specific manner. In addition, Urd pools remained elevated for up to 9 hr, except in spleen where the Urd concentration was elevated for up to 15 hr. Analysis of enzyme activities indicated that DP does not enhance the inhibitory effect of BAU against murine liver Urd phosphorylase. However, DP did inhibit plasma clearance of BAU, and this effect may partially explain the apparent synergistic effect of this combination. In spite of the prolonged and dramatic expansion of tissue Urd pools produced by BAU + DP, the total Ura nucleotide content in spleen, gut and colon tumor 38 (CT38) increased by less than 70% over a 12-hr period following administration of this combination. These findings are discussed in light of their biochemical and therapeutic implications.

Administration, Oral↗
PubMed1991

Dopamine uptake inhibition potentiates the effects of L-DOPA on rat substantia nigra zona compacta neurons.

Intracellular electrophysiological recordings (current and voltage-clamp mode) were used to assess whether the actions of L-DOPA on rat substantia nigra zona compacta neurons maintained in vitro are potentiated by drugs that block the dopamine uptake system (cocaine and nomifensine). Bath application of L-DOPA (100 microM) hyperpolarized the dopaminergic cells and inhibited the spontaneous occurring action potential discharge. Under voltage-clamp experiments, L-DOPA produced an outward current that was related to the hyperpolarization of the membrane. In the presence of 10 microM cocaine and 10 microM nomifensine, the cellular responses to L-DOPA application were augmented and prolonged. In contrast to this, amphetamine (a dopamine releasing drug), did not augment the membrane response to L-DOPA. Cocaine (10 microM), nomifensine (10 microM) and amphetamine (3 microM), slightly hyperpolarized the membrane potential and inhibited the firing activity of the cells. It is concluded that the dopamine uptake system have an important role in regulating the cellular responses (membrane hyperpolarization or outward current) to L-DOPA application in the substantia nigra zona compacta.

Action Potentials↗
PubMed1991

Human microvascular endothelial cells express receptors for platelet-derived growth factor.

Endothelial cells have been widely thought to be unresponsive to platelet-derived growth factor (PDGF, a major growth factor released from stimulated platelets at the sites of vascular insults) and devoid of PDGF receptors. Nevertheless, in examining the growth-factor responses of microvascular endothelial cells isolated from human omental adipose tissue, we were surprised to detect PDGF-induced tyrosine phosphorylation of a 180-kDa glycoprotein, subsequently identified as the cellular receptor for PDGF by specific immunoprecipitation. Scatchard analysis of 125I-labeled PDGF binding to human microvascular endothelial cells revealed 30,000 PDGF receptors per cell with a Kd of 0.14 nM. PDGF stimulated tyrosine phosphorylation of PDGF receptors and other cellular proteins in a dose- and time-dependent manner, with half-maximal receptor phosphorylation occurring at 0.3 nM recombinant human PDGF (B chain) and a less than or equal to 1-min exposure to PDGF. Normal cellular consequences of receptor activation were also observed, including tyrosine phosphorylation of a 42-kDa protein and serine phosphorylation of ribosomal protein S6. Furthermore, PDGF was mitogenic for these cells. Microvascular endothelial cells play a central role in neovascularization required for wound healing and solid tumor growth. Thus, the discovery of functional PDGF receptors on human microvascular endothelial cells suggests a direct role for PDGF in this process.

Cell Division↗
PubMed1991

GABA depolarizes neurons in the rat striatum: an in vivo study.

GABA, applied by iontophoresis to striatal neurons of the rat in an in vivo preparation, depolarized the membrane potential and decreased the input resistance in a dose-dependent manner. The null potential of the GABA depolarization was about -50 mV. In addition, a fading of the GABA-induced response was observed for prolonged and relatively high amino acid application. We conclude that GABA has a depolarizing effect on striatal cells. This is in line with recent in vitro works describing a depolarizing effect of GABA in the rat neostriatum.

Animals↗
PubMed1991

Electrophysiological effects of amineptine on neurones of the rat substantia nigra pars compacta: evidence for an inhibition of the dopamine uptake system.

1. Intracellular recordings were made from substantia nigra pars compacta neurones of the rat maintained in vitro in order to study the effects of the tricyclic antidepressant drug, amineptine. 2. Amineptine hydrochloride (1-30 microM) decreased spontaneous firing and slightly hyperpolarized the membrane potential. In neurones voltage-clamped at -50 or -60 mV, amineptine produced an outward membrane current. These actions were concentration-dependent and were completely antagonized by (-)-sulpiride. 3. The amineptine-induced hyperpolarization was resistant to tetrodotoxin (1 microM) but it was abolished in 0 mM Ca2+ (plus 13 mM MgCl2) solutions. 4. Amineptine (300 nM-30 microM) and cocaine (10-30 microM) increased the amplitude and duration of responses to exogenously applied dopamine. The effects of dopamine were potentiated about 5 fold by 10 microM amineptine; this potentiation persisted in calcium-free solutions. 5. Cocaine (10 microM) had no additional effect on the dopamine-induced responses in the presence of amineptine (30 microM). Amineptine (10 microM) produced no detectable effects in the presence of cocaine (30 microM). 6. It is concluded that amineptine acts as a dopamine uptake blocker in slices of rat substantia nigra.

Animals↗