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C Missale

Publications and source records attributed to C Missale.

At least 37 records · Page 2Linked to original sources
PubMed1997

Nerve growth factor suppresses the tumoral phenotype of human prolactinomas.

We summarize here our data showing that various phenotypical characteristics distinguish prolactinoma cell lines obtained from responder and nonresponder patients, as defined by their responses to bromocriptine administration. Nonresponder cell lines have a higher degree of malignancy than responder cells and do not express D2 receptors for dopamine. Both cell lines express NGF receptors. Exposure of the most malignant nonresponder cell lines to NGF, both in vitro and when transplanted in vivo in nude mice, results in their differentiation into the responder phenotype reexpressing D2 receptors. Sequential administration of NGF and bromocriptine thus may be a promising therapy for patients refractory to bromocriptine.

Animals↗
PubMed1996

Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism.

Nerve growth factor (NGF) is well characterized for its neurotrophic actions on peripheral sensory and sympathetic neurons and on central cholinergic neurons of the basal forebrain. Recent evidence, however, has shown high levels of NGF to be present in a variety of biological fluids after inflammatory and autoimmune responses, suggesting that NGF is a mediator of immune interactions. Increased NGF serum levels have been reported in both humans and experimental animal models of psychological and physical stress, thus implicating NGF in neuroendocrine interactions as well. The possible source(s) and the regulatory mechanisms involved in the control of serum NGF levels, however, still remain to be elucidated. We now report the presence of both NGF gene transcripts and protein in the anterior pituitary. Immunofluorescence analysis indicated that hypophysial NGF is selectively localized in mammotroph cells and stored in secretory granules. NGF is cosecreted with prolactin from mammotroph cells by a neurotransmitter-dependent mechanism that can be pharmacologically regulated. Activation of the dopamine D2 receptor subtype, which physiologically controls prolactin release, resulted in a complete inhibition of vasoactive intestinal peptide-stimulated NGF secretion in vitro, whereas the specific D2 antagonist (-)-sulpiride stimulated NGF secretion in vivo, suggesting that the anterior pituitary is a possible source of circulating NGF. Given the increased NGF serum levels in stressful conditions and the newly recognized immunoregulatory function of this protein, NGF, together with prolactin, may thus be envisaged as an immunological alerting signal under neuronal control.

Animals↗
PubMed1996

Dopamine receptors and brain function.

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.

Animals↗
PubMed1996

Increase of aldosterone secretion following acute haloperidol administration: possible clinical implications.

The present study was designed to investigate the effect of haloperidol on plasma corticosteroid levels in a small sample of unmediated psychiatric patients requiring acute care. Seven young male normotensive subjects in metabolic balance received a single dose of haloperidol (2 mg i.v.). Blood samples were collected for the radioimmunoassay of plasma renin activity, cortisol and aldosterone concentration at baseline and 3, 6, 12 and 24 h after injection. In five out of seven patients a significant, transient elevation of plasma aldosterone level was observed within 12 h from administration. In contrast, plasma renin activity and cortisol concentration were unchanged. Possible clinical implications of the neuroleptic-associated aldosterone elevations are discussed.

Adult↗
PubMed1996

Nerve growth factor controls proliferation and progression of human prolactinoma cell lines through an autocrine mechanism.

Two different human prolactinoma phenotypes (responders and nonresponders), which are distinguished by different tumorigenic potential and different responsiveness to dopaminergic therapy, have recently been identified. Responders show low proliferation rate, low tumorigenic potential, and expression of D-2 receptors for dopamine (DA), while nonresponders are characterized by high proliferation rate, high tumorigenic potential, and lack of expression of DA D-2 receptors. In this study it has been shown that both gp140trk and gp75 components of nerve growth factor (NGF) receptor are expressed in responder prolactinoma cell lines. High levels of both NGF gene transcript and protein were also found in responders, and biologically active NGF was detectable in the media conditioned by these cells. Ablation of NGF production in responder cells by hybridization arrest of translation through NGF antisense oligonucleotides resulted in: 1) loss of secreted NGF; 2) loss of expression of gp75; 3) loss of expression of DA D-2 receptors; and 4) a remarkable increase in the cell proliferation rate. These results thus suggest that a NGF-mediated autocrine loop essential to control cell proliferation and to preserve some phenotypical characteristics of mammotroph cells is present in responder prolactinoma cell lines. Analysis of nonresponders showed that these cells express gp140trk but no detectable levels of gp75. In addition, no NGF mRNA or protein was detectable in nonresponders. Exposure of these cells to NGF resulted in the permanent expression of NGF mRNA and in the production and secretion of NGF protein, thus establishing the same NGF-mediated autocrine loop present in responders. As a result, it has been shown that nonresponder cells treated with NGF acquire and maintain most of the phenotypic characteristics of normal mammotroph cells. In conclusion, the present work reports that a NGF-mediated autocrine loop with an inhibitory role in the control of cell proliferation and tumor progression is active in the more differentiated DA-sensitive prolactinoma cell lines and is lost in the most malignant prolactinoma cells refractory to the dopaminergic therapy. Alterations in the expression of this autocrine loop thus may lead to cell transformation and tumor progression.

Animals↗
PubMed1995

Different neurotransmitter systems are involved in the development of esophageal achalasia.

Clinical and pharmacological evidence suggests that several neurotransmitters are involved in the control of the esophageal motility; in fact, besides the well known cholinergic and sympathetic innervation, Vasoactive Intestinal Polypeptide (VIP)-containing fibers as well as dopamine (DA)-containing nerve endings have been identified within the esophageal wall. Lower Esophageal Sphincter (LES) achalasia is a neuromuscular disorder characterized by the absence of peristalsis in the body of the esophagus and by the failure of the LES to relax in response to swallowing. Stimulation of both VIP receptors and D-2 DA receptors induce a decrease in LES pressure, while D-1 receptors mediates LES contractions. In the present study we show that both VIP and DA system is disregulated in LES achalasia. In particular, this disease is associated not only with the lack of VIP nerves in the LES, but also with a failure in the responsiveness of postsynaptic receptors to VIP stimulation. Furthermore, we demonstrate a selective functional loss of the D-2 DA receptor component, without changes in the D-1 DA receptor mediated responses.

Adenylyl Cyclases↗
PubMed1995

Nerve growth factor and bromocriptine: a sequential therapy for human bromocriptine-resistant prolactinomas.

Nerve growth factor (NGF) administration to athymic mice with transplanted human bromocriptine-resistant prolactinoma, results in the expression of dopamine D-2 receptors in the tumour and restores sensitivity to subsequent treatment with bromocriptine, which then produces normalisation of plasma prolactin and tumour regression. Sequential administration of NGF and bromocriptine thus may be a promising therapy for patients refractory to bromocriptine.

Animals↗
PubMed1995

Dopaminergic drugs in congestive heart failure: hemodynamic and neuroendocrine responses to ibopamine, dopamine, and dihydroergotoxine.

Ibopamine has hemodynamic and neurohumoral effects potentially useful for the treatment of congestive heart failure (CHF), but its mechanism of action is not completely clear. To evaluate the role of dopaminergic receptor stimulation in the hemodynamic and neurohumoral activity of ibopamine, we compared the effects of ibopamine, 100 mg orally (p.o.) with those of the dopamine 2, 4, and 6 micrograms/kg/min intravenously (i.v.) and of the DA2 agonist dihydroergotoxine 6 micrograms/kg i.v. in 13 patients with chronic CHF [left ventricular ejection fraction (LVEF) < or = 35%]. All patients underwent right heart Swan-Ganz catheterization with determination of hemodynamic parameters at baseline, after 30 min of infusion of each dose of dopamine (DA) and < or = 6 h after ibopamine and dihydroergotoxine administration. Blood samples for the assessment of plasma renin activity (PRA), aldosterone, norepinephrine (NE), and epinephrine (Epi) were also obtained. Ibopamine induced a peak 21% increase of cardiac index (CI) with a 23 and 25% increase in stroke volume (SV) and stroke work indexes (SWI), respectively, and an 18% reduction in systemic vascular resistance (SVR). Similar changes were observed after DA infused at the doses of 2 and 4 micrograms/kg/min, whereas with the dose of 6 micrograms/kg/min heart rate (HR) increased by 23% and SV index (SVI) did not change further. Dihydroergotoxine administration induced only a significant 9% decrease in mean arterial pressure (MAP), with a 13% reduction in SVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Nerve growth factor promotes the differentiation of pituitary mammotroph cells in vitro.

It is well known that the differentiation of somatotroph cells is dependent on GRF. The extracellular signals that direct the initial proliferation and differentiation of mammotroph cells during pituitary development, however, have remained elusive. In the present study we first report that somatomammotroph and mammotroph cells present in early postnatal rat pituitary cultures express the receptor for nerve growth factor (NGF) and contain NGF. In addition, we demonstrate that endogenous NGF supports the proliferation and terminal differentiation of mammotroph cells during postnatal in vitro maturation. Early postnatal rat pituitary cells were cultured for 1-12 days, double stained with antibodies to PRL and GH, and analyzed by fluorescence-activated cell sorting. Mature mammotroph cells were generated in culture as shown by 1) the increase in PRL production, 2) the spreading of cells secreting only PRL in relation to those producing both PRL and GH, and 3) the expression of D-2 receptors for dopamine. Exposure of cell cultures to NGF produced a remarkable increase in the rate of appearance of mammotroph cells and an increase in their abundance from 20 +/- 0.5% to 44 +/- 1%. Deprivation of secreted NGF by means of a specific antibody completely prevented the generation of mature mamotrophs. The fluorescence-activated cell sorting analysis of cells grown in the presence of the antibody to NGF showed, in fact, that although the proportions of somatotrophs and somatomammotrophs were unchanged, that of mammotrophs was much lower than that in untreated cultures. We, thus, conclude that NGF is critical for generation of the mammotroph phenotype during pituitary maturation.

Animals↗
PubMed1994

Opposing roles for D-1 and D-2 dopamine receptors in the regulation of lower esophageal sphincter motility in the rat.

In the present study we have identified biochemically DA receptors in rat Lower Esophageal Sphincter (LES) and have identified their role in the control of the sphincter motility. Dopamine (DA) both stimulated and inhibited cyclic AMP formation in rat LES; the pharmacological characterization of these effects indicated that they were mediated by D-1 and D-2 receptors, respectively. The results obtained with LES helical strips showed that DA plays both inhibitory and stimulatory effects on the sphincter function; the pharmacological characterization with selective D-1 and D-2 agonists and antagonists strongly suggested that D-1 receptors are involved in LES contraction, while D-2 receptors mediate the relaxation of the sphincter. The same results were obtained by measuring intraluminal LES pressure in anesthetized rats. The selective D-1 agonist fenoldopam (40 micrograms/kg, i.v.) increased the LES pressure; on the other hand bromocriptine (10 micrograms/kg, i.v.), which preferentially interacts with D-2 receptors, induced a decrease of the resting LES pressure.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Epidermal growth factor promotes uncoupling from adenylyl cyclase of the rat D2S receptor expressed in GH4C1 cells.

In anterior pituitary cells or when transfected into host cell lines, the D2 dopamine receptor inhibits adenylyl cyclase and activates potassium channels. The GH-3 pituitary tumor cell line, which lacks functional D2 receptors, responds to epidermal growth factor (EGF) by expressing a D2 receptor that, paradoxically, couples to potassium channel activation but poorly inhibits adenylyl cyclase; this was correlated with a pronounced increase in alpha subunit of the G protein Gi3. In this study we have investigated the effects of EGF on the transduction mechanisms of D2 receptors in GH4C1 cells transfected and permanently overexpressing the rat short D2 receptor. Activation of D2 receptors in these cells resulted in both inhibition of adenylyl cyclase and opening of potassium channels and inhibition of prolactin release by both cyclic AMP-dependent and independent mechanisms. Exposure of the transfected GH4C1 cells to EGF caused a dramatic decrease in the coupling efficiency of the D2 receptor to inhibit cyclic AMP-dependent responses, leaving its activity toward potassium channels unchanged. The EGF treatment led to the concomitant increase in the membrane content of Gi3 protein. These results suggest that the transmembrane signaling specificity of G protein-coupled receptors can be modulated by the relative amounts of different G proteins at the cell membrane.

Adenylyl Cyclase Inhibitors↗
PubMed1994

Nerve growth factor directs differentiation of the bipotential cell line GH-3 into the mammotroph phenotype.

GH-3 is an established cell line which, for the production of both PRL and GH, may be related to the bipotential somatomammotroph from which both somatotroph and mammotroph cells derive. In the present study we first report that GH-3 cells express both the gp140trk and the gp75 components of the nerve growth factor (NGF) receptor and that NGF dictates a nonneuronal type of differentiation of this cell line of ectodermal origin. After exposure to NGF, GH-3 cells markedly decreased their proliferation rate. This effect, which was maximal (50% inhibition) 3 days after beginning the treatment and was maintained during the following days of exposure, was paralleled by a change in the hormone production. The secretion of PRL was increased 6-fold, but that of GH was remarkably inhibited. Moreover, GH-3 cells expressed the mammotroph-specific D-2 receptor protein in response to NGF, as shown by binding with the D-2 receptor ligand N-(p-aminophenetyl)spiperone coupled to fluorescein. The present data thus show that NGF induces the differentiation of GH-3 cells into one of their physiological counterparts, the mammotroph cell, and together with the finding that NGF receptors are expressed in the anterior pituitary suggest a physiological role for the neurotrophic factor in pituitary ontogenesis.

Cell Differentiation↗
PubMed1993

Nerve growth factor suppresses the transforming phenotype of human prolactinomas.

The most effective therapy of human prolactinomas is represented by dopamine D-2 receptor agonists; there is, however, a population of nonresponder patients who require surgical intervention. In the present study, we report that prolactinomas totally resistant to pharmacological therapy have a high potential of both growing in soft agar and forming tumors in nude mice and lack D-2 receptors for dopamine. These tumors express the receptors for nerve growth factor (NGF) and are sensitive to its differentiating activity. After exposure to NGF for 4 days, prolactinoma cells decreased their proliferation rate, lost their capability to form colonies in soft agar, lost their tumorigenic activity in nude mice, and reexpressed the lactotroph-specific D-2 receptor protein inhibiting prolactin release. These effects were permanent after NGF withdrawal and were reproducible in vivo in nude mice transplanted with the tumors. NGF in fact remarkably and lastingly depressed tumor growth and induced expression of D-2 receptors when injected intravenously once a day for 5 days into prolactinoma-bearing nude mice. These data suggest that NGF may induce a long-lasting switch of gene expression in human prolactinomas, modifying their transforming phenotype and reverting them to more differentiated, less malignant, dopamine-sensitive lactotroph-like cells. The possibility thus arises that short-term treatment with NGF may restore the refractory patients to conventional pharmacological therapy with D-2 agonists.

Animals↗
PubMed1992

L-alpha-glycerylphosphorylcholine antagonizes scopolamine-induced amnesia and enhances hippocampal cholinergic transmission in the rat.

The effects of L-alpha-glycerylphosphorylcholine (alpha-GPC) on scopolamine-induced memory impairment and on brain acetylcholine (ACh) synthesis and release were investigated in rats. Oral administration of alpha-GPC 3 h before the behavioural test prevented the learning impairment induced by scopolamine given 30 min before the acquisition of a passive avoidance response. Similarly, retrograde amnesia induced by scopolamine, given immediately after acquisition training, was also completely reversed by the drug. These effects were dose-dependent with a maximum at 300 mg/kg. The mechanism of action of this compound was investigated by measuring hippocampal ACh synthesis and release both in vivo by means of the microdialysis technique and in vitro in tissue slices. alpha-GPC dose dependently increased ACh release with a maximum at 300 mg/kg. In addition, i.v. injection of [14C]alpha-GPC resulted in [14C]ACh formation. The data suggest that the behavioural effects of alpha-GPC may be related to its property to increase hippocampal ACh synthesis and release.

Acetylcholine↗