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Biomedical subjects

G Schettini

Publications and source records attributed to G Schettini.

At least 37 records · Page 2Linked to original sources
PubMed1994

Lipopolysaccharide modulation of eicosanoid and corticotrophin-releasing hormone release from rat hypothalamic explants and astrocyte cultures in vitro: evidence for the involvement of prostaglandin E2 but not prostaglandin F2 alpha and lack of effect of nerve growth factor.

Bacterial lipopolysaccharide (LPS) and prostaglandins (PG) E2 and F2 alpha are putative activators of the hypothalamo-pituitary-adrenal axis. Certain of the biological effects of LPS may be mediated by cytokines such as interleukin-1 beta (IL-1 beta), while IL-1 beta itself may operate via induction of the prostaglandins and/or nerve growth factor (NGF). As IL-1 beta stimulates the release of corticotrophin-releasing hormone (CRH) from acute rat hypothalamic explants directly, the effects of these substances on the release of CRH in vitro were investigated in short- and medium-term (20 and 60 min) incubations. The effect of LPS on the release of PGE2 and PGF2 alpha from these explants, as well as from cortical astrocyte cultures, was also studied. LPS did not modify the release of CRH, PGE2 or PGF2 alpha in 20-min incubations. In 60-min incubations, LPS stimulated the release of PGE2, whereas the release of CRH was weakly, but significantly, reduced; PGF2 alpha was not altered. PGE2 significantly stimulated CRH release in the 60-min but not in the 20-min experiments. This effect appeared to be selective for PGE2, since PGF2 alpha did not modify CRH release, alone or in combination. LPS also selectively released PGE2 but not PGF2 alpha from cortical astrocyte cultures after 24-h incubation. NGF had no effect on the release of explant CRH, regardless of the length of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Positive response to compound CV 205-502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine.

The clinical effects of CV 205-502, a potent and non-ergot-derived dopamine agonist, were investigated in 24 selected patients with hyperprolactinemia previously treated with standard oral bromocriptine, the slow-release oral form of bromocriptine (BRC-SRO) and/or the long-acting injectable form of bromocriptine (BRC-LAR); 14 were chosen because of their resistance to treatment and ten because they were intolerant of the different forms of bromocriptine. A macroprolactinoma was present in seven patients and a microprolactinoma in ten, whereas seven had no radiological images of a pituitary tumor and were classified as having non-tumoral hyperprolactinemia. All the 24 patients were treated with CV 205-502 at a daily dose of 0.075-0.6 mg for 3-12 months. All the patients had gonadal dysfunction and galactorrhea. Basal serum prolactin values ranged from 70 to 1677 ng/ml. CV 205-502 was effective in 11 of the 14 patients resistant bromocriptine, BRC-SRO and BRC-LAR; serum prolactin levels became normal within 6 months and a tumor shrinkage was obtained in five of the seven macroprolactinomas. In general, the drug was effective and well tolerated. Only three patients (two resistant and one intolerant) manifested nausea, vomiting and postural hypotension. In conclusion, this study shows that CV 205-502 is effective in bromocriptine-resistant hyperprolactinemic patients. Furthermore, CV 205-502 has insignificant and tolerable side-effects in patients intolerant of bromocriptine. CV 205-502 can, therefore, be considered a useful and effective drug, and an interesting therapeutic alternative to the ergot-derived dopamine-agonist drugs in use today.

Administration, Oral↗
PubMed1993

Norepinephrine and thyrotropin stimulation of [Ca++]i in PC C13 a rat thyroid epithelial cell line: effect of transformation by E1A gene adenovirus and polyomavirus middle-T antigen gene.

The effect of thyrotropin and norepinephrine on cytosolic calcium levels were evaluated in normal (PC C13) and transformed (PC E1A, PC Py and PC E1APy) rat thyroid epithelial cell lines. A different pattern of response to both norepinephrine and thyrotropin was observed among the distinct cell lines. In PC C13 the cytosolic calcium rise induced by norepinephrine, characterized by an early transient spike followed by a second phase of sustained calcium levels, was greatly enhanced by thyrotropin. The effect of norepinephrine on calcium concentrations was less affected by thyrotropin in PC C13 transformed by the adenovirus E1A oncogene. Conversely, in Polyoma middle-T transformed PC C13 the increase in cytoplasmic calcium was still sensitive to thyrotropin. The most malignant PC E1APy were totally independent of thyrotropin.

Adenoviridae↗
PubMed1993

Effect of acetyl-L-carnitine treatment on brain adenylate cyclase activity in young and aged rats.

The aim of the present study has been to evaluate the effect of acetyl-L-carnitine (ALCAR) on brain adenylate cyclase (AC) activity in adult and aged rats. In in vitro studies, ALCAR (1, 10 and 100 microM) did not exert any effect on frontal cortex basal AC activity. Acute and subchronic administrations of ALCAR were carried out in 4- and 25-month-old male Fisher rats and AC activity was determined in rat frontal cortex under both basal and stimulated conditions. The acute treatment of young rats with ALCAR (100 and 500 mg/kg s.c.) did not affect AC activity, whereas the subchronic administration of 250 mg/kg s.c. ALCAR enhanced the stimulation of AC by carbamylcholine (CCh), norepinephrine (NE) and dopamine (DA), without affecting the basal AC activity. Basal AC activity in old rats was lower than in young rats and was not modified by acute and subchronic ALCAR administration. Moreover, the response of the enzyme to CCh, NE and DA was potentiated by the subchronic administration of ALCAR. The concentration-response curve of CCh stimulation of AC activity in ALCAR-treated rats is shifted to the left in both young and aged rats. We conclude that ALCAR, subchronically administered, is able to enhance receptor-stimulated AC response in frontal cortex of both young and aged rats.

Acetylcarnitine↗
PubMed1993

Bacterial lipopolysaccharide induction of IL-6 in rat telencephalic cells is mediated in part by IL-1.

Interleukin-6 (IL-6) appears in the cerebrospinal fluid (CSF) of patients with acute infection of the central nervous system, and in the brains and CSF of experimental animals following systemic or intracerebral injection of bacterial endotoxin (Escherichia coli lipopolysaccharide, LPS). Since LPS is known to induce secretion of interleukin-1 (IL-1) in many cell types including those of the brain, and IL-1 can induce IL-6 in brain tissue it appeared reasonable to postulate that the effects of LPS on IL-6 production were mediated through IL-1 induction. To test this hypothesis, the effects of IL-1 receptor antagonist (IL-1Ra) on LPS and IL-1-induced IL-6 secretion were tested in a mixed brain cell culture from 17-day fetal rat, after 12-14 days in culture. IL-6 secretion was induced by IL-1 beta in a concentration as low as 1 x 10(-10) M (p = 0.0008); addition of IL-1Ra was shown to inhibit IL-1-induced changes by 87% (p = 0.0012) at a molar ratio of 100:1, and by 100% at a molar ratio of 1,000:1, LPS stimulated IL-6 secretion progressively over the concentration of 1-100 ng/ml (p = 0.0001). LPS 10 ng/ml-induced IL-6 secretion was inhibited by 66% by IL-1Ra in a concentration of 1,000 ng/ml (p = 0.0077). The inhibitory effect of IL-1Ra was not significantly greater even when used at a concentration of 5,000 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Direct effect of adenosine on prolactin secretion at the level of the single rat lactotroph: involvement of pertussis toxin-sensitive and -insensitive transducing mechanisms.

We studied the effect of adenosine on prolactin secretion by the anterior pituitary, and the transduction mechanisms whereby the purine exerts its action. Adenosine inhibited prolactin release in basal and in vasoactive intestinal peptide (VIP)- or TRH-stimulated conditions. Pertussis toxin pretreatment reduced the inhibition of VIP-stimulated prolactin secretion which was induced by adenosine, while it completely abolished the effect of the purine on TRH-evoked prolactin release. In membrane preparations of anterior pituitary cells, adenosine reduced the adenylate cyclase activity stimulated by VIP. Such an inhibition was not blocked by pertussis toxin pretreatment. Furthermore, the purine reduced TRH-stimulated inositol phosphate production in cultured anterior pituitary cells, an effect that was reversed by pretreatment with pertussis toxin. In addition, the nucleoside did not significantly affect the TRH-induced rise in intracellular calcium. In conclusion, our data show that adenosine inhibits prolactin secretion, acting on purinergic receptors coupled to the adenylate cyclase enzyme and phospholipase C. The effect of the nucleoside on adenylate cyclase seems to be achieved either by the involvement of an adenosine receptor coupled to the catalytic subunit of the enzyme via a pertussis toxin-sensitive G protein, or by the activation of a site directly coupled to the catalytic subunit of the adenylate cyclase (the P site). Its effect on phospholipase C seems to be mediated by a purinergic receptor coupled to the intracellular effector via a pertussis toxin-sensitive G protein.

Adenosine↗
PubMed1992

Clinical management of prolactinomas: a ten-year experience.

A ten-year experience on 36 patients bearing macroprolactinomas (MP) and 86 others bearing microprolactinomas (mP) is reported in this study. Different therapeutical approaches were used: 1) trans-sphenoidal surgery in 24 patients with MP and in 25 with mP; 2) medical therapy with the oral form of bromocriptine (BRC) in all the 24 patients with MP previously subjected to surgery, in 48 patients with mP ab initio, and in 16 out of 25 patients with mP previously subjected to surgery; 3) medical therapy with the long-acting injectable forms of BRC in 12 MP- and 13 mP-bearing patients, and 4) conventional radiotherapy in 12 of the 24 patients with MP previously subjected to surgery. The follow-up, performed five years after surgery, showed that: a) all the 24 patients with MP but one had normal PRL levels during BRC administration, with a rebound of hyperprolactinemia in all cases after withdrawal; b) during the treatment BRC caused normalization of PRL in 15 of the 16 mP-bearing patients surgically treated and in all the 48 mP-bearing patients only treated with BRC; c) in 20 of the 25 patients the treatment with injectable retard BRC caused the normalization of plasma PRL and the shrinkage of the tumor mass in all the patients with MP but one, as revealed by seriate CT scans. In conclusion, the surgical treatment of prolactinomas was ineffective to normalize plasma PRL levels in most patients whereas BRC, in standard or in retard forms, was able to normalize plasma PRL levels, reduce the tumoral mass and preserve the pituitary residual tissue. BRC should be, therefore, used as first choice therapy both for MP and mP.

Adolescent↗
PubMed1992

Effectiveness and long-term tolerability of the slow release oral form of bromocriptine on tumoral and non-tumoral hyperprolactinemia.

The effectiveness and long-term tolerability of a new formulation of bromocriptine with slow gastrointestinal release (Parlodel SRO) has been evaluated on ten patients with macroprolactinoma, seven patients with microprolactinoma and five patients with nontumoral hyperprolactinemia during a period of 1-30 months. Six out of ten macroprolactinoma-bearing patients obtained a rapid normalization of plasma PRL levels with reduction of the tumor size recorded by CT scan follow-up. Four of six microprolactinomas and all the five nontumoral hyperprolactinemic patients became normoprolactinemic with recovery of gonadal functions while in two other microprolactinomas Parlodel SRO significantly reduced plasma PRL levels with restoration of menses. Only in two patients the treatment was withdrawn for the appearance of side effects. In conclusion, Parlodel SRO is an effective drug in the management of tumoral and nontumoral hyperprolactinemia. The good long-term tolerability together with the hypoprolactinemic activity makes this drug a very good choice therapy in hyperprolactinemic syndromes even in case of poor tolerability to the standard formulation of the drug.

Administration, Oral↗
PubMed1992

Interleukin 6 modulation of second messenger systems in anterior pituitary cells.

We investigated the effect of interleukin-6 (IL-6) on second messenger systems in anterior pituitary (AP) cells. The acute exposition of membranes derived from the pituitary gland to IL-6 did not modify basal and forskolin-stimulated adenylate cyclase (AC) activity, as well as inositol phosphate (IP) production and free [Ca(++)]i. Preincubation of AP cells with IL-6 for 20 min did not affect basal second messengers levels, while completely abolished the stimulation by VIP of AC activity, partially inhibited forskolin-stimulated cAMP formation and reduced TRH-stimulated IP production. Finally, the pretreatment of AP cells for 20 min with IL-6 also reduced the TRH-induced rise in free [Ca(++)]i.

Adenylyl Cyclases↗
PubMed1992

Molecular mechanisms mediating the effects of L-alpha-glycerylphosphorylcholine, a new cognition-enhancing drug, on behavioral and biochemical parameters in young and aged rats.

The behavioral effects of the acute and subchronic administration of L-alpha-glycerylphosphorylcholine (alpha-GPC) on passive and active avoidance behavioral tasks were investigated. When administered IP after training together with scopolamine 2 h before retest, alpha-GPC reverses the scopolamine-induced amnesia in the passive avoidance conditioning in young and old rats. Furthermore, the subchronic treatment with alpha-GPC positively and significantly influences the performance of both young and old animals in the active avoidance test. Moreover, in in vitro/ex vivo experiments alpha-GPC potentiates receptor-stimulated phosphatidylinositol hydrolysis in cortical synaptoneurosomes derived from young and old animals. In young but not old animals, alpha-GPC significantly potentiates potassium (40 mM)-stimulated intrasynaptosomal calcium oscillations in purified synaptosomes derived from the hippocampus. These results show that alpha-GPC improves the performance of animals in both active and passive conditioning tasks. Furthermore, subchronic treatment with the compound enhances in young and restores in aged animals the transduction of the signal, namely, the receptor-mediated production of inositol phosphate and the potassium-induced calcium mobilization. These modifications may represent at least part of the molecular mechanism of action of the compound.

Adenylyl Cyclases↗
PubMed1992

Maitotoxin-induced intracellular calcium rise in PC12 cells: involvement of dihydropyridine-sensitive and omega-conotoxin-sensitive calcium channels and phosphoinositide breakdown.

The biological activities of maitotoxin are strictly dependent on the extracellular calcium concentration and are always associated with an increase of the free cytosolic calcium level. We tested the effects of voltage-sensitive calcium channel blockers (nicardipine and omega-conotoxin) on maitotoxin-induced intracellular calcium increase, membrane depolarization, and inositol phosphate production in PC12 cells. Maitotoxin dose dependently increased the cytosolic calcium level, as measured by the fluorescent probe fura 2. This effect disappeared in a calcium-free medium; it was still observed in the absence of extracellular sodium and was enhanced by the dihydropyridine calcium agonist Bay K 8644. Nicardipine inhibited the effect of maitotoxin on intracellular calcium concentration in a dose-dependent manner. The maitotoxin-induced calcium rise was also reduced by pretreating cells with omega-conotoxin. Pretreatment of cells with maitotoxin did not modify 125I-omega-conotoxin and [3H]PN 200-110 binding to PC12 membranes. Nicardipine and omega-conotoxin inhibition of maitotoxin-evoked calcium increase was reduced by pertussis toxin pretreatment. Maitotoxin caused a substantial membrane depolarization of PC12 cells as assessed by the fluorescent dye bisoxonol. This effect was reduced by pretreating the cells with either nicardipine or omega-conotoxin and was almost completely abolished by the simultaneous pretreatment with both calcium antagonists. Maitotoxin stimulated inositol phosphate production in a dose-dependent manner. This effect was reduced by pretreating the cells with 1 microM nicardipine and was completely abolished in a calcium-free EGTA-containing medium. The findings on maitotoxin-induced cytosolic calcium rise and membrane depolarization suggest that maitotoxin exerts its action primarily through the activation of voltage-sensitive calcium channels, the increase of inositol phosphate production likely being an effect dependent on calcium influx. The ability of nicardipine and omega-conotoxin to inhibit the effect of maitotoxin on both calcium homeostasis and membrane potential suggests that L- and N-type calcium channel activation is responsible for the influx of calcium following exposure to maitotoxin, and not that a depolarization of unknown nature causes the opening of calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Modulation by GTP of basal and agonist-stimulated striatal adenylate cyclase activity following chronic blockade of D1 and D2 dopamine receptors: involvement of G proteins in the development of receptor supersensitivity.

Rats receiving injections of specific antagonists of dopamine receptors (SCH 23390 for D1, haloperidol for D2, and haloperidol+SCH 23390) once daily for 21 days develop a selective supersensitivity of the blocked receptors. To study the molecular correlates of these adaptive changes, we evaluated the involvement of GTP-binding proteins in the development of supersensitivity of dopamine receptors. By means of adenylate cyclase studies, we tested whether any of the treatments modified the functional response to GTP in striata dissected from control and treated rats. Our data show that the chronic blockade of D1 and/or D2 receptors potentiates both basal and dopamine receptor-stimulated adenylate cyclase activity in response to GTP. D1 receptor up-regulation correlates with an increased adenylate cyclase response to GTP, whereas D2 receptor up-regulation is accompanied by an enhanced GTP-induced inhibition of enzyme activity, in both basal and receptor-activated conditions. This potentiation does not seem to match the changes in mRNA content of Gs and Gi alpha subunits. Unexpectedly, however, a significant increase in Gi alpha subunit mRNA was found after the chronic blockade of D1 receptors; this result could be explained by cross-regulation between GTP-binding protein-mediated pathways. This cross-regulation could serve as a protective mechanism whereby cells exposing up-regulated receptors protect themselves from a condition of hyperactivity of the adenylate cyclase enzyme.

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

Evaluation of GH paradoxical responses to TRH and LHRH in acromegalic patients during long-term treatment with octreotide.

In some acromegalics, GH release can be induced by TRH and/or LHRH administration. The pathogenesis of these GH paradoxical responses was supposed to be a somatotroph-reduced sensitivity to somatostatin, somatotrophin release-inhibiting factor (SRIF), or an hypothalamic derangement of the SRIF release. In this study, this hypothesis was investigated by means of GH suppression during chronic therapy with octreotide [Somatostatin analogue (SMS)] in order to evaluate the possible correlation between GH and insulin-like growth factor 1 (IGF-1) normalization and the disappearance of these paradoxical responses in 15 acromegalic patients: 15/15 with a paradoxical GH rise after TRH and 7/15 with a paradoxical GH rise after LHRH. SMS therapy was administered subcutaneously at the dose of 150-450 micrograms/day. During the treatment, GH and IGF-1 levels normalized in 12 patients and were reduced in the remaining 3 others. The GH response to TRH disappeared in 7 patients, while the GH response to LHRH disappeared in 4 patients. chi 2 analysis failed to show any significant correlation between GH and IGF-1 normalization and the disappearance of GH response to TRH and LHRH (chi 2 = 0.00686). No linear correlation existed between GH/IGF-1 decrease and GH peak or area under the curve at any time ('r' values: TRH test, GH -0.47, IGF-1 -0.48; LHRH test, GH -0.50, IGF-1 -0.49). The absence of any significant correlation between GH/IGF-1 normalization and the disappearance of GH paradoxical responses during chronic octreotide administration suggests that other factors apart from SRIF sensitivity are involved in the genesis of these responses.

Acromegaly↗
PubMed1992

Dopamine and somatostatin inhibition of prolactin secretion from MMQ pituitary cells: role of adenosine triphosphate-sensitive potassium channels.

The sulfonylurea glibenclamide, which is known to block ATP-sensitive potassium channels, increases, in a dose-dependent manner, the release of PRL from MMQ pituitary cells. Glibenclamide does not reduce the dopaminergic inhibition of forskolin-stimulated PRL secretion; conversely it almost completely abolishes the inhibitory effect of somatostatin (SRIF) on this parameter. The sulfonylurea dose dependently increases basal [Ca++]i, without affecting the increase in [Ca++]i induced by high concentrations of extracellular potassium. Glibenclamide does not modify dopamine-induced [Ca++]i reduction, whereas it abolishes the inhibitory effect of SRIF on basal [Ca++]i. In the presence of diazoxide, an opener of ATP-sensitive potassium channels, which lowers basal [Ca++]i, dopamine still reduces [Ca++]i whereas SRIF does not induce a further decrease. Glibenclamide induces the depolarization of the cell membrane and prevents the SRIF-evoked hyperpolarization. The hyperpolarization of the cell membrane induced by dopamine is not modified by glibenclamide. Diazoxide induces a cell membrane hyperpolarization that is enhanced by dopamine but not by SRIF. Finally, glibenclamide does not affect basal and stimulated adenylate cyclase activity. In conclusion, our findings show that, in MMQ cells, glibenclamide stimulates PRL release, suggesting an involvement of ATP-sensitive potassium channels in the regulation of PRL secretion. The reversal by glibenclamide of the effects of SRIF on calcium homeostasis, membrane potential, and PRL release suggests that this type of potassium channel participates to the somatostatinergic inhibition of PRL secretion. Conversely, we found that glibenclamide does not modify the dopaminergic inhibition of PRL secretion and second messenger systems, suggesting that ATP-sensitive potassium channels may not be involved in the inhibitory effect of dopamine on PRL release.

Adenosine Triphosphate↗
PubMed1992

Effect of a short-term treatment with recombinant growth hormone (GH) on adrenal responsiveness to corticotrophin stimulation in children affected by isolated GH deficiency.

Recent evidence suggests that GH and insulin growth factor-I (IGF-I) play a role in adrenal steroidogenesis. On the other hand, it has been shown that ACTH stimulates IGF-I secretion by cultured fasciculata adrenal cells. Aim of the present study was to investigate the influence of GH administration on adrenal steroids and IGF-I responsiveness to ACTH in children affected with isolated GH deficiency. Ten children (seven males and three females, 5-10 yr old) affected with isolated GH deficiency underwent a synthetic ACTH 1-17 test before and after administration of human recombinant GH at a dose of 4 IU/day sc for 10 days. After the therapy, no significant differences were detected in the responses of cortisol, dehydroepiandrosterone-sulfate, androstenedione, and 17-hydroxyprogesterone to ACTH 1-17, whereas an increased 11-deoxycortisol responsiveness to ACTH 1-17 was noted (P less than 0.005). Surprisingly, IGF-I significantly increased in response to ACTH 1-17 after short-term rGH administration (P less than 0.006). In conclusion, our data indicate that in isolated GH deficiency a short-term GH therapy does not substantially modify the adrenal responsiveness to exogenous ACTH, even if an increased 11-deoxycortisol and an induced IGF-I responsiveness to ACTH were observed.

Adrenal Glands↗
PubMed1991

Age-related alterations of somatostatin gene expression in different rat brain areas.

Numerous experimental and clinical studies have demonstrated that brain somatostatinergic neurotransmission plays an important role in the modulation of several brain functions, including learning and memory processes. Due to the gradual decline of cognitive performances occurring during aging, we evaluated whether an age-related modification of brain somatostatin gene activity occurred in discrete rat brain areas. Our study demonstrates that a significant reduction of pre-prosomatostatin mRNA levels occurred in aged animals (25 months) in the frontal cortex (-49%), in the parietal cortex (-80%) and in the striatum (-69%), despite the absence of changes in beta-actin gene expression. Conversely, no statistical differences were observed in the pre-prosomatostatin mRNA content of old animals in the hypothalamus. These results demonstrate that age-related alterations in somatostatin gene expression occur in the rat, and suggest that such alterations may be involved in the behavioral and cognitive impairments that occur during the aging process.

Aging↗