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Biomedical subjects

F Nicoletti

Publications and source records attributed to F Nicoletti.

At least 235 records · Page 13Linked to original sources
PubMed1989

Repeated calcitonin treatment reduces the stimulation of inositol phospholipid by norepinephrine and serotonin in rat hippocampus and cerebral cortex.

Stimulation of inositol phospholipid hydrolysis by norepinephrine or 5-hydroxytryptamine was reduced in hippocampal or cortical slices from rats repeatedly injected with (Asu1.7)eel-calcitonin (2.5 IU/kg i.p.). This effect was specific, as the basal or carbamylcholine-stimulated inositol phospholipid hydrolysis was unchanged in slices from calcitonin-injected animals. The reduced responsiveness to norepinephrine did not reflect a decreased number or affinity of alpha 1-adrenergic recognition sites, suggesting that calcitonin treatment leads to a reduced coupling between alpha 1-adrenoceptors and phospholipase C.

Animals↗
PubMed1989

Activation of excitatory amino acid receptors reduces thymidine incorporation and cell proliferation rate in primary cultures of astrocytes.

Addition of quisqualate (a heterocyclic analogue of glutamate) reduced [methyl-3H]thymidine incorporation and cell proliferation in primary cultures of rat cortical astrocytes. The inhibitory action of quisqualate was mimicked by glutamate and ibotenate, whereas kainate, N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) were inactive. These results suggest that activation of a specific class of excitatory amino acid receptors contributes to the regulation of growth and proliferation of glial cells in primary culture.

Animals↗
PubMed1989

Induction of protooncogene fos by extracellular signals in primary glial cell cultures.

In the present study various extracellular factors, acting through different second messenger systems, were examined for their capacity to increase the level of c-fos mRNA in primary glial cell cultures. In particular EGF, 12-O-tetradecanoylphorbol 13-acetate, the beta-adrenergic agonist isoproterenol, and the glutamate agonists, ibotenic and quisqualic acid, were studied. All the extracellular stimuli tested induced a rapid and transient increase in c-fos mRNA level in glial cell cultures regardless of the signal transduction pathway and the final effect on cell proliferation.

Animals↗
PubMed1989

Gangliosides attenuate NMDA receptor-mediated excitatory amino acid release in cultured cerebellar neurons.

Release of both D-[3H]aspartate and endogenous amino acids was measured in primary cultures of cerebellar granule cells. Two hour-pretreatment with the glycosphingolipids, GM1 or GT1b, attenuated the stimulation of excitatory amino acid release induced by depolarizing concentrations of K+ (50 mM). Gangliosides inhibited the phencyclidine (PCP)-sensitive component of depolarization-induced release, i.e. the amplification of release that follows activation of NMDA receptors by the endogenous glutamate.

Amino Acids↗
PubMed1989

Inositol hexakisphosphate (phytic acid) enhances Ca2+ influx and D-[3H]aspartate release in cultured cerebellar neurons.

Inositol hexakisphosphate (InsP6) increased 45Ca2+ uptake in cultured cerebellar granule cells. This increase was concentration dependent (EC50 = 20 microM), exhibited slow kinetics, and was present after 5 days of cell maturation in culture. InsP6 also enhanced D-[3H]aspartate release in cerebellar granule cells at 11-12 days in vitro. Stimulation of 45Ca2+ uptake was also produced by inositol pentakisphosphate but not by inositol 1,3,4,5-tetrakisphosphate. The increase in 45Ca2+ influx induced by InsP6 was independent of extracellular Na+ and was only partially reduced by the organic calcium channel blocker nifedipine. The intrinsic action of InsP6 was not affected by competitive or noncompetitive glutamate receptor antagonists. In addition, stimulations of 45Ca2+ uptake by InsP6 and glutamate were additive. These data provide evidence that InsP6 directly activates a specific population of neurons in the CNS.

Animals↗
PubMed1989

Stimulation of inositol phospholipid hydrolysis by excitatory amino acids is enhanced in brain slices from vulnerable regions after transient global ischemia.

Stimulation of inositol phospholipid hydrolysis by transmitter receptor agonists was measured in slices from hippocampus, cerebral cortex, and corpus striatum at various intervals after transient global ischemia in rats. Ischemia was induced through the four-vessel occlusion model. Stimulation of [3H]inositol monophosphate formation by excitatory amino acids was greatly enhanced in hippocampal slices prepared from ischemic rats at 24 h or 7 days after reperfusion. This potentiation was more evident using ibotenic acid and was also observed in cerebral cortex, but not in corpus striatum. This regional profile correlated with the pattern of ischemia-induced neuronal damage observed under our experimental conditions. The enhanced responsiveness to excitatory amino acids was always accompanied by an increase in both basal and norepinephrine-stimulated [3H]inositol monophosphate formation. In contrast, stimulation of [3H]inositol monophosphate formation by carbamylcholine was not modified in hippocampal or cortical slices from ischemic animals.

Animals↗
PubMed1989

Glycine potentiates the stimulation of inositol phospholipid hydrolysis by excitatory amino acids in primary cultures of cerebellar neurons.

Glycine potentiates stimulation of inositol phospholipid hydrolysis by glutamate and N-methyl-D-aspartate, but not by quisqualate or carbamylcholine, in primary cultures of cerebellar granule cells. This potentiation occurs in the absence of extracellular Mg2+, but is more evident when stimulation of inositol phospholipid hydrolysis by N-methyl-D-aspartate is measured in the presence of 1 mM Mg2+. The action of glycine is not antagonized by strychnine. These results suggest that glycine acts as a positive modulator of signal transduction at a specific class of N-methyl-D-aspartate-sensitive glutamate receptors coupled to inositol phospholipid hydrolysis in cerebellar granule cells.

Amino Acids↗
PubMed1988

Pertussis toxin inhibits signal transduction at a specific metabolotropic glutamate receptor in primary cultures of cerebellar granule cells.

In primary cultures of cerebellar granule cells, glutamate receptors have been classified into metabolotropic (GP1 and GP2) and ionotropic (GC1 and GC2). The GP1 and GC1 receptors are negatively modulated by magnesium and noncompetitively inhibited by phencyclidine; GP2 and GC2 receptors are insensitive to inhibition by magnesium and phencyclidine (Costa, Fadda, Kozikowski, Nicoletti and Wroblewski, 1988). Exposure of cultured cerebellar granule cells to pertussis toxin (PTX, 1 microgram/ml for 14-16 hr) reduced the stimulation of the hydrolysis of inositol phospholipids (PI) by the GP2 receptor agonists, glutamate and quisqualate in the presence of magnesium, but did not inhibit the stimulation of the hydrolysis of PI by GP1 receptor agonists. The stimulation of the hydrolysis of PI by the muscarinic cholinergic receptor agonist, carbamylcholine, remained unchanged after pretreatment with pertussis toxin. In membranes prepared from cerebellar granule cells in primary culture, the addition of guanosine 5'-0-(3-thiotriphosphate) (GTP-gamma-s), a nonhydrolyzable analogue of GTP, enhanced the hydrolysis of PI and reduced the Bmax of quisqualate-displaceable binding of [3H]glutamate. These results indicate that, in primary cultures of cerebellar granule cells, a specific class of metabolotropic glutamate receptors (the GP2 receptor) is coupled with the hydrolysis of PI through a pertussis toxin-sensitive GTP-binding protein.

Animals↗
PubMed1988

Spatial learning potentiates the stimulation of phosphoinositide hydrolysis by excitatory amino acids in rat hippocampal slices.

Stimulation of phosphoinositide (PI) hydrolysis by excitatory amino acids (glutamate and ibotenate) or norepinephrine was potentiated in hippocampal slices from rats trained in an eight-arm radial maze, used as a test of spatial learning. No difference in basal or carbamylcholine-stimulated PI hydrolysis was found between control and trained animals. An increased PI response to excitatory amino acids and norepinephrine was not found in hippocampal slices prepared from animals trained in a shock conditioning avoidance test. These results suggest a possible involvement of specific glutamate receptors coupled with PI hydrolysis in the synaptic mechanisms underlying formation and/or storage of spatial memory.

Animals↗
PubMed1988

Phorbol esters attenuate glutamate-stimulated inositol phospholipid hydrolysis in neuronal cultures.

The phorbol diesters 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate, but not 4-alpha-phorbol-didecanoate, inhibited the stimulation of inositol phospholipid hydrolysis by excitatory amino acids and carbamylcholine in primary cultures of cerebellar neurons. This inhibition was mimicked by the synthetic diacylglycerol 1,2-dioleoyl-rac-glycerol (DOG) and was selective for a specific glutamate-phosphoinositide receptor subtype (GP2 receptor) activated by glutamate and quisqualate. TPA was nearly inactive in inhibiting the stimulation of inositol phospholipid hydrolysis by N-methyl-D-aspartate, a selective agonist of the GP1 receptor. Phorbol diesters and DOG attenuated the stimulation of inositol phospholipid hydrolysis by glutamate and quisqualate also in cerebellar slices from 9-15-day-old rats; however, using this preparation, their action was weak and required high concentrations (greater than 1 microM). The inhibition of signal transduction by phorbol diesters was not consequent to a reduced binding of glutamate to its membrane recognition sites. In fact, TPA induced only a small increase in the KD but no change in the Bmax of [3H]glutamate binding in cerebellar membranes. Phorbol diesters may act to inhibit specific GTP-binding proteins or particular molecular forms of phosphoinositidase C associated with GP2 or muscarinic cholinergic receptors.

Animals↗
PubMed1988

Controlled study on the anxiolytic activity of a newly-developed benzodiazepine, metaclazepam.

A double-blind, parallel group study was carried out in 50 patients with an anxiety disorder to compare the anxiolytic efficacy and tolerability of a recently developed benzodiazepine, metaclazepam, with that of bromazepam. Patients were allocated at random to receive treatment for 2 weeks with either 15 mg metaclazepam or 4 mg bromazepam per day in two divided doses. Assessments were made using the Hamilton anxiety rating scale (physician) on entry and after 7 and 13-days' treatment, and a visual analogue scale (patients) on entry and at the end of the study. The results showed that there was a significant, marked reduction in anxiety rating scores after 1 and 2 weeks in both groups and a significant improvement in the patients' subjective assessment of their condition after treatment. Few side-effects were reported in either group.

Adolescent↗
PubMed1987

Lesions of putative glutamatergic pathways potentiate the increase of inositol phospholipid hydrolysis elicited by excitatory amino acids.

The stimulation of inositol phospholipid (PI) hydrolysis by excitatory amino acids was measured in the rat hippocampus or striatum after 3 different chemical or surgical lesions of putative glutamatergic pathways. Intrahippocampal infusions of kainate preferentially destroyed neurons in the CA3-4 areas, denervating the CA1 area of the ipsilateral and contralateral hippocampus. Infusions of colchicine selectively destroyed granule cells of fascia dentata, denervating the CA3 area of the ipsilateral hippocampus. Ablation of the frontal cortex selectively reduced the glutamatergic afferents to the striatum. These 3 lesions potentiated the ibotenate, glutamate and quisqualate stimulation of PI hydrolysis, while N-methyl-D-aspartate remained ineffective. This stimulation was inhibited by 2-amino-4-phosphonobutyric acid but not by phencyclidine. These lesions also increased the stimulation of PI hydrolysis elicited by norepinephrine, but failed to enhance the stimulation by carbamylcholine. These results support the hypothesis that signal transduction in a subclass of excitatory amino acid receptors present in rat brain may undergo plastic modifications following denervation.

Amino Acids↗
PubMed1987

Phencyclidine is a negative allosteric modulator of signal transduction at two subclasses of excitatory amino acid receptors.

Phencyclidine (PCP) and some of its pharmacological congeners inhibit the signal transduction at specific excitatory amino acid receptors of cerebellar granule cells in primary cultures. These drugs do not bind to the transmitter recognition sites, and affinity of this specific binding site is increased by the presence of the transmitter bound to its recognition sites. PCP inhibits phosphatidylinositol phosphate hydrolysis mediated by Mg2+-sensitive glutamate receptors (GP1) but not that mediated by Mg2+-insensitive glutamate receptors (GP2). In addition, PCP inhibits Ca2+ influx and cGMP formation mediated by the activation of Mg2+-sensitive glutamate receptors (GC1) but not that mediated by Mg2+-insensitive glutamate receptors (GC2). In this cell culture the activation of phosphatidylinositol phosphate hydrolysis by muscarinic receptor agonists is not affected by PCP. Since PCP inhibits noncompetitively GP1 and GC1 signal transduction it may act as a negative allosteric modulator of signal transduction at both receptors. The pharmacological profile of PCP and its congeners delimits a class of drugs modulating allosterically the action of the primary transmitter at GP1 and GC1 receptors. These drugs need the presence of the transmitter to act and they cannot be termed inverse agonists because they are devoid of activity in the absence of the transmitter; moreover, they do not bind to the transmitter recognition site nor do they prevent the transmitter binding to its recognition sites.

Allosteric Regulation↗
PubMed1987

Magnesium ions inhibit the stimulation of inositol phospholipid hydrolysis by endogenous excitatory amino acids in primary cultures of cerebellar granule cells.

Omission of Mg2+ from the incubation buffer results in a six- to eightfold increase in [3H]inositol-1-phosphate ([3H]Ins-1-P) accumulation in primary cultures of cerebellar granule cells at 7-9 days in vitro. This increase is reversed by low concentrations of 2-amino-5-phosphono-valerate (APV), a result indicating that the absence of Mg2+ facilitates the activation of a specific receptor by the endogenous excitatory amino acids (presumably L-glutamate and L-aspartate) released from the granule cells. The absence of Mg2+ also potentiates the action of exogenously applied N-methyl-D-aspartate (NMDA), L-glutamate, L-aspartate, and kainate. In contrast, the action of quisqualate is virtually unaffected by Mg2+ and is resistant to APV inhibition. Addition of the depolarizing agent veratridine enhances the accumulation of [3H]Ins-1-P also in Mg2+-containing buffer. The action of veratridine is antagonized by APV, a result suggesting that, under depolarized conditions, the NMDA receptor can be activated by the endogenously released excitatory amino acids, despite the presence of Mg2+. Accordingly, in the presence of Mg2+, veratridine potentiates the action of exogenously applied NMDA but does not facilitate the action of quisqualate.

2-Amino-5-phosphonovalerate↗
PubMed1987

Excitatory amino acid receptors coupled with guanylate cyclase in primary cultures of cerebellar granule cells.

Primary cultures of cerebellar granule cells have been used in pharmacologically and functionally characterizing excitatory amino acid recognition sites coupled with guanylate cyclase. When granule cells were incubated in physiological culture conditions (Locke's solution, pH 7.4), only kainate and, to a lesser extent, L-glutamate increased cyclic GMP (cGMP) levels. Under these conditions, L-aspartate, N-methyl-D-aspartate (NMDA), and quisqualate were inactive. When granule cells were incubated in the absence of extracellular Mg2+ or in the presence of the depolarizing agent veratrine, L-glutamate, L-aspartate, and NMDA became as effective as kainate in enhancing cGMP formation. The action of kainate was preferentially antagonized by 2,3-cis-piperidindicarboxylate, whereas the action of L-glutamate was preferentially antagonized by (+/-)2-amino-5-phosphonovalerate. These data suggest that 2 different excitatory amino acid recognition sites (activated by kainate or by L-glutamate, L-aspartate, and NMDA, respectively) are coupled with guanylate cyclase in primary cultures of cerebellar granule cells: While the coupling of the recognition site for kainate with guanylate cyclase operates under resting conditions and in the presence of Mg2+, the coupling of the recognition site for L-glutamate, L-aspartate, and NMDA with guanylate cyclase requires depolarizing conditions or the absence of extracellular Mg2+.

Amino Acids↗
PubMed1986

Kindling enhances the stimulation of inositol phospholipid hydrolysis elicited by ibotenic acid in rat hippocampal slices.

The increment of inositol phospholipid hydrolysis elicited by ibotenic acid (IBO) is greater in hippocampal slices prepared from brain of rats receiving single or repeated hippocampal electrical stimulation or electrically induced amygdala kindling. In the latter group of rats, a potentiation of IBO stimulation of inositol phospholipid hydrolysis was associated with stage 3-4 of kindling according to Racine's scale. This increment returned to normal within one month after withdrawal from electrical stimulations. In both control and stimulated animals, 2-amino-4-phosphonobutyric acid antagonized the increment of inositol phospholipid metabolism elicited by IBO. The stimulation of inositol phospholipid hydrolysis elicited by carbamylcholine and norepinephrine was virtually unaffected by amygdala kindling.

Amygdala↗