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Biomedical subjects

S Govoni

Publications and source records attributed to S Govoni.

At least 19 recordsLinked to original sources
PubMed1992

Oxygen isosteric derivatives of 3-(3-hydroxyphenyl)-N-n-propylpiperidine.

Some substituted 3-phenylmorpholines (10a-e,j,k) and 3-thienylmorpholines (10f,g), isosteres of 3-(3-hydroxy-phenyl)-N-n-propylpiperidine (3-PPP), were prepared and submitted to binding assays on D-2 dopaminergic and 5-HT1 and 5-HT2 serotonergic receptors, in comparison with 3-PPP and its analogue 3a,b. The results show the loss of D-2 affinity for all morpholines, while a certain activity was still observable for piperidine derivatives. Regarding the serotonergic affinity, only chloro and methoxy derivatives (10a-d) were moderately active on the 5-HT1A receptor, either when the substituent was in the C-2 or C-3 position, whereas no tested compounds showed affinity toward the 5-HT2 receptor.

Animals↗
PubMed1992

Protein kinase C increase in rat brain cortical membranes may be promoted by cognition enhancing drugs.

Protein Kinase C (PKC) activity was measured in soluble and particulate fractions of rat individual brain cortices after in vivo treatment with two cognition enhancers: oxiracetam and alpha-glicerylphosphorylcholine. Both drugs induced an increase (+40-50%) of PKC particulate activity at 1 hr after the treatment. The effect was transient; at 5 hours PKC activity was lower than in controls. The dose response curve to oxiracetam was bell shaped, the increase of PKC being significant at 100 mg/kg. At higher doses the drug induced a decrease in enzyme activity. The increased PKC activity may be related to the cortical effects of these compounds.

Animals↗
PubMed1992

G protein modulation of omega-conotoxin binding sites in neuroblastoma x glioma NG 108-15 hybrid cells.

Electrophysiological evidence shows that voltage-dependent calcium channel (VDCC) activity can be regulated by a large number of neurotransmitters. In particular, guanine nucleotide binding regulatory protein (G protein)-mediated inhibitory modulation of the channel activity has been deduced from evidence that GTP analogues and purified G proteins are able to mimic this effect. The G proteins involved are pertussis toxin (PTx) sensitive. The purpose of the present study was to investigate, using biochemical techniques, whether G protein activation modulates the recognition site for omega-conotoxin GVIA (CgTx), a peptide neurotoxin that selectively labels a population of high-threshold VDCC. Undifferentiated and differentiated (1 mM dibutyryl cyclic AMP, 4 days) NG 108-15 cells were used. In both crude cellular extracts specific binding of 125I-CgTx was characterized. Differentiation induced a sixfold increase in the number of binding sites and doubled the KD value. The in vitro addition of guanylylimidodiphosphate (GMP-PNP; a nonhydrolyzable analogue of GTP) to extracts prepared from differentiated cells reduced the 125I-CgTx binding by 48%. This effect, observed in undifferentiated cells as well, was also caused by other triphosphate guanine nucleotides, such as GTP, but not by guanosine 5'-O-(2-thiodiphosphate) or adenine nucleotides. Treatment of the cells with PTx prevented the GMP-PNP effect. Moreover, the results obtained after preincubation with specific antisera raised against the alpha subunits of Gi1-2 and Go suggest that Go is the G protein responsible for the observed effect.

Animals↗
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↗
PubMed1991

Evidence for protein kinase C modulation of the ciliary muscle response to carbachol and desensitization.

The role of protein kinase C (PKC) in the desensitization of muscarinic receptor-mediated responses in bovine ciliary muscle was examined. Exposure of the bovine ciliary muscle to phorbol esters, used to activate PKC, resulted in antagonism of muscarinic receptor-mediated contraction. On the other hand, staurosporine, a known PKC inhibitor, caused a significant potentiation of the contractile effect induced by carbachol. Staurosporine reduced the desensitization induced by repeated additions of carbachol and completely suppressed that induced by phorbol esters. The results also indicate that desensitization mediated by phorbol esters as well as that mediated by muscarinic receptor agonists is heterologous.

Alkaloids↗
PubMed1991

Modulation of rat skeletal muscle chloride channels by activators and inhibitors of protein kinase C.

The membrane electrical parameters and component conductances of rat extensor digitorum longus muscle fibres were studied in vitro at 30 degrees C with standard two microelectrode square pulse cable analysis in the presence of protein kinase C (PKC) activators and inhibitors. The PKC activator, 4-beta-phorbol-12,13 dibutyrate (4-beta-PDB), (2-90 nM) blocked up to 67% chloride conductance (GCl) in rat skeletal muscle fibres and induced myotonic hyperexcitability. The concentration necessary to produce a 50% block of the membrane GCl was 23 nM. The "inactive" 4-alpha-phorbol-12,13 dibutyrate had no effect at 2 microM. The blocking effect of 4-beta-PDB on GCl was prevented by preincubation of the preparations with the PKC inhibitors, staurosporine (1-5 microM) and tetrahydropapaverolone (50-100 microM). The blocking effects on membrane GCl of 4-beta-PDB and its antagonism by the inhibitors used support the concept of the involvement of PKC in regulating Cl channels of mammalian skeletal muscle fibres.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

The aging brain: protein phosphorylation as a target of changes in neuronal function.

There is evidence that senescence affects neurotransmission at different levels. In particular, this review summarizes the studies on age-dependent modifications in protein phosphorylation, which represents the final pathway in the action of transmitters and hormones at neuronal level. Cyclic AMP-dependent protein kinase and protein kinase C have been reported to be modified during aging in various cerebral areas; the changes may involve either enzyme activity or substrate availability. These findings can be related to the alterations in neurotransmitter function and synaptic efficiency observed in the senescent brain. The activity of the other types of protein kinases (tyrosine-, cGMP-, calcium/calmodulin-dependent) during aging needs to be explored. An emerging point is the role of protein phosphorylation in the transfer of membrane signals to the nucleus, for the activation or disactivation of specific genes responsible for long-term neuronal events. Along this view, alterations in protein kinase pathway during senescence would ultimately affect gene expression, resulting in long term modifications of cell function. The reviewed literature opens the perspective of restoring some of the deficits associated with senescence by modulating protein phosphorylation pathway.

Aging↗
PubMed1991

Effect of a new cognition enhancer, alpha-glycerylphosphorylcholine, on scopolamine-induced amnesia and brain acetylcholine.

The present study investigates the effect of the administration of alpha-glycerylphosphorylcholine (alpha-GPC) on scopolamine-induced amnesia and on brain acetylcholine (ACh) levels and release in rats. The results indicate that alpha-GPC, when administered orally, reverses the amnesia caused by scopolamine in passive avoidance. The peak effect is observed using 600 mg/kg IG, 5 h before training. The effect of the drug is long lasting (up 30 h) in accordance with its pharmacokinetic characteristics. Since, alpha-GPC administered IG is cleaved within the gut mucosal cells to glycerophosphate and free choline, it is tempting to speculate that this drug acts by increasing the ACh precursor pool. This view is supported also by the observation that alpha-GPC partially counteracts the decrease of brain ACh levels elicited by scopolamine administration. The effect is observed in the hippocampus and cortex, but not in the striatum. Moreover, in ex vivo experiments, alpha-GPC is able to increase the amount of ACh released by rat hippocampus slices following potassium stimulation.

Acetylcholine↗
PubMed1991

Evaluation of beta-endorphin/beta-lipotropin immunoreactivity content in the CSF of patients affected by deafferentation pain syndromes.

Beta-endorphin/beta-lipotropin immunoreactivity (BE/BLPH-IR) content was evaluated in the CSF of patients suffering by deafferentation pain syndromes. BE/BLPH-IR CSF concentrations of these patients were compared with those obtained in a group of patients affected by low back pain and in a control group without pain problems. No statistically significant variation in BE/BLPH-IR levels were found between controls and subjects with different types of chronic pain.

Adult↗
PubMed1990

Calcium antagonists inhibit met-enkephalin immunoreactive material release: in vitro and ex vivo experiments.

Depolarizing stimuli increase the release of neurotransmitter met-enkephalin from rat striatal slices. Bay K8644, a calcium agonist, significantly enhances the submaximal release of this peptide. Several organic calcium antagonists, including nimodipine, nifedipine, nicardipine, gallopamil and flunarizine, are able to inhibit the potassium-evoked met-enkephalin release both in vitro and ex vivo. The data suggest that the release of this neuropeptide is modulated by calcium antagonist-sensitive calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Biochemical and functional evidence for the presence of dopamine D1 receptors in the bovine ciliary body.

The present paper reports both functional and biochemical evidence for the presence of dopamine D1 receptors in the bovine ciliary body. Dopamine (DA) and dopamine D1 agonists (such as SKF 38,393) but not D2 agonists (such as LY 141,865) produced a concentration-related decrease in the tone induced by a maximally active concentration of carbachol (1 x 10(-4)-5 x 10(-4) M). The maximal relaxation obtained was 100% of the carbachol response using 10(-5) M dopamine or 5 x 10(-6) M SKF 38,393. SCH 23,390, a D1 antagonist, but not (-)-sulpiride, antagonized the effect of DA and SKF 38,393. In accordance with the functional data, radioreceptor binding experiments revealed the existence of a high affinity saturable [3H]SCH 23,390 binding to membranes prepared from ciliary body (Bmax: 344 fmol mg protein-1; Kd: 0.87 nM). The binding was specifically displaced by SCH 23,390, dopamine and dopamine D1 agonists, but not by norepinephrine, D2 agonists, or antagonists such as LY 141,865 and sulpiride. No specific binding was found when using dopamine D2 ligands, such as tritiated spiroperidol.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Modulation of dihydropyridine-sensitive calcium channels: a role for G proteins.

The present study investigates the effect of G protein activation on dihydropyridine recognition sites in PC12 cell membranes. The addition of a stable analogue of GTP, GMP-PNP, increases the displacement of tritiated PN 200-110 produced by Bay K 8644 without modifying the one produced by nitrendipine. This effect is prevented by Pertussis toxin treatment. Functional studies based on the measurement of intracellular calcium concentrations by means of the fura 2 technique show that Pertussis toxin reduces the ability of Bay K8644 to potentiate the increase of cytosolic calcium elicited by 80 mM K+. The results support the hypothesis that a G protein may modulate the activity of voltage-dependent, dihydropyridine-sensitive calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Decrease in phorbol ester receptors in human brain tumors.

We have characterized the specific binding of [3H]-phorbol-12,13-dibutyrate in the white and gray matter of normal human brain and in cerebral tumors as an index of the availability of protein kinase C enzyme molecules. White matter has less than 50% phorbol-ester-binding capacity in comparison to gray matter. The binding is lower in tumors of glial origin when compared with normal white matter. Tumors of nonglial origin such as neurinoma and meningioma have a lower binding capacity than glial tumors. Metastatic tissues have the lowest binding capacity. The analysis of binding parameters in tumors and in the corresponding normal peritumoral tissues confirms the decreased binding capacity of neoplastic tissues in comparison to tissues not undergoing malignant transformation. These data suggest that brain glial tumors have a low availability of protein kinase C enzyme molecules and point to the potential involvement of this system in malignant transformation of human brain cells.

Adult↗
PubMed1988

Lead neurotoxicity: a role for dopamine receptors.

Chronic lead exposure differentially affects dopamine receptor subtypes (D1 and D2). In particular dopamine D2 recognition sites in striatum are up-regulated while in nucleus accumbens they are down-regulated. These changes may be correlated to the observed alterations of dopamine terminal activity. Consistent with these biochemical changes behavioral studies indicate that lead-treated rats show more pronounced basal activity, attenuation of apomorphine (63 micrograms/kg s.c.) induced hypomotility and tendency to increased stereotyped response to apomorphine (300 micrograms/kg s.c.). On the contrary, both behavioral and biochemical markers of D1 receptors are unmodified by lead treatment. In fact, SKF 38393-induced grooming behavior, [3H]SCH 23390 binding and the dopamine stimulated adenylate cyclase activity are comparable in controls and lead-exposed rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Direct coupling of a G-protein to dihydropyridine binding sites.

Electrophysiological data support the existence of GTP-binding proteins interacting with voltage dependent calcium channels. Along this line the present study investigates the effect of GMP-PNP, a stable GTP analogue, on the displacement of [3H]-PN 200-110 binding by agonist and antagonist dihydropyridines in synaptic membranes prepared from rat cortex. The results show that GMP-PNP increases the ability of the agonist dihydropyridine BAY K 8644 to displace [3H]-PN 200-110 binding. The in vivo treatment with Pertussis Toxin abolishes the effect produced by the non-hydrolysable GTP analogue.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Mechanisms of the effect of lead on brain neurotransmission: a calcium mediated action.

Data on the effect of chronic lead ingestion on brain neurochemistry in laboratory rodents show the involvement of several neurotransmitters including catecholamines. In the case of dopamine (DA), the action of lead is not uniform in all the DA-innervated areas. The reason for the regional susceptibility to the effect of lead is at present unknown, but points to the existence of specific neuronal mechanisms. Results obtained from animals exposed from birth to lead show that calcium channels are differentially modified in various brain areas. In particular, calcium antagonists display regional sensitivity both after in vivo lead treatment and after in vitro lead addition. These data support the concept that the area selective effects of the metal on neurotransmission may depend on the mechanisms controlling nerve terminal activity in different neuronal populations.

Animals↗