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Biomedical subjects

S Barone

Publications and source records attributed to S Barone.

At least 55 records · Page 3Linked to original sources
PubMed1991

The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine.

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COLCH; 2.5 micrograms/site) or artificial cerebrospinal fluid (ACSF; 0.5 microliter) through chronic indwelling cannulae into the dentate gyrus. At the time of COLCH injection, a unilateral intracerebroventricular (ICV) cannula was implanted. One week later, when animals were tested in activity chambers for 60 min, COLCH-treated rats showed a significant increase in spontaneous locomotor activity. Two weeks after COLCH treatment, animals were assigned to various post-treatment groups and received 1.0 microliter of rat fetal hippocampal cell suspensions (ED-17 or 18) or Earle's basic salt solution in the same site as previous hippocampal infusions. Modified Alzet miniosmotic pumps (0.25 microliter/h) containing NGF (10 ng/microliter) or ACSF with cytochrome C (20 ng/microliter) were implanted subcutaneously and attached to the previously implanted ICV cannulae. The animals were tested for learning ability in a Morris water maze task starting 6 or 12 weeks post-COLCH. During both test periods, COLCH lesions significantly impaired acquisition and retention. At 6 weeks postlesion, NGF treatment ameliorated this COLCH-induced behavioral deficit while the presence of transplants did not ameliorate the COLCH-induced learning deficit. COLCH/transplant/NGF-treated rats performed better than both COLCH-lesioned rats with or without transplants. At 12 weeks postlesion COLCH-induced behavioral deficits were not ameliorated by NGF or transplants. Morphological examination performed after behavioral testing confirmed the presence of viable transplants and COLCH-induced granule cell loss. Exogenous NGF infusions appeared to have no effect on the morphological measures taken. These data demonstrate a time-dependent facilitative effect of exogenously applied NGF on functional deficiencies produced by experimentally induced neurodegeneration in the dentate gyrus of the hippocampus.

Animals↗
PubMed1991

Long-term changes in phosphoinositide hydrolysis following colchicine lesions of the nucleus basalis magnocellularis.

The effect of bilateral colchicine lesions of the nucleus basalis magnocellularis (NBM) on agonist-stimulated phosphoinositide (PI) hydrolysis was examined in cortical slices 1, 3, or 14 months after surgery. Colchicine lesions resulted in a loss of acetylcholinesterase staining in the cortex which recovered to control levels by 14 months. Choline acetyltransferase activity in the cortex was decreased by 43% one month after lesioning, but returned to control levels by 3 months. In vitro stimulation with carbachol produced a concentration-dependent increase in PI hydrolysis, which was enhanced 3 and 14 months after NBM lesions. Norepinephrine and quisqualate-stimulated PI hydrolysis was also enhanced 14 months after NBM lesions. These results suggest a slow up-regulation of postsynaptic receptor function following presynaptic loss of transmitter.

Acetylcholinesterase↗
PubMed1991

Long-term behavioral and neurochemical effects of intradentate administration of colchicine in rats.

Previous work in our laboratory has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. Deficits in learning and memory and alterations in the signal transduction process for the cholinergic muscarinic receptor have been observed up to 12 weeks after colchicine treatment. To study the long-term effects of colchicine administration on cognitive function and the cholinergic system, 6 month-old male, Fischer-344 rats were injected with 2.5 micrograms of colchicine bilaterally in the dorsal and ventral hippocampus. Twelve months later the animals were tested for the acquisition of a spatial reference memory task in the Morris water maze for 8 days, with 4 trials of 60 seconds each day. At the completion of the behavioral testing, one set of rats from each treatment group was used for histochemical studies. The remaining animals were sacrificed, the hippocampi removed and used for the estimation of receptor-stimulated turnover of phosphoinositides (Pl). [3H]-inositol was incorporated into the hippocampal slices, and various receptor agonists (carbachol, norepinephrine, serotonin) used to stimulate Pl turnover in the presence of lithium. A significant deficit in acquisition in the water maze was observed in animals 1 year after colchicine administration. Neurochemical studies showed an increase in carbachol-induced Pl metabolism in the rat hippocampus 1 year post-lesion with colchicine. However, in contrast to results obtained 12 weeks after lesioning, no significant changes were observed in norepinephrine or serotonin-induced Pl metabolism 1 year after lesioning. Pirenzepine, a M1 receptor antagonist, produced a greater degree of inhibition (62%) in lesioned animals as compared to the age-matched controls (20%). Increased staining for acetylcholinesterase was found in the hippocampus of treated rats. This effect is similar to that observed 12 weeks after lesioning. These data suggest that the effects of colchicine on the cholinergic system are long-lasting and can be observed a year after treatment.

Acetylcholine↗
PubMed1990

Neurotoxic lesions of the nucleus basalis induced by colchicine: effects on spatial navigation in the water maze.

Neuronal loss in the nucleus basalis magnocellularis (NBM) has been consistently associated with learning and memory impairments. Previous studies have used excitotoxicants such as kainic acid or ibotenic acid to examine the behavioral consequences of NBM lesions. In the present study, rats were given bilateral injections of the neurotoxicant colchicine (1.0 micrograms/site) into the NBM and examined for changes in learning and memory. Unlike excitotoxicants, which can produce extensive subcortical damage, colchicine produced a lesion limited to the site of injection. Histological studies demonstrated that colchicine decreased the number of choline acetyltransferase (ChAT)-positive cells in the NBM, and resulted in a marked loss of cortical acetylcholinesterase staining. Separate neurochemical analysis showed that colchicine lesions decreased ChAT activity in the neocortex but not the hippocampus or caudate nucleus. Similar to previous studies, rats with NBM lesions showed a large deficit in a passive avoidance task. Lesions of the NBM impaired acquisition of a reference memory task in the Morris water maze. However, the deficit was transient and with continued training lesioned rats performed as well as controls. In a reversal test in the water maze the learning deficit reappeared. These data suggest that colchicine may be useful in producing lesions of the NBM, which primarily affects the rate of acquisition of a spatial reference memory task.

Animals↗
PubMed1989

Electrophilic derivatives of purines as irreversible inhibitors of A1 adenosine receptors.

Functionalized congeners derived from 1,3-dipropyl-8-phenylxanthine and from N6-phenyladenosine were derivatized to contain electrophilic groups (isothiocyanate, N-hydroxysuccinimide ester, maleimide, sulfonyl chloride, or alpha-haloacyl group) capable of reaction with nucleophiles on biopolymers. The goal was to inhibit chemically the A1 adenosine receptor by using reactive agonist and antagonist ligands. Some of the electrophilic derivatives were synthesized through acylation of amine-functionalized congeners using hetero- or homobifunctional reagents available for protein cross-linking. The affinity for A1 adenosine receptors was evaluated in competitive binding assays by using rat and bovine brain membranes. Several xanthine and adenosine thiourea derivatives prepared from 1,3- and 1,4-phenylene diisothiocyanate (DITC) were potent irreversible inhibitors of adenosine receptors. Derivatives of m-DITC, at concentrations between 10 and 500 nM, irreversibly eliminated binding at 90% of the A1-receptor sites. Receptor affinity of both xanthine and adenosine derivatives containing distal phenylthiourea substituents was diminished by electron-donating groups on the ring.

Adenosine↗
PubMed1989

Sulfur-containing 1,3-dialkylxanthine derivatives as selective antagonists at A1-adenosine receptors.

Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [( 3H]-N6-(phenylisopropyl)adenosine as radioligand] or striatum [3H]-5'-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxy-methyl)oxyl] phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was greater than 740-fold A1 selective.

Animals↗
PubMed1989

Adenosine receptor prodrugs: towards kidney-selective dialkylxanthines.

XAC (xanthine amine congener, 8-[4-[(2-aminoethyl)-aminocarbonylmethyloxy]phenyl]-1,3-dipropy lxanthine is a potent adenosine antagonist that reverses the reduction in urine flow, sodium excretion and heart rate produced by the adenosine agonist, N6-cyclohexyladenosine. New derivatives of XAC in which the primary amino group has been condensed to the gamma-carboxyl group of glutamic acid have been synthesized as prodrugs. These amino acid-XAC conjugates, which are considerably less potent than XAC in competitive binding assays at A1-adenosine receptors, are designed for selective enzymatic activation in the kidneys. The gamma-glutamyl xanthine derivatives are substrates for gamma-glutamyl transferase (EC 2.3.2.2) to generate an amine-functionalized xanthine. N-acetyl-gamma-L-glutamyl-XAC is not active in vivo, consistent with inability of renal acylase (EC 3.5.1.14) to hydrolyze the acetyl group, a prerequisite step for the production of XAC from this molecule. The xanthine derivatives, gamma-L-glutamyl-XAC and gamma-L-glutamyl-gamma-L-glutamyl-XAC are metabolized to XAC and produce a diuresis in vivo.

Adenosine↗
PubMed1987

Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors.

Chemically functionalized congeners of N6-phenyladenosine and 1,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglycerides, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosine binding to A1-adenosine receptors in rat cerebral cortex membranes. A xanthine-phosphatidylethanolamine conjugate bound with a Ki value of 19 nM. Various xanthine esters of low potency are potential prodrugs. Amides of an adenosine amine congener (ADAC) with 18-carbon fatty acids exhibited Ki values at A1-adenosine receptors of 70 pM, representing a 130-fold enhancement over the affinity of the corresponding acetyl amide. The very high affinity of adenosine-lipid conjugates may be due to stabilization of these adducts in the phospholipid microenvironment of the receptor protein.

Adenosine↗
PubMed1987

The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines.

In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (-)-adrenaline. Oestradiol (40 mumol/l), 2-hydroxyoestradiol (2OHE2) (20 mumol/l), and 2-methoxyoestradiol (2MeOE2) (20 mumol/l) all sensitized the rabbit aorta to contractile responses to (-)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (-)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. Oestradiol and 2OHE2 did not increase responses of the aorta to (-)-noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE3. The potentiating effect of 2OHE2 on contractile responses to (-)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mumol/l). Conversely, pretreatment of the tissue with 2OHE2 prevented the augmented aortic contraction to (-)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE2 and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mumol/l). Oestradiol and 2MeOE2 reduced the formation of both the 3H-O-methylated, 3H-deaminated and the 3H-O-methylated deaminated metabolites of 3H-(-)-adrenaline (0.15 mumol/l) during exposure of the aorta to the tritiated catecholamine.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗
PubMed1987

Effect of maternal fasting on ovine fetal and maternal branched-chain amino acid transaminase activities.

Activities of branched-chain amino acid transaminase were assayed in maternal skeletal muscle, liver and fetal skeletal muscle, cardiac muscle, liver, kidney and placenta obtained from fed and 5-day-fasted late gestation ewes. Very high activities were found in placenta; fetal skeletal muscle also had high activity. Fetal brain had intermediate activity, followed by cardiac muscle and kidney. Fetal liver possessed negligible activity. Activities were low in both maternal liver and skeletal muscle. Trends were seen for fasting to increase activities in fetal placenta, skeletal muscle, brain, kidney, heart and maternal liver, but these changes were statistically significant only for fetal brain and placental tissue. Fetal skeletal muscle activity was 100 times that of maternal skeletal muscle. These data imply differences in the metabolism of the branched-chain amino acids by fetal and adult ruminants and expand the thesis that branched-chain amino acids are important to the metabolism of the ovine fetus.

Amino Acids, Branched-Chain↗
PubMed1986

O-methylation of isoproterenol by the endothelium of the rabbit thoracic aorta.

We have examined the influence of endothelial cell removal upon the O-methylation of the isomers of isoproterenol in the isolated rabbit aorta. Endothelial cells were removed by mechanically abrading isolated segments of rabbit aorta. The latter procedure resulted in the abolition of acetylcholine-mediated relaxation of tissues, a process dependent upon the presence of endothelial cells. In addition, histological staining and electron-microscopic analysis indicated the presence of endothelial cells in tissues not subjected to mechanical abrasion and the absence of endothelial cells in tissues subjected to abrasion. Moreover, ultrastructural analysis revealed that the influence of abrasion was limited to the luminal side of the internal elastic lamina. The removal of endothelial cells from the isolated rabbit aorta was associated with a decrease (approximately 30%) in the O-methylation of the isomers of isoproterenol. Inhibition of the extraneuronal uptake process with deoxycorticosterone (DOCA) produced a predicted decrease in the O-methylation of isoproterenol in tissues with the endothelium intact. In the absence of endothelial cells, the inhibition of the O-methylation of isoproterenol mediated by DOCA persisted. The results suggest that the O-methylation of catecholamines can occur in both medial and endothelial structures in this blood vessel and support the results of immunohistochemical studies that suggested a presence of catechol-O-methyltransferase in vascular endothelial structures. In addition, the findings exclude a possibility that the extraneuronal uptake process for catecholamines resides exclusively in endothelial structures. The functional consequences of vascular endothelial cell O-methylation are discussed.

Acetylcholine↗
PubMed1985

The stereoselective O-methylation of isoprenaline in the isolated rabbit thoracic aorta.

This investigation examined the stereoselective nature of the steroid-sensitive extraneuronal O-methylation process for the isomers of isoprenaline in the rabbit aorta. The rate of O-methylation of (-)- and (+)-isoprenaline was linear with substrate concentration in the range 0.24 to 4.7 mumol X 1(-1). There was marked preference for the O-methylation of (-)-isoprenaline rather than (+)-isoprenaline at low (less than 0.94 mumol X 1(-1) substrate concentrations. In contrast, at concentrations equal to or greater than 9.4 mumol X 1(-1) the rates of O-methylation of (-)- and (+)-isoprenaline were similar. Phenoxybenzamine (30 mumol X 1(-1) inhibited but did not abolish the O-methylation of both (-)- and (+)-isoprenaline when the isomers were present in a concentration range of 0.24 mumol X 1(-1) to 9.4 mumol X 1(-1). Phenoxybenzamine did not significantly influence the O-methylation of either (-)- or (+)-isoprenaline when the isomers were present at a concentration of 24 mumol X 1(-1). Deoxycorticosterone acetate (DOCA) produced an equipotent and marked inhibition of the O-methylation of both (-)- and (+)-isoprenaline at a low (0.24 mumol X 1(-1) substrate concentration. When higher substrate concentrations were used, there was a significantly greater resistance to the inhibition of O-methylation of (-)-isoprenaline than was the case for (+)-isoprenaline. At a concentration of 9.4 mumol X 1(-1), the steroid failed to inhibit the O-methylation of (-)-isoprenaline but was effective in inhibiting the O-methylation of (+)-isoprenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Nonintracellular, cell-associated O-methylation of isoproterenol in the isolated rabbit thoracic aorta.

The present study examines the subcellular site of catecholamine O-methylation in extraneuronal tissue. S-Adenosyl-l-methionine, a methyl donor that does not diffuse across biological membranes, was used to assess the participation of plasma membrane bound catechol-O-methyltransferase vs. cytoplasmic catechol-O-methyltransferase in the catecholamine O-methylating process. Segments of rabbit thoracic aorta incubated with [methyl-3H]-S-adenosyl-l-methionine and isoproterenol generate [3H]methoxy-isoproterenol. The formation of [3H]methoxy-isoproterenol from [methyl-3H]-S-adenosyl-l-methionine was proportional to the isoproterenol concentrations in the range of 0.1 to 1.0 microM. There was a marked preference for the O-methylation of the (+)- rather than the (-)-isomer of isoproterenol. The O-methylation of isoproterenol in the presence of [methyl-3H]-S-adenosyl-l-methionine was stimulated as much as 8-fold by the removal of calcium ions from the incubation solutions. In contrast, the O-methylation of (+)-[3H]isoproterenol by endogenous, intracellular S-adenosyl-l-methionine was only slightly inhibited by the removal of calcium ions from incubation solutions. The formation of [3H]methoxy-isoproterenol from [methyl-3H]-S-adenosyl-l-methionine and isoproterenol was not inhibited by pretreatment of tissues with phenoxybenzamine (32 microM) or treatment with metanephrine (27 mumol 1(-1] or deoxycorticosterone acetate (27 microM), i.e., drug treatments that inhibit the extraneuronal uptake and O-methylation of [3H]-isoproterenol by endogenous intracellular S-adenosyl-l-methionine. The results of this study provide evidence for a nonintracellular, cell-associated site of O-methylation of isoproterenol in the rabbit aorta.

Animals↗
PubMed1984

Non-radiochemical procedure for the measurement of O-methylation of the stereoisomers of isoprenaline.

A non-radiochemical procedure has been developed which permits the separation and measurement of isoprenaline (ISO) and the O-methylated metabolite, 3-methoxyisoprenaline (MeOISO). This methodology employs alumina chromatography and toluene solvent extraction to separate the catecholamine, ISO, from the O-methylated derivative, MeOISO. High-performance liquid chromatography with electrochemical detection has been used to quantify these compounds. The biological application of this procedure includes the evaluation of O-methylation of the stereoisomers of ISO by intact tissues.

Animals↗
PubMed1984

Neuronal deamination of endogenous and exogenous noradrenaline in the mesenteric artery of the spontaneously hypertensive rat.

The noradrenaline (NA) content of the mesenteric arteries from spontaneously-hypertensive rats (SHR) are greater than those in arteries from normotensive Kyoto Wistar rats (WKY). The possibility that impaired neuronal monoamine oxidase (MAO) activity in mesenteric arteries from SHR rats was responsible for the differences in NA content was explored. The in-vitro formation of dihydroxyphenylethylene glycol (DOPEG) by intact segments of mesenteric arteries was used as an index of neuronal MAO activity. There were no differences in the production of DOPEG from endogenous NA by arteries from normotensive and hypertensive rats. Moreover, the formation of DOPEG from exogenous NA was similar in arteries from SHR and WKY rats. The neuronal uptake of NA was indistinguishable between mesenteric arteries from SHR and WKY rats. The results argue against an impairment of neuronal MAO in contributing to the enhanced content of NA in the mesenteric artery of the SHR rat.

Animals↗
PubMed1980

[Angioimmunoblastic lymphadenopathy. Treatment of 2 cases].

Following a review of the literature, 2 cases of angioimmunoblastic lymphadenopathy with dysproteinaemia are reported. Anatomo-pathological examination of the lymphonodes shows widespread change in the structure with vascular and lympho-immunoblastic proliferation and deposit of amorphous eosinophil substance. The most significant clinical and morphological aspects are reported and these are related to the therapeutic response. The effectiveness of cortisone therapy is shown by comparison of laboratory examination data at admittance and after three months.

Adrenal Cortex Hormones↗