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Biomedical subjects

M Lanza

Publications and source records attributed to M Lanza.

At least 19 recordsLinked to original sources
PubMed1997

Changes in the permeability of the blood-brain barrier following sodium dodecyl sulphate administration in the rat.

The blood-brain barrier (BBB) arises from epithelial-like tight junctions that virtually cement adjoining capillary endothelium together in the brain microvasculature. Several experimental manipulations have been shown able to increase the permeability of brain capillaries, by altering endothelial cell membrane integrity or activating specific biochemical pathways involved in regulation of BBB functionality. Because of its amphiphilic nature, sodium dodecyl sulphate (an anionic surfactant widely used as solubilizer or stabilizer in several pharmaceutical preparations; SDS) may enter into interactions with the major membrane components, which are lipids and proteins. The aim of the present study was to determine the effect of an intracarotid infusion of SDS (25, 50 and 100 microg/kg; infusion rate: 3 ml/min for 30 s) on the functionality of the BBB in the rat. An extensive, dose-dependent Evans blue extravasation was observed, in the ipsilateral brain hemisphere, 15 min following SDS infusion. These results were confirmed by the significant increase in [14C]alpha-aminoisobutyric acid ([14C]AIB) transport (evaluated by calculating a unidirectional transfer constant, Ki, for the tracer from blood to brain) measured in several ipsilateral brain regions 2 min after SDS infusion; this SDS-elicited BBB opening to [14C]AIB proved to be reversible. Since the BBB is created by the plasma membrane and tight junctions of the endothelial cells, the change in BBB permeability caused by SDS might be explained as a nonspecific surfactant-membrane interaction. Furthermore, SDS might affect the functional characteristics of brain vascular endothelial cells by an interaction with specific BBB proteins and/or biochemical pathways. In conclusion, one can suggest that intracarotid infusion of SDS might provide a useful clinical approach for the intentional introduction of different substances into the brain. On the other hand, these findings should call attention to possible dangerous consequences of using SDS as solubilizer in drug excipients.

Animals↗
PubMed1997

Characterization of a novel putative cognition enhancer mediating facilitation of glycine effect on strychnine-resistant sites coupled to NMDA receptor complex.

The effects of (S)-4-amino-5-[(4,4-dimethylcyclohexyl)amino]-5-oxo-pentanoic acid ((S)CR 2249), a new chemical entity selected among a series of glutamic acid derivatives, were investigated on N-methyl-D-aspartate (NMDA)-evoked release of [3H]noradrenaline from rat hippocampal slices. (S)CR 2249 facilitated glycine-mediated reversion of kynurenate antagonism at strychnine-insensitive glycine receptors coupled to the NMDA receptor. The potency of glycine (EC50 = 21.5 microM +/- 4.2) was not significantly influenced by (S)CR 2249. Nevertheless, the efficacy of the glycine effect was enhanced in a concentration-dependent manner (3-10-30 microm) by (S)CR 2249. The interaction of (S)CR 2249 with NMDA receptors was also studied with binding experiments, in which we examined the effect of (S)CR 2249 on the modulation by glutamate, glycine and spermine of [3H]dizocilpine (MK-801) binding. (S)CR 2249, increased [3H]MK-801 binding in a concentration-dependent manner and we found positive cooperative interactions between glycine and (S)CR 2249, indicating that (S)CR 2249 probably acts at a separate allosteric site to increase NMDA receptor functionality.

Animals↗
PubMed1996

Transport of alpha-tocopherol and its derivatives through erythrocyte membranes.

PURPOSE: To investigate the transport of alpha-tocopherol (T), tocopherol succinate (TS) and tocopherol succinate-3-glucose (a newly synthetized, less hydrophobic T ester; TSG) through bovine erythrocyte membranes. METHODS: Our experiments were carried out on erythrocytes (obtained from heparinized fresh bovine blood), because they represent a suitable model for investigations of membrane transport. RESULTS: T was shown to reside almost completely in the suspension medium, while the greater part of TS disappeared from the suspension medium and was mainly incorporated into erythrocyte membranes. In comparison with T, a larger amount of TSG was incorporated into erythrocyte membranes and taken up by cells; however the TSG intracellular accumulation was significantly lower than that observed with TS. Furthermore, the transport of TS and TSG was partially inhibited by p-chloromercuribenzenesulfonate (which inhibits monocarboxylate uptake; PCMBS) and by maltose (a competitive inhibitor of glucose transport) respectively, with a concomitant increase in drug membrane incorporation. No significant change in drug transport was observed in the presence of 4,4'-diisothiocyanostilbene-2,2'-disulfonate, a selective and irreversible blocker of band 3 protein (DIDS). CONCLUSIONS: Our results show 1) the existence of large differences in membrane incorporation of T, TS and TSG (very likely caused by differing abilities to fill spaces in the lipid bilayer) and 2) a specific contribution of the monocarboxylate transport protein and of the glucose transport protein in the cellular uptake of TS and TSG, respectively. A tempting suggestion is that the unique cytoprotective properties of TS may be related to the differences in the transmembrane mobility observed between T and its succinate ester. Furthermore, T conjugation to a monocarboxylate or glycoside moiety could provide suitable substrates for active membrane transport, thus appearing as a promising pharmaceutical strategy for the improved delivery of tocopherol derivatives.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

CR 2249: a new putative memory enhancer. Behavioural studies on learning and memory in rats and mice.

The effects of S-4-amino-5-[4,4-dimethylcyclohexyl)amino]-5-oxopentanoic acid (CR 2249), a new entity selected from a new series of glutamic acid derivatives, has been investigated in different paradigms for screening nootropics. CR 2249 ameliorated the memory retention deficit produced by scopolamine in step-through-type passive avoidance in rats and by electroconvulsive shock in step-down-type passive avoidance in mice. CR 2249 was also capable of improving performance in behavioural tests of learning and memory in the absence of cholinergic hypofunction or cognitive deficit. The activity was determined using different passive and active avoidance behavioural test procedures on rats. CR 2249 was active only when given 45 min before training and did not show any effect when administered immediately after the learning training or before the retention trial. No changes in the general behaviour or motor activity of the animals were observed, indicating that CR 2249 effects cannot be attributed to sensory-motor deficit. Microdialysis experiments have shown that CR 2249 significantly increased noradrenaline release in the hippocampus of freely moving rats and reduced 3,4-dihydroxyphenylglycol efflux. These effects have led us to hypothesize that CR 2249 memory effect might be mediated by a direct or indirect action on noradrenergic transmission. These behavioural results suggest that this new agent has clinical application in memory disorders.

Animals↗
PubMed1995

Systemic cytokine administration can affect blood-brain barrier permeability in the rat.

The aim of the present study was to clarify the effect of intracarotid injection of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on the permeability of the blood-brain barrier (BBB) in the rat. A regional blood-to-brain transfer constant (Ki) for [14C] alpha-aminoisobutyric acid ([14C]AIB) and the cerebral residual blood volume were calculated 10 min following administration of cytokines (CKs; 1000 U/rat). The injection of IL-2 and IL-6 (but not of IL-1 beta) induced a significant enhancement of Ki values for [14C]AIB within several brain areas; conversely, when the rats were given TNF-alpha, a striking decrease in BBB permeability was observed. The cerebral regional blood volumes appeared significantly lower in the rats injected with IL-6 than in the control animals, but markedly increased following TNF-alpha administration. Our findings confirm the ability of some CKs to affect the permeability of the BBB and/or to act, probably indirectly, as vasomodulator agents of the cerebral microvessel endothelium.

Aminoisobutyric Acids↗
PubMed1995

Flavonoids as antioxidant agents: importance of their interaction with biomembranes.

Flavonoids, a group of phenolic compounds widely occurring in the plant kingdom, have been reported to possess strong antioxidant activity. In the present study, four flavonoids (quercetin, hesperetin, naringenin, rutin), chosen according to their structural characteristics, were tested in two different in vitro experimental models: (1) Fe(2+)-induced linoleate peroxidation (Fe(2+)-ILP), by detection of conjugated dienes; and (2) autooxidation of rat cerebral membranes (ARCM), by using thiobarbituric acid for assay of free malondialdehyde production. The results obtained were also interpreted in the light of flavonoid interactions, studied by differential scanning calorimetry, with dipalmitoylphosphatidylcholine (DPPC) vesicles as a biological membrane model. The antilipoperoxidant activity of the flavonoids tested can be classified as follows: rutin > hesperetin > quercetin > naringenin in the Fe(2+)-ILP test: quercetin > rutin > hesperetin > naringenin in the ARCM test. Quercetin, hesperetin, and naringenin interacted with DPPC liposomes causing different shifts, toward lower values, of the main transition peak temperature (Tm) typical for DPPC liposomes; however, no change in Tm of DPPC dispersion was observed in the presence of rutin. The hypothesis will be discussed that flavonoid capacity to modify membrane-dependent processes, such as free-radical-induced membrane lipoperoxidation, is related not only to their structural characteristics but also to their ability to interact with and penetrate the lipid bilayers.

Animals↗
PubMed1994

Bleeding time and bleeding: an analysis of the relationship of the bleeding time test with parameters of surgical bleeding.

The bleeding time is currently the only clinically available comprehensive test to explore primary hemostasis. It is currently performed mostly as a screening procedure before surgery, to detect otherwise unknown defects in platelet-vessel wall interactions, but its use in this specific setting has been seriously questioned by recent reanalyses of previously published literature. We studied the relationship of the bleeding time from a standardized cutaneous incision with other parameters of bleeding derived from the analysis of the bleeding time curve and prospectively investigated possible correlations of these alternative parameters, as well as of the bleeding time, with a number of indices of actual bleeding during or after coronary bypass surgery. Four parameters (bleeding time, total bleeding, peak bleeding rate, and time to peak bleeding) were derived from the analysis of bleeding time curves measuring blood losses from a standardized cutaneous incision at 30-second intervals in 118 subjects. Parameters from the bleeding time curve were subsequently obtained in duplicate as a preoperative assessment in 40 patients with a negative bleeding history and no recent intake of non-steroidal anti-inflammatory drugs who were undergoing elective pure coronary bypass surgery performed by the same operator. These parameters were correlated in simple linear regression analysis with estimates of surgical bleeding (chest tube drainage, transfusion requirements, percentage of hematocrit, percentage of platelet level decrease, and times to hematocrit and platelet level nadir) and then, in multiple regression analysis, with indices of operation complexity (number of bypasses, total duration of the operation, and duration of the extracorporeal circulation). Bleeding time was significantly correlated, among parameters derived from the bleeding time curve, with total bleeding and peak bleeding rate, but not with time to peak bleeding. Bleeding time, total bleeding, and peak bleeding rate were similarly affected by acute interventions with intravenous aspirin (500 mg) and sublingual nitroglycerin (0.3 mg). None of these parameters, which were obtained in duplicate in each patient preoperatively, was significantly related to actual indices of bleeding at surgery. Thus, in patients with a negative history of bleeding and no recent intake of non-steroidal anti-inflammatory drugs, higher values for bleeding time and bleeding time-related parameters are not associated with higher indices of perioperative and postoperative bleeding at coronary bypass surgery. Therefore, we do not recommend the use of the test in this setting to predict perioperative or postoperative bleeding.

Aspirin↗
PubMed1994

Protective effect of glutathione on kainic acid-induced neuropathological changes in the rat brain.

1. Glutathione (GSH), injected by slow intravenous (i.v.) infusion (7.9 microliters/min, for 4 hr; total dose: 1.5 g/kg), starting 10 min after i.v. injection of kainic acid (KA; 12 mg/kg) in the rat reduced the decrease in local cerebral glucose utilization observed 48 hr following the administration of the neurotoxin. 2. Furthermore, it blocked the neuronal loss in hippocampal CA1 and CA3 regions, and prevented, in the hippocampus, the development of edema and the marked depletion in the endogenous brain GSH pool. 3. One can speculate that this protective effect of exogenous GSH is correlated to its capacity to scavenge free radicals, thus preventing the accumulation of oxidant chemical species and the consequent reduction of cellular antioxidant defense.

Animals↗
PubMed1994

Genetically epilepsy-prone rodents show some changes of ion levels in the brain.

In the present study the water and ion (Na+, K+, Ca2+, Fe3+, Se4+, Mg2+, Mn2+, Mn2, Se4+, Cu2+) content in the brain of genetically epilepsy-prone rats (GEPRs) and of 21-, 45-, and 60-day-old DBA/2 mice were determined, and compared with those measured in normal controls (Sprague-Dawley rats and Swiss mice), to verify whether the predisposition to audiogenic seizures (AGS) may be partially related to changes in the cerebral osmotic and ionic state. Our findings clearly evidenziate two points: a) a more complex shift in brain ionic balance (rather than a peculiar modification in the concentration of a single ion) seems very likely involved in AGS susceptibility; (b) brain Ca2+ and Se4+ amounts, together with the water content, appear to be really important factors to which a role in abnormal seizure predisposition may be attributed.

Acoustic Stimulation↗
PubMed1993

CGP 52432: a novel potent and selective GABAB autoreceptor antagonist in rat cerebral cortex.

As previously reported GABAB receptors are heterogeneous. Three pharmacologically distinct receptor subtypes mediating inhibition of gamma-aminobutyric acid (GABA), glutamate or somatostatin release, respectively, exist on axon terminals of rat cerebral cortex. We investigated the novel GABAB receptor antagonist, [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxy-methyl) phosphinic acid (CGP 52432), on the above receptor subtypes. The effects of (-)-baclofen on the K(+)-evoked release of GABA, glutamate or somatostatin from rat cortical synaptosomes were antagonized by CGP 52432. The IC50 of the drug at GABA autoreceptors (0.085 microM) was 35- and 100-fold lower than at the receptors regulating somatostatin and glutamate overflow, respectively. At the autoreceptor the calculated pA2 for CGP 52432 amounted to 7.70, which makes the drug about 1000-fold more potent than phaclofen at this receptor. The potency and selectivity characteristics of CGP 52432 indicate that the drug is by far the most appropriate tool to investigate the terminal GABAB autoreceptors of the rat cerebral cortex.

Animals↗
PubMed1993

Release of endogenous glutamic and aspartic acids from cerebrocortex synaptosomes and its modulation through activation of a gamma-aminobutyric acidB (GABAB) receptor subtype.

The depolarization-evoked release of endogenous glutamate (GLU) and -aspartate (ASP) and its modulation mediated by gamma-aminobutyric acid (GABA) heteroreceptors was investigated in superfused rat cerebrocortical synaptosomes. Exposure to 12 mM K+ enhanced the release of GLU and ASP. The K(+)-evoked overflow of both amino acids was largely Ca(2+)-dependent. Exogenous GABA inhibited the K(+)-evoked overflow of GLU (EC50 2.8 microM) and ASP (EC50 2.7 microM). The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (EC50 2.0 microM for GLU and 1.3 microM for ASP release) but not by the GABAA receptor agonist muscimol, up to 100 microM. Accordingly, the GABA-induced inhibition of GLU and ASP release was not affected by the GABAA receptor antagonists, bicuculline or picrotoxin, but was antagonized by the GABAB receptor antagonist, 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348). The GABA effect was, however, insensitive to another GABAB receptor antagonist, phaclofen, up to 1,000 microM. It can be concluded that GABA heteroreceptors of the GABAB type regulating the depolarization-evoked release of GLU and ASP are present on cortical GLU/ASP-releasing nerve terminals. These receptors may be classified as a phaclofen-insensitive GABAB receptor subtype.

Animals↗
PubMed1993

[A rare cause of hypercalcemia: familial hypocalciuric hypercalcemia].

BACKGROUND: Familial hypocalciuric hypercalcemia is a rare disease with autosomal dominant transmission. Its basic defect is unknown and it requires no treatment. CASE REPORT: A 4 month-old girl was admitted for unexplained crying. She was found to have hypercalcemia (2.8 mmol/l) and later values of blood calcium were 3, 3.1 and 3 mmol/l. The serum free ionic calcium level was also elevated. The serum concentrations of protein, phosphorus, magnesium and the alkaline phosphatase activity were all normal. Serum concentrations of 25-(OH)-D3, 1.25-(OH)-2-D3 and PTH were also normal. The urinary calcium/creatinine ratio was normal and the urinary calcium excretion was 1.08 mg/kg/d. Screening of family members showed hypercalcemia in the father (2.8 mmol/l) and a brother aged 7 years (2.9 mmol/l). Short-term treatment with disodium etidronate lowered the serum calcium level to normal, but hypercalcemia reappeared once the treatment was discontinued. CONCLUSIONS: This asymptomatic familial hypercalcemia has the characteristics of familial hypocalciuric hypercalcemia. There was no associated endocrine disorder. Screening of family members is worthwhile.

Calcium↗
PubMed1990

[Research on Kathon CG in cosmetic and personal hygiene products].

Kathon is an anti-microbial agent that is used as a preservative in cosmetics and bodily hygiene products. At the recommended levels of usage Kathon is innocuous and has a recognised efficacy. Nevertheless, following reappearance of contact allergic eczemas due to cosmetics and bodily hygiene products different authors have reported increase in sensitisation to it. We have met the same problems in the Service de Dermatology++ of the Hospital Sainte Marguerite at Marseille and we wished to make a deeper examination of the question and to ascertain whether the current cosmetics contained Kathon CG. For this we have developed a technique of liquid chromatography and tested 44 creams. Eight contained Kathon CG, of which 2 were responsible for contact eczema in patients.

Chromatography, High Pressure Liquid↗