Biomedical subjects

C Sanfeliu

Publications and source records attributed to C Sanfeliu.

33 records · Page 2Linked to original sources

PubMed1990

Exposure to N-methyl-D-aspartate increases release of arachidonic acid in primary cultures of rat hippocampal neurons and not in astrocytes.

The release of [3H]arachidonic acid (ARA) was investigated from prelabelled primary cultures of hippocampal neurons and astroglial cells. The activation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors resulted in a dose-dependent stimulation of [3H]ARA release. The half maximal effect was obtained at about 15 microM NMDA, whereas the maximum concentration (50 microM NMDA) produced about a 2-fold increase in 7-day-old cultures. This elevation in [3H]ARA release was blocked in a dose-related manner by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV), and by Mg2+ which blocks NMDA receptor-linked Ca2+ ion channels. The removal of external Ca2+ inhibited NMDA-induced release, whereas treatment with calcimycin (A 23187, a Ca2+ ionophore) greatly increased the [3H]ARA release. The inhibitors of phospholipase A2, nordihydroguaiaretic acid and mepacrine, decreased the NMDA-dependent [3H]ARA release in a dose-related manner, maximum inhibition reaching to about 90% at high doses. Entry of Ca2+ brought about by opening the voltage-sensitive channels by high K+ had no effect on the release of [3H]ARA, indicating that NMDA gated channels are situated in a part of the neuron where Ca2+ entry through this route is more efficiently coupled to the activation of phospholipase A2. Treatment with NMDA had no significant effect on [3H]ARA release in hippocampal astroglial cells as opposed to neurons. This was not due to inability of astrocytes to release ARA, for ATP still evoked [3H]ARA release, and this was markedly inhibited by mepacrine. It is suggested that ARA act as both intracellular and intercellular messengers in the functioning of NMDA receptors in synaptic transmission and plasticity in the hippocampus.

Adenosine Triphosphate↗

PubMed1990

Death of subcortical cholinergic neurons in certain neurodegenerative disorders may not be due to an overstimulation of N-methyl-D-aspartate receptors.

Stimulation of N-methyl-D-aspartate (NMDA) receptors increases the activity of enzymes involved in the synthesis of nerve cell specific neurotransmitters. In the present study this phenomenon has been used to identify the neurons in the septal-diagonal band region having NMDA receptors. Exposure of cultures relatively enriched in subcortical cholinergic neurons to a depolarizing concentration of K+ (40 mM) significantly enhanced the expression of choline acetyltransferase (ChAT) activity. In contrast, when these septal cells were treated with as much as 100 microM NMDA no significant increase was observed in the activity of choline acetyltransferase, although there was a marked enhancement in glutamate decarboxylase activity. The results would indicate that subcortical cholinergic neurons do not possess excitatory amino acid receptors of the NMDA subtype, and that therefore neurotoxicity mediated through NMDA receptors may not be involved in the death of cholinergic neurons in degenerative disorders of the brain, such as Down's syndrome and Alzheimer's disease, which entail major losses of these neurons.

Animals↗

PubMed1990

Cell-type specific effects of N-methyl-D-aspartate on biochemical differentiation of subcortical neurons in culture.

The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the biochemical differentiation of cultured neurons derived from the medial frontal part of the forebrain containing the septum-diagonal band region was studied in terms of the activities of enzymes important in the synthesis of neurotransmitter compounds. The activity of choline acetyltransferase (ChAT) was used as a marker for cholinergic neurons, glutamate decarboxylase (GAD) for GABAergic neurons and phosphate-activated glutaminase (GLNase) and aspartate aminotransferase (ASP-AT) for glutamatergic neurons, while lactate dehydrogenase (LDH) was included as an ubiquitous enzyme. The exposure of cultures to a depolarizing concentration of K+ (40 mM) for the last 3 days (i.e. between 2 and 5 days in vitro) significantly enhanced the expression of ChAT, GAD and GLNase activities, but high K+ caused little alteration in the activities of ASP-AT and LDH. On the other hand, treatment with NMDA markedly elevated the specific activities of GAD and GLNase only, and the compound had no significant effects on the activities of ChAT, ASP-AT and LDH enzymes. The enhancements of the specific activities of GAD and GLNase were completely blocked by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid, and by the NMDA receptor-linked Ca2+ ion channel blocker, MK-801. On the basis of the present findings it is concluded that, (a) contrary to an earlier proposal, ASP-AT does not appear to be a good marker for the glutamatergic neurons, (b) the failure of the subcortical cholinergic neurons to respond by an increase in ChAT activity to NMDA may indicate that these nerve cells lack NMDA subtype excitatory amino acid receptors, and (c) as the septal GABAergic input in the hippocampus is involved in the modulation of long-term potentiation, the presence of NMDA receptors on these neurons would now suggest that NMDA receptors are linked to both the initiation and the modulation of hippocampal plasticity in the mammalian brain.

Animals↗

PubMed1989

Effects of L-asparaginase on rat embryonic development and yolk sac membrane in vitro.

A comparative analysis of the teratogenic effects of L-asparaginase on 10.5- and 11.5-day rat embryos after 24 and 48 hours of exposure in vitro, respectively, were performed. Several medium concentrations of L-asparaginase (0.05, 0.25, and 1.5 IU/ml) were tested in both embryo series. Resulting embryos were submitted to morphological studies in a search for a specific route of pathogenesis. Morphological alterations of the visceral yolk sac were also studied to investigate its contribution to L-asparaginase teratogenicity in rats. Main embryonic malformations (open truncal neural tube, open encephalic vesicles, anophthalmia, lack of inversion, abnormal frontolateral protrusions, great vascular dilations at the cephalic level) and developmental retardation were already generated after the first 24 hours of culture (embryos of 10.5 days) and presented a dose-response relationship. Vascular dilations and neurulation disturbances seemed to be related to an early mesenchyme deficiency. Reduced number of mesenchymal cells was more evident in embryos of 10.5 days than those of 11.5 days, suggesting the existence of a later compensatory mechanism of cellular proliferation in the older embryo. Visceral yolk-sac endodermal cells at both embryonic stages were greatly deformed and enlarged by an increase of the high electron-dense vacuolar system. Therefore, both a blockage of the processes of lysosomal digestion and derived trophic deficiencies probably existed. A double teratogenic mechanism for L-asparaginase is postulated: a direct action mainly in younger embryos (before invagination of the embryo into the yolk sac) and a yolk sac-mediated one.

Analysis of Variance↗

PubMed1989

Regional changes in brain 2-14C-deoxyglucose uptake induced by convulsant and non-convulsant doses of lindane.

Lindane-induced dose- and time-related changes in regional 2-14C-deoxyglucose (2-DG) uptake were examined in 59 discrete rat brain structures using the 2-DG autoradiographic technique. At different times (0.5-144 hr) after administration of a seizure-inducing single dose of lindane (60 mg/kg), 2-DG uptake was significantly increased in 18 cortical and subcortical regions mainly related to the limbic system (e.g., Ammon's horn, dentate gyrus, septal nuclei, nucleus accumbens, olfactory cortex) and extrapyramidal and sensory-motor areas (e.g., cerebellar cortex, red nucleus, medial vestibular nucleus). There was also a significant increase in superior colliculus layer II. In addition, significant decreases occurred in a group of 6 regions (e.g., auditory and motor cortices). Non-convulsing animals treated with the same dose of lindane showed a regional pattern of 2-DG uptake less modified than the convulsant group. A non-convulsant single dose of lindane (30 mg/kg) also modified significantly the 2-DG uptake (0.5-24 hr) in some brain areas. Although the various single doses of lindane tested produced different altered patterns of brain 2-DG uptake, some structures showed a similar trend in their modification (e.g., superior colliculi and accumbens, raphe and red nuclei). Repeated non-convulsant doses of lindane produced defined and long-lasting significant elevations of 2-DG uptake in some subcortical structures (e.g., dorsal cochlear nucleus, dentate gyrus). Considering the treated groups all together, 2-DG uptake increased significantly in 26 of the 59 regions examined but only decreased significantly in 9 of them during the course of lindane effects. This fact can be related to the stimulant action described for this neurotoxic agent. The observed pattern provides a descriptive approach to the functional alterations occurring in vivo during the course of lindane intoxication. These results may be linked to the proposed mechanism of lindane neurotoxicity postulating an initial action on the GABAA receptor-chloride channel sites.

Animals↗

PubMed1988

Cerebral glucose uptake in lindane-treated rats.

The pesticide and ectoparasiticide lindane, gamma-isomer of hexachlorocyclohexane, is a powerful CNS-stimulant inducing convulsions and other signs of hyperexcitability in mammals. The present work was carried out to investigate the effect of lindane on brain regional glucose uptake at convulsant and non-convulsant doses. Local glucose uptake was measured in male Wistar rats using a modification of the 2-deoxyglucose (2-DG) method. Animals received i.p. [3H]2-DG and the amount of label in different brain structures of control and lindane-treated animals was assayed by a liquid scintillation counting of 18 dissected regions. Lindane at single convulsant dose (150 mg/kg, p.o.) increased 2-DG uptake in olfactory tubercules, hypothalamus, hippocampus, parafloculi and hypophysis. The uptake was decreased in parietal cortex, thalamus and pons-medulla. The pattern of 2-DG uptake after a single non-convulsant dose of 30 mg/kg p.o. was not so modified. After 1 week of treatment with 10 mg/kg per day p.o., increased 2-DG uptake was observed in superior colliculi while it was decreased in parietal cortex. The increase of 2-DG uptake in limbic regions observed at the convulsive dose agrees with the experimental association between poisoning signs induced by lindane and damage in the limbic system.

Animals↗

PubMed1988

Regional distribution of lindane in rat brain.

Lindane distribution in brain areas after oral (30 mg/kg) and i.v.(0.3 mg/kg) administration was studied using autoradiography-imaging analysis and dissection-liquid scintillation counting techniques. Both experimental approaches gave similar results. An heterogeneous distribution of lindane-label in brain regions was observed. Radiolabel concentration in white matter was higher than in grey matter and the concentration ratio was time increasing. Higher concentrations of lindane-label were found in thalamus, mid-brain and pons-medulla at different times after administration when compared to the whole brain mean value. Pretreatment with 300 mg/kg of the alpha-HCH isomer did not induce significant modification in the pattern of lindane radioactivity distribution in brain. Lindane affinity for white matter and myelinated structures could be related to its lipophilic behaviour and is not in disagreement with the current proposed mechanism of action for this xenobiotic.

Administration, Oral↗

PubMed1986

Teratogenic effects of L-asparaginase in rat embryos in vitro.

The teratogenic potential of L-asparaginase has been assayed in New cultures of explanted rat embryos. Embryos treated on day 9.5 with 1.5 IU L-asparaginase/ml of culture medium exhibited growth and development retardation together with malformations of the brain (exencephalia), eyes (anophthalmia or rudimentary sulcus opticus), face (characteristic appearance with anomalous frontolateral protrusions) and trunk (myeloschisis and turning absence). Neural ectoderm alterations were observed upon histological examination (anomalous fusions between the confronted neural folds as a consequence of the lack of turning and thickening) together with strong vascular dilatations at the cephalic level. Treatment on day 10.5 only caused minor differences in growth and protein content with respect to the control embryos. The possible teratogenic mechanism of this enzyme is discussed.

Abnormalities, Drug-Induced↗

PubMed1983

Anti-ulcer activity and other pharmacological properties of lozilurea.

As a result of trials on a large series of compounds, one of these, N' -3-chlorobenzyl-N'-ethylurea (lozilurea, ITA 312) has shown marked anti-ulcer activity. It has shown itself to be active against chemically and neurogenically induced gastric and duodenal lesions in various experimental animal models. It has no major anti-secretory action. The experimental data obtained suggest that the mechanism of action of lozilurea consists in increasing the protective function of the mucus barrier. In the screening trials carried out in order to detect the side effects of lozilurea, it has shown sedative, antipyretic and vasodilatory actions.

Animals↗

PubMed1981

Toxicological studies of plafibride. Part 1: Acute toxicity and its determination after several administrations of plafibride.

Acute toxicity studies of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) were carried out in mouse, rat, guinea pig and hamster by different administration routes. The effect of pretreatment with plafibride on acute toxicity was also studied for several days. Plafibride had low toxicity. Its LD50 p.o. was about 4000 mg/kg in rat, mouse and hamster. The LD50 i.p. was between 760 (673-859) mg/kg in NMRI mouse and 1050 (830-1328) mg/Kg in hamster. The LD50 i.v. was similar for rat and mouse (about 100 mg/kg). Pretreatment with plafibride did not alter acute toxicity, which implies the absence of accumulation of the compound which would have led to an increase in toxicity. Nor was there any appearance of enzymatic induction, in which case a decrease would be observed in the toxicity of the product.

Administration, Oral↗

PubMed1981

Toxicological studies of plafibride. Part 2: Subacute and subchronic toxicity in rats and chronic toxicity in dogs.

The toxicity of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) was studied by repeated administration in Wistar rat for one and three months and in beagle dog for six months. Clofibrate was used as the standard product. In subacute toxicity in rat hepatomegaly and increase in kidney weight were observed in the animals treated with plafibride. A smaller increase in body weight was also observed in the males. The rats treated with 500 mg/kg of plafibride showed slight anaemia. Clofibrate at the same dose (500 mg/kg) caused the same effects as plafibride. In subchronic toxicity in rat for a period of 3 months both plafibride and clofibrate produced hepatomegaly and an increase in kidney weight but did not affect hepatic and renal functions. In chronic toxicity in beagle dog (6-month period) plafibride was tolerated at the dose of 100 mg/kg, causing slight anaemia, hepatomegaly and an increase in kidney weight, although no functional alterations of these organs were noticed. Clofibrate was administered at the dose of 50 mg/kg but was not tolerated at higher doses.

Animals↗

PubMed1981

Toxicological studies of plafibride. Part 3: Study of teratogenic activity in rats and rabbits.

Teratological studies of N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) were carried out in rats and rabbits. The rats were given doses of 125, 250 and 500 mg/kg/d p.o. and the rabbits 25, 50 and 100 mg/kg/d p.o. during the whole period of organogenesis. As a positive control, vitamin A was administered to the rats at the dose of 60,000 IU/rat p.o. for 3 days and thalidomide was given to the rabbits at the dose of 150 mg/kg/d p.o. A group was added treated with clofibrate at the dose of 500 mg/kg/d p.o. in rat and 100 mg/kg/d in rabbit. Plafibride caused malformations in both species. In rat a considerable number of fetuses appeared with hydrocephalus, correlated to the dose. In rabbit, malformations were observed at the lower doses whereas at 100 mg/kg the toxic action on the embryos avoided the appearance of malformed fetuses. Both vitamin A and thalidomide were teratogenic in the experiments in rat and rabbit, respectively. The number of malformations and postimplantations losses were significant in relation to the control group in both cases. The standard product, clofibrate, reduced the viability of the fetuses which showed weight loss in rat and lower survival rate in rabbit. Plafibride is advised against in pregnant women.

Animals↗

PubMed1981

Toxicological studies of plafibride. Part 4: Interaction of plafibride with other drugs.

The possible pharmacological interaction was studied between N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride, ITA 104) and a series of products with analgesic, anticoagulant, antidepressant, antidiabetic, Beta-blocking, diuretic, hypotensive, nootropic, tranquillizing and vasodilator activities. In the experiment the LD50 of each product was compared with that found for the joint administration of the product and plafibride. Plafibride increased the acute toxicity of reserpine and potentiated its hypothermic effect in the mouse; it did not alter its effect on arterial pressure in dog and rat nor its effect on palpebral ptosis in the mouse. Although plafibride did not potentiate the acute toxicity of warfarin, its anticoagulant activity was potentiated, possibly due to the movement of warfarin from its binding sites to the plasma proteins.

Animals↗

PubMedDate not supplied

Behavioral changes induced in developing rats by an early postnatal exposure to lindane.

The purpose of this study was to determine whether the behavioral developmental pattern was altered by an early postnatal exposure to lindane. Male and female offspring of Wistar rats were daily orally administered with a nonconvulsant dose of lindane (10 mg/kg) during 7 days either the 1st or the 2nd postnatal week days. Effects on pups were evaluated with a reduced developmental neurotoxicological test battery. Body weight evolution, neuromotor reflexes (surface righting, cliff avoidance and tail hang reflex) and spontaneous motor activity were analyzed from day 1 after birth up to day 28. The body weight pattern was unaffected by treatment with lindane and no signs of overt toxicity were observed. Lindane-treated pups showed an increased positive response of the neuromotor reflexes. Furthermore, lindane produced hyperactivity, especially manifested between days 12 and 16. A peak of activity was reached at day 16 in lindane-treated group, while control animals had a maximum between days 20 and 24. These results suggest that low nonconvulsant doses of lindane may induce behavioral changes in developing rats.

Aging↗

PubMedDate not supplied

Behavioral and monoaminergic changes after lindane exposure in developing rats.

The effects of lindane on behavior and central monoaminergic systems were studied in rat pups at 15 days of postnatal age. Pups were previously given nonconvulsant lindane PO doses, either a single 20 mg/kg or 7-day repeated 10 mg/kg doses. Both treatment schedules improved the passive avoidance acquisition but only the acute administration prolonged the step-through latency. Acute lindane decreased the motor activity, whereas the repeated dosing increased it. Increases of the ratio 5-HIAA/serotonin in several brain regions and of the ratio DOPAC/dopamine in the mesencephalon after a single dose of lindane suggest an enhanced monoaminergic turnover. In contrast, repeated lindane doses decreased monoamine/metabolite ratios excluding the striatum, where an increase of DOPAC/dopamine ratio correlates with the higher motor activity of these animals. It is postulated that both the imbalance of the central monoaminergic systems and the lindane-induced GABAergic blockade may be the basis of the behavioral alterations.

Animals↗