Biomedical subjects

C Sanfeliu

Publications and source records attributed to C Sanfeliu.

At least 19 recordsLinked to original sources

PubMed2006

Carboxyl-terminal fragment of amyloid precursor protein and hydrogen peroxide induce neuronal cell death through different pathways.

Carboxyl-terminal fragments (CTs) of the amyloid precursor protein have been shown to be highly neurotoxic and are though to contribute to the neuropathology of Alzheimer's disease. We compared the effects of expressing CT99 in the human neuroblastoma MC65 with the effects of hydrogen peroxide on the parental SK-N-MC cells. CT99 and hydrogen peroxide generated a different pattern of free radicals and their toxic effects were differentially protected by a battery of antioxidants. Hydrogen peroxide caused a cell cycle arrest at phase S and apoptosis mediated through caspase-3 activation in a pattern similar to that described for amyloid-beta neurotoxicity. However, CT99 apoptosis appeared to be mediated through an unidentified mitochondrial pathway. Both oxidative injury types induced heme oxygenase-1 expression as a neuroprotective response. Overall we found a coincidence in the nonespecific stress oxidative effects of CT99 and hydrogen peroxide, but clear differences on their respective potencies and pathways of neurotoxicity.

Amyloid beta-Protein Precursor↗

PubMed2003

Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, is under-expressed in Down syndrome fetal brains.

Suppression subtractive hybridization performed on Down syndrome (DS) versus control fetal brains revealed differential expression of peroxiredoxin 2 (PRDX2), mapped at 13q12. Peroxiredoxins are antioxidant enzymes involved in protein and lipid protection against oxidative injury and in cellular signalling pathways regulating apoptosis. The under-expression of PRDX2 observed in DS samples was confirmed by real-time PCR (0.73-fold). To test whether decreased expression is associated with enhanced sensitivity of DS neurons to reactive oxygen species, we down-regulated PRDX2 through stable transfections of SH-SY5Y neuroblastoma cells with antisense contructs of the complete PRDX2 coding sequence. In addition, we over-expressed SOD1 and compared the effects of the two genes on cell viability. Cells transfected with either construct showed similar sensitivity to oxidative stress in addition to increased apoptosis under basal conditions and after treatment with oxidative cytotoxic agents. This suggests that the decreased expression of PRDX2 may contribute to the altered redox state in DS at levels comparable to that of the increased expression of SOD1.

Apoptosis↗

PubMed2001

Antioxidant compounds and Ca(2+) pathway blockers differentially protect against methylmercury and mercuric chloride neurotoxicity.

The effects of the environmental contaminants methylmercury (MeHg) and inorganic mercury (HgCl(2)) on cell viability, intracellular calcium concentration ([Ca(2+)](i)), and reactive oxygen species (ROS) generation were studied in rat cerebellar granule neuron cultures using fluorescent methods. MeHg exhibited an LC(50) (2.47 microM) tenfold lower than that of HgCl(2) (26.40 microM). To study the involvement of oxidative stress and Ca(2+) homeostasis disruption in mercury-induced cytotoxicity, we tested the neuroprotective effects of several agents that selectively interfere with these mechanisms. After a 24 hr exposure, the cytotoxic effect of both mercury compounds was reduced by thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPase; the Ca(2+) channel blocker flunarizine; and the Na(+)/Ca(2+) exchanger blocker benzamil. All these compounds decreased the mercury-mediated [Ca(2+)](i) rise. These results indicate that Ca(2+) influx through Ca(2+) channels and the Na(+)/Ca(2+) exchanger and Ca(2+) mobilization from the endoplasmic reticulum are involved in mercury-mediated cytotoxicity. The antioxidants probucol and propyl gallate reduced the HgCl(2) toxicity. Probucol and vitamin E partially inhibited the MeHg toxicity after a 24 hr period, whereas propyl gallate completely prevented this effect. Probucol slightly reduced ROS generation in methylmercury-exposed cultures and decreased mercury-mediated rise of [Ca(2+)](i). Propyl gallate abolished ROS generation and partially inhibited the increase of [Ca(2+)](i) induced by both mercury compounds. Propyl gallate also protected human cerebral cortical neuron cultures from the MeHg effect even after 72 hr of MeHg exposure, thus showing a long-lasting effect. Our data suggest that disruption of redox equilibrium and Ca(2+) homeostasis contribute equally to HgCl(2)-mediated toxicity, whereas oxidative stress is the main cause of MeHg neurotoxicity.

Amiloride↗

PubMed2001

Methylmercury neurotoxicity in cultures of human neurons, astrocytes, neuroblastoma cells.

Neurotoxic effects of methylmercury, were investigated in vitro in primary cultures of human neurons and astrocytes isolatedfrom human fetal brain and in the human neuroblastoma cell line SH-SY5Y. The protection provided by agents with antioxidant properties was tested in these cultures to examine the oxidative stress mechanism of methylmercury poisoning. After 24 h of exposure to methylmercury, LC50 values were 6.5, 8.1 and 6.9 microM for human neurons, astrocytes and neuroblastoma cells, respectively, and the degree of cell damage increased at longer exposure times. Depletion of the cellular pool of reduced glutathione (GSH) by treatment with buthionine sulfoximine potentiated methylmercury cytotoxicity in all three cell types; neuroblastoma cells were the most sensitive. Addition of GSH extracellularly blocked methylmercury neurotoxicity in all cell types. The major beneficial effect of GSH could be attributed to its capacity to form conjugates with methylmercury, which reduces the availability of these organometallic molecules to the cells and facilitates their efflux. Cysteine protected astrocytes and neuroblastoma cells from methylmercury neurotoxicity, while selenite, Vitamin E and catalase produced some minor protective effects in three cell types, particularly in neurons. The present study showed that the human neural cells tested had differential responses to methylmercury: astrocytes were resistant to methylmercury neurotoxicity and neurons were more most responsive to protection afforded by antioxidants among the three cell types.

Antioxidants↗

PubMed2000

Trimethyltin and triethyltin differentially induce spontaneous noradrenaline release from rat hippocampal slices.

The environmental contaminants trimethyltin (TMT) and triethyltin (TET) stimulated the spontaneous release of [(3)H]noradrenaline ([(3)H]NA) from hippocampal slices in a time- and concentration-dependent manner. TMT was the most potent compound, exhibiting an EC50 value 10-fold lower (3.8 microM) than that of TET (39.5 microM). Metal-evoked [(3)H]NA release did not increase in the absence of desipramine and was completely blocked by reserpine preincubation, indicating a vesicular origin of [(3)H]NA release but not a mechanism involving reversal of the transmitter transporter. The voltage-gated Na(+) channel blocker tetrodotoxin (TTX) did not affect metal-evoked [(3)H]NA release. [(3)H]NA release elicited by TMT was partially extracellular Ca(2+)-dependent, since it was significantly decreased in a Ca(2+)-free EGTA-containing medium, whereas TET induced an extracellular Ca(2+)-independent release of [(3)H]NA. Neither inhibitors of Ca(2+)-entry through Na(+)/Ca(2+)exchanger and voltage-gated calcium channels, nor agents that interfere with Ca(2+)-mobilization from intracellular stores affected [(3)H]NA release induced by TMT. TET-evoked [(3)H]NA release was reduced by ruthenium red, which depletes mitochondrial Ca(2+)stores, but was not modified by caffeine and thapsigargin, which interfere with Ca(2+)mobilization from endoplasmic reticulum. The fact that TET effect was also attenuated by DIDS, an inhibitor of anion exchange, indicates that the effect of TET on spontaneous [(3)H]NA release may be mediated by intracellular mobilization of Ca(2+) from mitochondrial stores through a Cl(-) dependent mechanism.

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

PubMed2000

Pharmacological characterization of the effects of methylmercury and mercuric chloride on spontaneous noradrenaline release from rat hippocampal slices.

The environmental contaminants methylmercury (MeHg) and mercuric chloride (HgCl2) stimulated the spontaneous release of [3H]noradrenaline ([3H]NA) from hippocampal slices in a time- and concentration-dependent manner. Both MeHg and HgCl2 were similarly potent, with an EC50 of 88.4 microM and 75.9 microM, respectively. The releasing effects of MeHg and HgCl2 increased in the presence of desipramine, showing that the mechanism does not involve reversal of the transmitter transporter, and were completely blocked by reserpine preincubation, indicating a vesicular origin of [3H]NA release. The voltage-gated Na+ channel blocker tetrodotoxin (TTX) did not affect the response to mercury compounds. [3H]NA release elicited by MeHg was partially dependent on extracellular Ca2+, since it decreased significantly in a Ca2+-free EGTA-containing medium whereas HgCl2 induced a release of [3H]NA independent of extracellular Ca2+. Neither Ca2+-channels blockers, cobalt chloride (CoCl2) and (omega-conotoxin-GVIA, nor the Na+/Ca2+-exchanger inhibitor benzamil reduced MeHg-evoked [3H]NA release. Moreover, thapsigargin or caffeine, endoplasmic reticulum Ca2+-depletors, did not modify metal-evoked [3H]NA release, whereas ruthenium red, which inhibits the mitochondrial Ca2+ transport, decreased the effect of both MeHg and HgCl2. All these data indicate that, in hippocampal slices, mercury compounds release [3H]NA from the vesicular pool by a mechanism involving Ca2+ mobilization from mitochondrial stores.

Adrenergic Uptake Inhibitors↗

PubMed1999

Neurotoxicity of isoniazid and its metabolites in cultures of mouse dorsal root ganglion neurons and hybrid neuronal cell line.

Isoniazid (INH) is one of the anti-tuberculosis drugs widely prescribed for patients since the early 1950s. It is relatively nontoxic but some patients develop peripheral neuropathy attributed to a disturbance of vitamin B6 metabolism. Some isoniazid metabolites are hepatotoxic but little is known about their neurotoxic property. Isoniazid and its metabolites including acetylisoniazid, acetylhydrazine, diacetylhydrazine, isonicotinic acid and hydrazine were examined for their potential neurotoxic effects in cultured mouse dorsal root ganglion (DRG) neurons and mouse neuroblastoma x DRG neuron hybrid cell line N18D3. Isoniazid did not cause neurotoxicity at exposures up to 7 days. Hydrazine was found to be the most toxic metabolite with LC50 values of 2.7 mM and 0.3 mM after 7 days of exposure in DRG neurons and N18D3 hybrid neurons, respectively. Other metabolites including acetylisoniazid, acetylhydrazine, diacetylhydrazine and isonicotinic acid had moderate to minor neurotoxic effects on N18D3 hybrid neurons. Pyridoxine, which is used in clinical practice to prevent or ameliorate the isoniazid-induced neuropathy, did not consistently reverse the neurotoxicity of any of the metabolites in the cell cultures, but some interaction with hydrazine cannot be ruled out. Pyridoxine itself was found to be neurotoxic both in DRG neurons and N18D3 hybrid neurons, in agreement with human peripheral sensory neuropathy caused by prolonged overdosage. The enzymes catalase and superoxide dismutase and the antioxidant agent selenium showed some protection against hydrazine neurotoxicity, suggesting an involvement of the generation of reactive oxygen species in the pathogenesis of isoniazid neuropathy. Both mouse DRG neurons and N18D3 mouse hybrid neurons were shown to be useful culture systems for elucidating the neurotoxicity mechanisms of agents causing sensory neuropathies and general neurotoxic effects in the nervous system.

Animals↗

PubMed1997

Properties of ryanodine receptors in cultured cerebellar granule neurons: effects of hexachlorocyclohexane isomers and calcium.

The binding of [3H]ryanodine was determined in microsomal membrane preparations obtained from cultured cerebellar granule cells. A KD of 1 nM and a Bmax of 64 fmol/mg protein were calculated from saturation experiments. This binding was calcium dependent and maximum values were obtained at 100-300 microM Ca+2. Caffeine increased [3H]ryanodine binding only at Ca+2 concentrations lower than optimum. The binding of [3H]ryanodine was inhibited by ruthenium red, procaine and the delta-isomer of hexachlorocyclohexane (delta-HCH). Dantrolene, a ryanodine receptor antagonist in skeletal sarcoplasmic reticulum, and the pesticide gamma-HCH (lindane) had no effect on [3H]ryanodine binding. The obtained binding parameters, the Ca+2 dependence and the effects of the agents tested agree with previous reports using brain microsomal membranes, further indicating a neuronal localization of [3H]ryanodine binding sites. When the interaction between dantrolene and gamma- and delta-HCH was tested, no changes were detected on the effects of HCH isomers on [3H]ryanodine binding. Dantrolene, which inhibits Ca+2 release from sarcoplasmic reticulum and from unidentified internal Ca+2 stores in neurons, also inhibits the intracellular Ca+2 mobilization induced by gamma-HCH but only marginally that induced by delta-HCH in the same preparation of cerebellar granule cells (Rosa et al.; Toxicol Appl Pharmacol, in press). Thus, the results obtained in this work verify the presence of different intracellular sites of action for the two HCH isomers: the ryanodine Ca+2 channel for delta-HCH and an unidentified dantrolene-sensitive Ca+2 channel for the gamma-HCH isomer.

Anesthetics, Local↗

PubMed1997

The mechanism for hexachlorocyclohexane-induced cytotoxicity and changes in intracellular Ca2+ homeostasis in cultured cerebellar granule neurons is different for the gamma- and delta-isomers.

The cytotoxic action of the delta- and gamma-isomers of hexachlorocyclohexane (HCH) as well as their ability to induce changes in intracellular Ca2+ homeostasis was studied in cultured rat cerebellar granule neurons. Changes in the free intracellular Ca2+ concentration ([Ca2+]i) related to Ca2+ influx and release from intracellular stores were investigated using, in addition to the physiological incubation medium, media without added Ca2+ (nominally Ca2+ free) or containing verapamil or dantrolene, drugs which block influx through voltage-gated Ca2+ channels and release from intracellular stores, respectively. Cytotoxicity was monitored using leakage of lactate dehydrogenase (LDH) and staining of damaged cells with either trypan blue or propidium iodide. In the latter case, when fluorescence microscopy was employed, undamaged cells were visualized using the vital stain calcein acetoxymethyl ester (calcein-AM). The delta-isomer of HCH was found to be more potent and active as a cytotoxic agent than the gamma-isomer (lindane) and it was demonstrated that the moderate cytotoxic action of lindane could be ameliorated by dantrolene which on the other hand had no effect on cytotoxicity induced by delta-HCH. It was noticed that pronounced (50% increase in fluorescence) staining with propidium iodide was associated with only a marginal (20%) LDH leakage and staining of only a few (<25%) cells with trypan blue. Both delta- and gamma-HCH induced an increase in [Ca2+]i which was most pronounced in case of delta-HCH. Analysis of the different mechanisms governing the increase in [Ca2+li using dantrolene, verapamil, and Ca2+-free medium revealed distinct differences between the two isomers with regard to the Ca2+ pools affected. Both isomers stimulated Ca2+ influx through voltage-gated Ca2+ channels but only the gamma-isomer affected a Ca2+-dependent, dantrolene-sensitive pool. On the other hand, delta-HCH affected mainly a Ca2+-independent dantrolene-insensitive pool. The finding that delta-HCH was more toxic than lindane may be correlated to the differences between the isomers with regard to the action on the different Ca2+ pools. Thus, delta-HCH affected primarily the dantrolene-insensitive Ca2+ pools which partly reflect influx. On the contrary, lindane had little effect on these Ca2+ pools but affected primarily dantrolene-sensitive intracellular Ca2+ stores. This may suggest that delta-HCH may exert its cytotoxic action by stimulating a large influx of Ca2+ possibly leading to release of Ca2+ from dantrolene-insensitive stores. In contrast, the toxic action of lindane may be primarily related to release of Ca2+ from the dantrolene-sensitive stores.

Animals↗

PubMed1996

Stimulation of Phosphoinositide Hydrolysis by gamma- and delta-Hexachlorocyclohexane in Primary Cultures of Cerebellar Granule Cells: Interaction with Glutamate and Carbachol Receptor-Mediated Phosphoinositide Response and Effects of Specific Pharmacological Agents

The accumulation of [3H]inositol phosphates derived from phosphoinositide hydrolysis stimulated by gamma- and delta-hexachlorocyclohexane isomers was characterized in primary cultures of cerebellar granule cells. The EC50 for gamma- and delta-hexachlorocyclohexane was 106 and 85 μM, respectively. Stimulatory effects of hexachlorocyclohexane isomers were highly dependent on extracellular Ca2+ but they were not inhibited by classical voltage-sensitive Ca2+ and Na+ channel blockers. The Na+/Ca2+ exchanger blocker amiloride caused a significant inhibition of delta-hexachlorocyclohexane effects. A lack of additive effects on phosphoinositide hydrolysis stimulation between hexachlorocyclohexane isomers and depolarization by high K+ was observed. The effects of each hexachlorocyclohexane isomer on glutamate or carbachol-induced inositol phosphate stimulation were also not additive, whereas that of high K+ was less than additive or synergistic when combined with glutamate or carbachol, respectively. When neuronal cells were exposed to the combination of delta-hexachlorocyclohexane and glutamate or carbachol in the presence of the respective receptor antagonists only the delta-hexachlorocyclohexane stimulatory effect was observed. Thus, the inhibition of glutamate- and carbachol-stimulated phosphoinositide hydrolysis by delta-hexachlorocyclohexane seems to imply a receptor-independent mechanism. It is suggested that both gamma- and delta-hexachlorocyclohexane activate phosphoinositide-specific phospholipase C partly through Ca2+-related mechanisms.

Journal Article↗

PubMed1996

Effects of glucose and oxygen deprivation on phosphoinositide hydrolysis in cerebral cortex slices from neonatal rats.

The effects of glucose deprivation, hypoxia and glucose-free hypoxia conditions on phosphoinositide (PI) hydrolysis were studied in cortical slices from 8-day-old rats. Only glucose-free hypoxia induced a significant increase of inositol phosphate formation. The inositol phosphate formation induced by noradrenaline, carbachol and several excitatory amino acid receptor agonists, but not the Ca2+ ionophore A23187-induced stimulation, was blocked by glucose-free hypoxia and differentially reduced by glucose and oxygen deprivation depending on the neurotransmitter receptor agonist. The stimulatory effect of glucose-free hypoxia was not reduced by the muscarinic receptor antagonist atropine or by the inhibitors of the excitatory amino acid-stimulated PI hydrolysis DL-2-amino-3-phosphono-propionic acid and L-aspartate-beta-hydroxamate, and neither by the voltage-sensitive Na+ channel tetrodotoxin. The effect of glucose-free hypoxia was partially dependent on extracellular Ca2+ and it was blocked by verapamil and amiloride, but not by nifedipine, Co2+ and neomycin. These results suggest that Ca2+ influx through the Na(+)-Ca2+ exchanger underlies the PI hydrolysis stimulation induced by combined glucose and oxygen deprivation in neonatal cerebral cortical slices.

Animals↗

PubMed1996

Cytotoxicity of hexachlorocyclohexane isomers and cyclodienes in primary cultures of cerebellar granule cells.

The cytotoxicity of the neurotoxic hexachlorocyclohexane (HCH) isomers alpha, beta, gamma (lindane) and delta and of the cyclodienes aldrin, endrin and alpha-endosulfan were studied in primary neuronal cultures of cerebellar granule cells. Disruption of cell membrane integrity, as indicative of cytotoxicity, was measured by propidium iodide staining. Additionally, the effects of these xenobiotic agents on three endpoints of the cellular status, concentration of intracellular-free calcium, intracellular oxygen-free radical formation and mitochondrial transmembrane potential were analyzed in parallel cultures to understand better the mechanisms of their neurocytotoxic action. To measure these parameters, the probes of the acetoxymethyl ester of fluo-3, 2',7'-dichlorofluorescin diacetate and rhodamine 123, respectively, were used. The order of cytotoxic potency of the HCH-isomers and the cyclodienes (delta-HCH > gamma-HCH > alpha-HCH approximately equal to aldrin approximately equal to alpha-endosulfan >> endrin approximately equal to beta-HCH) was very different from their in vivo LD50 order. delta-, gamma- and alpha-HCH increased the concentration of intracellular-free calcium, whereas delta- and gamma-HCH and alpha-endosulfan increased mitochondrial transmembrane potential, but none of the compounds generated oxygen-free radicals. The inhibition of delta- and gamma-HCH effects by several specific pharmacological agents suggests that delta-HCH causes its cytotoxic effects in part through intracellular Ca++ mobilization from intracellular pools sensitive to neomycin, whereas gamma-HCH acts through Ca++ influx and dantrolene-sensitive intracellular Ca++ mobilization. The use of selected endpoints of the cellular status proved to be a valuable tool to study the mechanisms of cytotoxicity.

Animals↗

PubMed1994

Lindane cytotoxicity in cultured neocortical neurons is ameliorated by GABA and flunitrazepam.

The effect of lindane (gamma-hexachlorocyclohexane) on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding and GABA-stimulated 36Cl- influx was investigated in cultured cerebral cortical neurons. In addition, the cytotoxic action of lindane as well as a protection by GABA and flunitrazepam were studied together with the ability of lindane to increase the intracellular concentration of free Ca2+. Lindane was found to be toxic to the neurons, an effect that could be completely prevented by the simultaneous presence of GABA (0.1 microM) and flunitrazepam (100 microM) and reduced by GABA alone. An interaction with the GABA receptor-gated chloride channel was demonstrated by an inhibitory action of lindane on [35S]TBPS binding (IC50 188 +/- 51 nM) and on GABA-stimulated 36Cl- influx in the neurons. Lindane only marginally increased the intracellular Ca2+ concentration in the neurons. It is concluded that the cytotoxic action of lindane is mediated through interaction with GABA receptors in a manner essentially independent of changes in intracellular Ca2+ homeostasis.

Animals↗

PubMed1993

Effects of gamma and delta hexachlorocyclohexane isomers on inositol phosphate formation in cerebral cortex and hippocampus slices from developing and adult rat.

Hexachlorocyclohexane (HCH) isomers, mainly gamma-HCH (insecticide with stimulant and convulsant effects in man) and delta-HCH (neurodepressant agent), are known to inhibit the synthesis of phosphatidylinositol (PI) in diverse cell systems, but action on phosphoinositide hydrolysis has been scarcely studied. The present work examines the effects of gamma-HCH and delta-HCH on the accumulation of [3H]inositol phosphates (InsP) from the hydrolysis of prelabelled phosphoinositides, in cerebral cortical and hippocampal slices from developing (8-day-old) and adult rats. In developing and adult animals both isomers increased InsP formation in a concentration-related manner. delta-HCH was statistically more potent in developing than in adult animals (maximum effects obtained were 280% and 200% of basal InsP accumulation at 300 microM, respectively). gamma-HCH showed lower stimulation (maximal effect was 170% at 300 microM, at both ages) than delta isomer. No differences between brain regions were observed after treatment with HCH isomers. Effects of HCH isomers (200 microM) on phosphoinositide hydrolysis stimulation by glutamate, carbachol and noradrenaline were selective for the transmitter receptor agonist and age studied. delta-HCH inhibited glutamate and carbachol stimulation in cerebral cortex from developing animals and did not modify it in adults. Combination of delta-HCH and noradrenaline increased the effects of this neurotransmitter in immature rats, while only noradrenaline stimulation was observed in adult rats. A noticeable effect of gamma-HCH was that it did not increase glutamate and carbachol stimulation in cerebral cortex of developing rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Regulation of neurotransmitter enzyme by quisqualate subtype glutamate receptors in cultured cerebellar and hippocampal neurons.

The possible involvement of ionotropic and metabotropic quisqualate (QA) receptors in neuronal plasticity was studied in cultured glutamatergic cerebellar or hippocampal cells in terms of the specific activity of phosphate-activated glutaminase, an enzyme important in the synthesis of the putative neurotransmitter pool of glutamate. When cerebellar or hippocampal neurons were treated with QA, it elevated the specific activity of glutaminase in a dose-dependent manner. The half-maximal effect was obtained at about 0.1 microM, the maximum increase was at about 1 microM, but levels higher than 10 microM QA produced progressive reduction in glutaminase activity. In contrast, QA had little effects on the activities of lactate dehydrogenase and aspartate aminotransferase and the amount of protein, indicating that the increase in glutaminase was relatively specific. The QA-mediated increase in glutaminase was mimicked by the ionotropic QA receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; EC50, about 0.5 microM), but not by the metabotropic QA receptor agonist trans-(+-)-1-amino-cyclopentyl-1,3,dicarboxylate (t-ACPD; up to 0.5 mM). The specific ionotropic QA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited QA- and AMPA-mediated increases in glutaminase activity in a dose-dependent manner, whereas other glutamate receptor antagonists, D,L-2-amino-5-phosphonovalerate, gamma-D-glutamyl aminomethyl sulphonic acid and gamma-D-glutamyl diethyl ester were ineffective. The elevation of neurotransmitter enzyme was Ca(2+)-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Increase in rat pup ultrasonic isolation calls induced by lindane.

The neurotoxic agent lindane was tested for its ability to alter the rate of ultrasonic isolation calls of suckling rats. Doses that did not produce any sign of convulsant activity significantly increased the number of calls and the cumulative time of calling in male pups. At days 10-13 of age after a single dose of 20 mg/kg lindane, animals showed more than twice the control call values. After daily dosing with 10 mg/kg during the first week of age call increases also appeared. It is suggested that lindane has an anxiogenic effect mediated through its action on the benzodiazepine-GABAA receptor-chloride channel complex.

Animals↗

PubMed1991

Regional effects on the cerebral concentration of noradrenaline, serotonin and dopamine in suckling rats after a single dose of lindane.

The effect of a low single dose of lindane (gamma-hexachlorocyclohexane) on monoaminergic neurotransmission during brain postnatal development was studied in 8-, 15-, 22- and 29-day-old suckling rats. Concentrations of noradrenaline, serotonin, dopamine and their metabolites were determined in eight cerebral regions 1 h after dosing (20 mg/kg lindane per os). All these aminergic systems were altered in a regional- and age-related pattern. Decreases of noradrenaline in regions rich with noradrenergic terminals together with increases of the ratio 5-HIAA/serotonin and DOPAC/dopamine suggest, as a whole, an enhanced release of the monoamines. This increased neuronal activity does not exclude an initial action of lindane on the inhibitory GABAergic system that would activate the neurotransmitter release in other systems shortly after a single administration of the neurotoxic agent.

Aging↗

PubMed1990

Development and regulation of excitatory amino acid receptors involved in the release of arachidonic acid in cultured hippocampal neural cells.

Release of [3H]arachidonic acid mediated by excitatory amino acid (EAA) receptors was investigated from prelabelled primary cultures of hippocampal neurons and astroglial cells. Treatment with N-methyl-D-aspartate (NMDA), quisqualate (QA) and kainate resulted in age- and dose-dependent stimulation of [3H]arachidonic acid release. During development, the maximum response for NMDA was observed relatively earlier (at 7 days) than those for QA and kainate (at 14 days) in the hippocampal neuronal cultures. The half maximal effects were obtained at about 15 microM NMDA at all ages studied and about 0.5 microM QA at 14 and 20 days. At optimum concentrations NMDA- and QA-induced releases were additive. Unlike with neurons, treatment with all the 3 EAA receptor agonists, NMDA, QA and kainate, had no significant effect on [3H]arachidonate release in hippocampal astroglial cells. In cultured 14-day-old neurons, the increases in NMDA- and QA-mediated [3H]arachidonic acid release were completely blocked by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid, and the ionotropic QA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, respectively. But the iontropic QA receptor agonist alpha-amino-3-hydroxy-5-methyl-isoxazole-4- propionic acid (AMPA) had no significant effect on [3H]arachidonate release, indicating that interaction between ionotropic QA and metabolotropic QA receptors may be essential for optimal QA-mediated arachidonic acid release. At physiological concentrations of Mg2+ (1.2 mM), AMPA was found to potentiate NMDA-induced release of [3H]arachidonic acid; the effect appeared to be related to a removal of Mg2+ blockade mediated by mild depolarisation.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗