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J Bockaert

Publications and source records attributed to J Bockaert.

At least 109 records · Page 6Linked to original sources
PubMed1995

Action of argiotoxin636 on N-methyl-D-aspartate channels in cerebellar cells.

We investigated the mode of action of argiotoxin636 on isolated N-methyl-D-aspartate (NMDA) receptor channels in cultured cerebellar granule cells. We found that the toxin blocks NMDA channels by decreasing their opening probability and by inducing a flickering activity, in a voltage-dependent manner. Our results indicate that argiotoxin636 acts as an open-channel blocker and might therefore be a useful tool for studying the structure of glutamate-gated channels.

Animals↗
PubMed1995

Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses.

The effects of the phenylglycine derivatives, alpha-methyl-4-carboxyphenylglycine (MCPG), 4-carboxyphenylglycine (4CPG), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), 3-hydroxyphenylglycine (3HPG) and 3,5-dihydrohyphenylglycine (DHPG) were tested on LLC-PK1 cells transiently expressing the rat mGluR1a or mGluR5a receptors. As previously reported by others, (S)-3HPG and (RS)-DHPG were found to be partial agonists at mGluR1a, whereas(+)-MCPG,(S)-4CPG and (S)-4C3HPG competitively antagonized the effect of Glu. Surprisingly, the 4-carboxy derivatives of phenylglycine antagonized the effect of 1S,3R-ACPD on mGluR1a with lower KB values. On mGluR5a, (S)-3HPG and (RS)-DHPG are also partial agonists. However, in contrast to their effects on mGluR1a,(S)-4CPG did not inhibit the effect of Glu or 1S,3R-ACPD, and (S)-4C3HPG acted as an agonist at high concentration. Whereas no significant antagonism of the Glu effect on mGluR5a was observed with 1 mM (+)-MCPG, this compound was found to potently and competitively antagonize the effect of 1S,3R-ACPD. Finally, the effect of 4CPG was also examined on cultured cortical and cerebellar neurons that express mGluR5 and mGluR1 mRNA, respectively. 4CPG inhibited 1S,3R-ACPD-stimulated IP production in cerebellar neurons only. These results(1) demonstrate that phenylglycine derivatives can be used to discriminate between effects mediated by mGluR1 and mGluR5 and (2) suggest that the apparent potency of phenylglycine antagonists depends on the agonist used to activate these receptors.

Animals↗
PubMed1995

Modulation of calcium channels by metabotropic glutamate receptors in cerebellar granule cells.

We investigated the mechanisms by which metabotropic glutamate receptors (mGluRs) modulate specific Ca2+ channels in cerebellar granule cells. A large fraction of the current in granule cells is carried by L- and Q-type Ca2+ channels (about 26% each), whereas N- and P-type contribute proportionally less to the global current (9 and 15%, respectively). l-Aminocyclopentane-dicarboxylate (t-ACPD), (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCGI) and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], but not L(+)-2-amino-4-phosphonobutyrate (L-AP4) reduced the Ca2+ current amplitude. The t-ACPD-induced inhibition was fully antagonized by (+/-)-methyl-4-carboxyphenylglycine [(+/-)-MCPG] and blocked by pertussis toxin (PTX). These results are consistent with inhibitory response mediated by mGluR2/R3. The use of specific Ca2+ channel blockers provided evidence that mGluR2/R3 inhibited both L- and N-type Ca2+ currents. In PTX-treated cells, Glu or t-ACPD, but not L-CCGI or L-AP4, increased the Ca2+ current. Consistent with the activation of mGluR1, the antagonists (+)-MCPG and (S)-4C3HPG prevented the facilitation of Ca2+ current produced by t-ACPD. The mGluR1-activated facilitation was completely blocked by nimodipine, indicating that L-type Ca2+ currents were selectively potentiated.

Animals↗
PubMed1995

Combination chemotherapy with vindesine-ifosfamide-cisplatin (VIP) in locally advanced unresectable stage III and in stage IV non-small cell lung cancer: a phase II trial.

UNLABELLED: The efficacy and toxicity of a regimen adding ifosfamide to the more classical cisplatin-vindesine combination was studied in patients with advanced non-small cell lung cancer. Sixty-four good performance patients with inoperable stage III or stage IV were treated with VIP: vindesine 3 mg/m2 days 1 and 8, ifosfamide 1200 mg/m2 and platinum 30 mg/m2 days 1, 2 and 3, repeated every 4 weeks, up to a maximum of six cycles. Response rate, clinical data and radiological tests were rigourously reviewed by a panel. Overall response rate was 39% (95% confidence interval, 27%-51%) with three patients achieving a complete response; response rate in stage III was 48%. Median survival was 9 months. Toxicity consisted mainly of bone marrow toxicity and nausea/vomiting, but was manageable. There was no renal toxicity greater than grade 2, four severe infections, but no treatment-related deaths. CONCLUSION: VIP as mentioned above is very active in good performance patients with advanced non-small cell lung cancer. Its activity, together with its manageable toxicity--without severe renal or pulmonary toxicity--makes it an attractive candidate for induction chemotherapy.

Adenocarcinoma↗
PubMed1995

Get receptive to metabotropic glutamate receptors.

Glutamate activates not only ionotropic glutamate receptors, but also G-protein-coupled receptors, called metabotropic glutamate receptors. Recent studies have revealed that these metabotropic receptors share distinctive structural properties and that they form a subgroup within the heptahelical receptor family. The development of ligands that bind specifically to these receptors has provided a means of characterizing the important roles they play in the tuning of fast synaptic transmission, including the induction of long-term changes in synaptic strength. Their involvement in the control of movement, spatial and olfactory memory and nociception has recently been demonstrated.

Animals↗
PubMed1995

Central 5-HT4 receptors.

Activation of the 5-HT4 receptor mediates widespread effects in central and peripheral nervous systems. Recent developments, such as the identification of novel, selective agonists and antagonists, as well the cloning of the receptor, have provided insights into the physiological role of the receptor. In this article, Richard Eglen and colleagues assess the emerging evidence relating to the function of the 5-HT4 receptor in the brain. The cerebral distribution of the receptor, along with neurochemical and electrophysiological data, suggests a role in cognition. The role of the receptor in modulation of dopamine transmission and anxiolysis is also addressed.

Animals↗
PubMed1995

Epidemiology of interstitial lung disease (ILD) in flanders: registration by pneumologists in 1992-1994. Working group on ILD, VRGT. Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding.

Worldwide almost no epidemiologic data are available on the prevalence or incidence of interstitial lung diseases (ILD) in the general population. Therefore, a registration programme of ILD-prevalence was organised by the VRGT (Vereniging voor Respiratoire Gezondheidszorg en Tuberculosebestrijding), among about 100 Flemish pneumologists since 1990. Most categories of the classification by Crystal et al. (1) were included and the diagnostic criteria (histology, laboratory tests, clinic, radiology) were registered. The present paper presents the results of 1992-1994: twenty pneumologists had forwarded the summary files of 237 patients to the central office in 1992 (n = 68), 1993 (n = 90) and 1994 (n = 79). The diagnoses that were most frequently made were: sarcoidosis in 27%, idiopathic pulmonary fibrosis in 20%, hypersensitivity pneumonitis in 14% (of which 68% by birds) and collagen-vascular disease in 10% (of which 54% in rheumatoid arthritis). Less frequent causes were eosinophilic pneumonia (4%), inhalation of inorganic material (4%, anthracosilicosis being excluded), histiocytosis X (3%), drugs (3%), angiitis and granulomatosis (2%), pulmonary hemosiderosis (1%), lymphocytic infiltrative lung disease (1%) and lymphangioleiomyomatosis (1%). The order of relative frequencies of the different categories of diseases was the same in the 3 registration years. In 9% of the patients the diagnosis was confined to "undefined fibrosis". The diagnosis was confirmed by histology in 63% of the cases. The overall male-female ratio was nearly one, with, however, a male preponderance in hypersensitivity pneumonitis (22/12), UIP(8/3) and "undefined fibrosis" (14/7).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Glutamate stimulates insulin secretion and improves glucose tolerance in rats.

We previously showed in vitro that glutamate stimulates insulin release via an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Here we address a more physiological question concerning the in vivo effect of intravenously or orally administered glutamate on insulinemia and glycemia in fed and fasted rats. In anesthetized fed rats, the intravenous administration of glutamate at 9 and 30 mg/kg transiently increased insulinemia in a dose-dependent manner. The insulin-secretory effect of glutamate (9 mg/kg) was blocked by an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. In anesthetized fasted rats, glutamate at 9 mg/kg was ineffective, but during an intravenous glucose tolerance test (0.5 g/kg), glutamate markedly potentiated insulin release and increased the glucose disappearance rate. In conscious rats, the intragastric administration of glutamate at 200 mg/kg elicited a transient insulin response in fed animals and had no effect in fasted animals but, during an oral glucose tolerance test (1 g/kg), enhanced insulin secretion and reduced the hyperglycemia. Glutamate was effective at plasma concentrations of 200-300 microM. In conclusion, intravenously and orally administered glutamate stimulates insulin secretion in vivo via an excitatory amino acid receptor and improves glucose tolerance.

Administration, Oral↗
PubMed1995

Differential expression of pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptor subtypes in clonal pituitary somatotrophs and gonadotrophs.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are hypothalamic factors believed to play a role in the regulation of anterior pituitary cell function. However, little is known about the expression of PACAP/VIP receptor (PVR) subtypes in such cells. Three PVR subtypes have recently been cloned: the PACAP-selective PVR1, and PVR2 and PVR3, which exhibit similar affinities for PACAP and VIP. In the present study we used the reverse transcription-polymerase chain reaction with PVR-specific primers to identify the PVR messenger RNAs (mRNAs) expressed in the somatotroph-like GH4C1 and the gonadotroph-like alpha T3-1 cell lines. In parallel, the effects of PACAP and VIP on intracellular signaling were studied. GH4C1 cells were found to express mRNA only for the PVR3, and neither PVR1 nor PVR2 mRNA was found. PACAP and VIP stimulated Ca2+ influx responses in individual GH4C1 cells and were equipotent in stimulating cAMP production (EC50, 15 nM) in GH4C1 cell populations, but failed to stimulate inositol phospholipid (PI) turnover, results consistent with the expression of a PVR3. In contrast, alpha T3-1 cells expressed mRNA for PVR1 and PVR3, but not PVR2. The predominant splice variant forms of PVR1 observed were PVR1s and PVR1hop, although the other forms (PVR1hiphop and PVR1hip) were also seen at much lower levels. PACAP stimulated a Ca2+ store-dependent Ca2+ spike and a sustained Ca2+ influx in individual alpha T3-1 cells, whereas VIP only stimulated Ca2+ influx. PACAP (EC50, 3 nM) was approximately 1000-fold more potent than VIP (EC50, approximately 3 microM) in stimulating cAMP production. PACAP also stimulated PI turnover (EC50, approximately 20 nM), whereas VIP stimulated PI turnover only at very high (10 microM) concentrations. These results are indicative of the expression of a PVR1. Rat anterior pituitary tissue expressed mRNAs for PVR1, PVR3, and low levels of PVR2. The coexpression of different PVRs in the same cell type and the differential expression of PVRs in different cell types would allow for a complex regulation of anterior pituitary gland function by PACAP and VIP.

Animals↗
PubMed1995

Involvement of divalent ions in the nitric oxide-induced blockade of N-methyl-D-aspartate receptors in cerebellar granule cells.

We have previously shown that nitric oxide blocks the N-methyl-D-aspartate (NMDA) receptor without affecting the agonist binding site. We now report that in cerebellar granule cells nitric oxide decreases the NMDA channel conductance and open probability, in voltage-dependent and -independent manners, respectively, by acting on an extracellular site different from the redox, glycine, and pH modulatory sites of the receptor-channel complex. This inhibition is not additive with those of Mg2+ and Zn2+. Moreover, removal of trace concentrations of metal ions in the external medium by means of metal ion-chelators significantly reduced the inhibitory action of nitric oxide on NMDA currents. These results indicate that divalent ions are required for the blockade of NMDA receptors by NO donors.

Animals↗
PubMed1995

Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1.

The main excitatory neurotransmitter in the brain, glutamate (Glu), activates not only receptor-channels, but also receptors coupled to G-protein called metabotropic Glu receptors (mGluRs). Eight genes coding for mGluRs have been characterized to date giving rise to even more proteins due to alternative splicing phenomena. Here we characterized a splice variant of mGluR5, called mGluR5b which contains a 32 amino acid fragment inserted in the cytoplasmic tail, 50 residues after the 7th transmembrane domain. mGluR5b mRNAs are present in different regions of the adult rat brain and are expressed at a higher level than mGluR5a mRNA. Functional analysis of mGluR5a and mGluR5b revealed that they share all the properties of mGluR1a, but not those of mGluR1b or 1c. Like mGluR1a, both mGluR5a and mGluR5b activate a rapid and transient current in Xenopus oocytes. When expressed in LLC-PK1 cells, they show the same subcellular distribution as mGluR1a, and stimulate both inositol phosphate (IP) and cAMP production. Moreover, cells expressing mGluR5a or mGluR5b, like those expressing mGluR1a have a higher basal PLC activity that is not inhibited by glutamate-pyruvate transaminase (GPT), suggesting that these receptors have an intrinsic activity. Interestingly, the pharmacological profiles of mGluR5a and b are identical, but different from that of mGluR1a. Most agonists, except glutamate, are more potent on mGluR5a/b than on mGluR1a. Interestingly, the mGluR1a antagonists MCPG and 4CPG have no effect on mGluR5a/b; 4C3HPG which is a full antagonist at mGluR1a is a partial agonist at mGluR5a/b. These results indicate that the long C-terminal intracellular domain present only in mGluR1a and mGluR5a/b, although not well conserved, is likely to be involved in the specific functional properties of these receptors. Although the ligand recognition sites of mGluR5a/b and mGluR1a are highly conserved, these receptors have different pharmacology.

Alternative Splicing↗
PubMed1995

Facilitatory coupling between a glutamate metabotropic receptor and dihydropyridine-sensitive calcium channels in cultured cerebellar granule cells.

The effect of metabotropic glutamate receptor activation on Ca dihydropyridine (DHP)-sensitive channels recorded in the presence of 1 microM Bay K 8644 was examined on cultured cerebellar granule cells using the patch-clamp technique in the cell-attached configuration. Bath-applied agonist (trans-ACPD, 1S,3R-, and 1R,3S-ACPD isomers, and glutamate or quisqualate in the presence of CPP and CNQX) evoked an increase in Ca channel activity with a variable latency of 8.9 +/- 8.6 sec in 40% of the recorded cells. Neither L-CCG1, L-AP3, L-AP4, nor AMPA or NMDA activated Ca channels. Two dihydropyridine-sensitive channels present in this cell type were activated by trans-ACPD: the classical 24 pS L-type channel and a smaller-conductance 7 pS channel. The effect was shown to be mediated by neither intracellular Ca2+ nor a pertussis toxin (PTX)-sensitive G protein. Interestingly treatment with BAPTA-AM increased the number of responding patches and the activity was more sustained throughout the drug application. After overnight PTX treatment, activation of the Ca channels persisted even after washout of the agonist. These results indicate that mGluR1/mGluR5 probably mediate the facilitation of dihydropyridine-sensitive Ca channels.

Animals↗
PubMed1995

Homologous desensitization of 5-hydroxytryptamine4 receptors in rat esophagus: functional and second messenger studies.

We have studied agonist-induced desensitization of 5-hydroxytryptamine (5-HT4) receptor-mediated relaxation and 5-HT4 receptor-mediated increases in cAMP in rat esophageal tunica muscularis mucosae. In both cases, the desensitization time course was biphasic. The first phase was very rapid because more than 50% of desensitization was obtained after a 5-min incubation period with 10 microM of 5-HT. The second phase was slower and led to a complete suppression of the response after 2 h. Desensitization progressively reduced the maximal relaxation of esophagus induced by 5-HT without significantly affecting the EC50. Desensitization was a receptor-mediated event because cross-desensitization was observed between two chemically unrelated 5-HT4 receptor agonists, 5-HT itself and (S)-zacopride. Inasmuch as the kinetics of desensitization were the same when second messenger production or final responses were measured, this suggests that the limiting step in the desensitization process is at the level of the receptor itself or in its coupling to adenylyl cyclase. The desensitization was of the homologous type because exogenously applied cAMP, 8-Bromo-cAMP, or compounds increasing cAMP in the esophageal tunica muscularis mucosae such as isoproterenol and forskolin, were unable to induce any desensitization of the 5-HT4 receptor-induced relaxation response. Homologous desensitization was not followed by a rapid down-regulation of 5-HT4 receptors because no decrease in the Bmax of [3H]-GR113808 binding was observed after 30-min incubation with 10 microM 5-HT.

4-Aminobenzoic Acid↗
PubMed1994

5-HT6 receptors positively coupled to adenylyl cyclase in striatal neurones in culture.

5-HT receptor positively coupled to adenylyl cyclase in striatal neurones in culture does not correspond to the 5-HT4 receptor. 5-HT induces an increase in cAMP level with an EC50 of 125 nM. 5-HT agonists displayed the following rank order of potencies 5-HT > LSD > 5-MeOT > 5-CT. 8-OH-DPAT, RU 24969 and cisapride were inactive. The most efficacious antagonists were methiothepin and tricyclic antipsychotic drugs (clozapine, amitriptyline and nortryptyline). The pharmacological profile defined by both functional studies (cAMP level) and binding experiments ([125I]-LSD binding), and its localization in striatal neurones are in favour of the presence of the recently cloned 5-HT6 receptor in these cells.

Adenylyl Cyclases↗
PubMed1994

NADPH diaphorase-positive cells in the brain after status epilepticus.

Using NADPH-diaphorase (NADPH-d) histochemistry, the expression of nitric oxide synthase (NOS) was studied in the rat brain 1 week after kainate-induced status epilepticus. Major changes were observed in the hippocampi of epileptic animals, especially a loss of NADPH-d positive fibres in the periphery of degenerative pyramidal cells, the survival of NOS-containing interneurones in the dentate hilus, a different pattern of NADPH-d staining in lesioned areas, probably corresponding to the expression of inducible NOS by glial cells and an increased staining of the vasculature. These different sources of NO may exert different functions in the epileptic focus.

Animals↗
PubMed1994

Up-regulation in late pregnancy of both Go1 alpha and Go2 alpha isoforms in human myometrium.

The nature of the 39 kDa pertussis toxin substrate previously detected in human pregnant myometrium was investigated. Comparison of membranes from non-pregnant and from 39-40 week pregnant myometrium revealed a higher level at 39 kDa of pertussis toxin ADP-ribosylation and Go alpha immunoreactivity in late pregnancy. Furthermore, quantification of both Go alpha isoforms with specific anti-alpha o1- and alpha o2-antibodies revealed an increase in their expression in late pregnancy. At the same time, only limited changes in the levels of Gi1,2, Gi3 and Gq were observed. In rat myometrial membranes, neither pertussis toxin substrate nor Go alpha immunoreactivity could be detected at the 39 kDa level. These results demonstrate that, in the human myometrium in late pregnancy, there is an increase in the expression of both isoforms of the Go alpha subunits, suggesting a role for these proteins throughout gestation and/or near term for parturition.

Adenosine Diphosphate Ribose↗