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Biomedical subjects

C Chabot

Publications and source records attributed to C Chabot.

At least 19 recordsLinked to original sources
PubMed2005

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist, alleviates disturbances of novelty discrimination in a social context in rats, a putative model of selective attention deficit.

RATIONALE: Selective attention deficit, characterised by the inability to differentiate relevant from irrelevant information, is considered to underlie many cognitive deficits of schizophrenia, and appears to be only marginally responsive to treatment with current antipsychotics. OBJECTIVES: We compared the activity of the putative atypical antipsychotic SSR181507 (a dopamine D(2) receptor antagonist and 5HT(1A) receptor agonist) with reference compounds, on disturbances of novelty discrimination in a social context in rats, a behavioural paradigm that putatively models selective attention deficit. METHODS: A first (familiar) juvenile rat was presented to an adult rat for a period (P1) of 30 min. A second (novel) juvenile was then introduced at the end of P1 for a period (P2) of 5 min. The ability of the adult rat to discriminate between the two juveniles, presented at the same time, was evaluated by measuring the ratio of the time spent in interaction with the novel vs the familiar juvenile during P2. RESULTS: Adult rats spent more time exploring the novel than the familiar juvenile. This novelty discrimination capacity was disrupted by: (1) parametric modification of the procedure (reduction of time spent in contact with the familiar juvenile during P1); (2) acute injection of psychotomimetics that are known to induce schizophrenia-like symptoms in humans, such as phencyclidine (PCP; 3 mg/kg, i.p.) and d-amphetamine (1 mg/kg, i.p.) and (3) neonatal treatment with PCP (three injections of 10 mg/kg, s.c.), a model based on the neurodevelopmental hypothesis of schizophrenia. The potential atypical antipsychotic SSR181507 (0.03-3 mg/kg, i.p.) and the atypical antipsychotics clozapine (0.1-1 mg/kg, i.p.) and amisulpride (1-3 mg/kg, i.p.) attenuated deficits in novelty discrimination produced by parametric manipulation and by acute or neonatal treatment with PCP. The typical antipsychotic haloperidol (up to 0.3 mg/kg, i.p.) attenuated only deficits in novelty discrimination produced by parametric modification. CONCLUSION: Collectively, these results suggest that SSR181507 can alleviate disturbances of novelty discrimination in a social context in rats, and that this paradigm may represent a suitable animal model of selective attention deficits observed in schizophrenia.

Age Factors↗
PubMed2001

Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease.

The NS3 serine protease enzyme of the hepatitis C virus (HCV) is essential for viral replication. Short peptides mimicking the N-terminal substrate cleavage products of the NS3 protease are known to act as weak inhibitors of the enzyme and have been used as templates for the design of peptidomimetic inhibitors. Automated solid-phase synthesis of a small library of compounds based on such a peptidomimetic scaffold has led to the identification of potent and highly selective inhibitors of the NS3 protease enzyme.

Combinatorial Chemistry Techniques↗
PubMed2000

A rational approach towards successful crystallization and crystal treatment of human cytomegalovirus protease and its inhibitor complex.

The crystallization and subsequent crystal treatment of both free human cytomegalovirus (hCMV) protease and its inhibitor complexes are reported. For free-enzyme crystals, diffraction was greatly improved by optimizing the crystallization conditions, raising the precipitant concentration in the reservoir and soaking the crystals in artificial mother liquors. Each of the six components in the final crystallization formula (16% PEG 4000, 0.1 M MES pH 6.0, 0.4 M LiCl, 10% glycerol, 5% t-butanol and 5 mM Na(2)S(2)O(3)) plays a distinctive role and is indispensable. A synergistic effect of Na(2)SO(4) and t--butanol on diffraction was observed and studied. A 2.0 A multiwavelength anomalous diffraction (MAD) data set was collected using a synchrotron-radiation source, leading to the elucidation of the three-dimensional structure of the enzyme. For the inhibitor-complex crystals, initial attempts with co-crystallization and soaking experiments at pH 6.0 did not produce conclusive results. Subsequently, experiments were designed to co-crystallize the complex at pH 8.0, the optimal pH for the enzyme and the inhibitor activity. Using 20-50 mM spermine in the crystallization buffer, crystals of two peptidomimetic inhibitor complexes were obtained at pH 7.5 and 8.0. Spermine was required for the inhibitor complexes to be crystallized at pH 8.0, possibly neutralizing net negative charges of hCMV protease owing to its acidic pI of 5.5. A 2.7 A data set was collected from one of the inhibitor complexes and the structure was determined using the molecular-replacement method.

Crystallization↗
PubMed1999

Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice.

Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.

Acetylcholine↗
PubMed1999

Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy.

A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.

Administration, Oral↗
PubMed1999

Frozen wave induced by high frequency horizontal vibrations on a CO2 liquid-gas interface near the critical point.

We used the liquid-vapor equilibrium of CO2 near its critical point (T(C)-T=1 to 150 mK) in order to study the stability of an interface between a gas and a liquid having close densities rho(L) approximately rho(V) when submitted to high frequency f (3-57.5 Hz) horizontal vibrations (of amplitude a from 0.1 to 2.5 mm). Above a given velocity threshold (2piaf )(0) we observed a "frozen wave," corresponding to an interface profile of sinelike shape which is stationary in the reference frame of the vibrated sample cell. By varying the vibration parameters, the surface tension, and the density difference between the two phases via the temperature, it was found that the wavelength and the amplitude of the stationary profile are both increasing functions of the frequency and of the amplitude of the vibration and that they are proportional to the capillary length. Our measurements are consistent with a model of inviscid and incompressible flow averaging the effect of the vibration over a period and leading to a Kelvin-Helmholtz-like instability mechanism due to the relative motion of the two fluids.

Journal Article↗
PubMed1998

beta-Lactam derivatives as inhibitors of human cytomegalovirus protease.

The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.

Animals↗
PubMed1998

Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A2 in the hippocampus.

The synaptic modifications underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in various brain structures may result from changes in the properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. In the present study, we report that treatment of rat synaptoneurosomes with increasing concentrations of phospholipase A2 (PLA2) produces a biphasic effect on AMPA receptor binding, with low concentrations causing a decrease and high concentrations an increase in agonist binding. Analysis of the saturation kinetics of 3H-AMPA binding revealed that the biphasic effect of PLA2 was due to modifications in receptor affinity and not to changes in the maximum number of binding sites for AMPA receptors. The 12-lipoxygenase inhibitors preferentially reduced PLA2-induced decrease in AMPA binding and treatment of hippocampal synaptoneurosomes with arachidonic acid (AA) or 12-HPETE, the first metabolite generated from the hydrolysis of AA by 12-lipoxygenases, decreased 3H-AMPA binding. Moreover, electrophysiological experiments indicated that the 12-lipoxygenase inhibitor baicalein totally blocked LTD formation in area CA1 of hippocampal slices. The decrease in 3H-AMPA binding elicited by low concentrations of PLA2, as well as the level of LTD, were partially reduced by AA-861, a 5-lipoxygenase inhibitor, while the cyclooxygenase inhibitor indomethacin did not prevent LTD formation or the effects of PLA2 on 3H-AMPA binding. Our results provide evidence for a possible involvement of lipoxygenase metabolites in the regulation of AMPA receptor during synaptic depression. In addition, they strongly support the idea that the same biochemical pathway, i.e., NMDA receptor activation and endogenous PLA2 stimulation, may represent a common mechanism resulting in AMPA receptor alterations for both LTP and LTD formation.

Animals↗
PubMed1998

Potent beta-lactam inhibitors of human cytomegalovirus protease.

A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several beta-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.

Antiviral Agents↗
PubMed1997

Peptidomimetic inhibitors of the human cytomegalovirus protease.

The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

Antiviral Agents↗
PubMed1997

Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats.

The mechanisms by which diabetes impairs cognitive function are not well-established. In the present study, we determined the electrophysiological and biochemical nature of disturbances in the mechanism of long-term potentiation (LTP) in diabetic rats. As previously reported, the administration of streptozotocin (STZ) was found to reduce the magnitude of LTP in the CA1 region of the hippocampus, while the same treatment did not interact with the capacity of the hippocampus to generate long-term depression induced by low-frequency stimulation. In addition, STZ treatment did not modify the component of excitatory postsynaptic potentials mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, suggesting that NMDA receptor function remained intact in STZ-treated slices. At the biochemical level, the capacity of calcium to increase [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (3H-AMPA) binding to glutamate/AMPA receptors in rat brain tissue sections was markedly affected in most regions of the hippocampus of STZ-treated rats. Moreover, changes in 3H-AMPA binding properties elicited by both exogenous phospholipase A2 and melittin, a potent activator of endogenous phospholipases, were also altered in synaptoneurosomes from diabetic rats. Taken together, the present data suggest that the loss of LTP maintenance in STZ-treated rats is more likely the result of disruption of calcium-dependent processes that are suspected to modulate postsynaptic AMPA receptors during synaptic potentiation. Understanding the biochemical factors participating in the impairment of AMPA receptor modulation might provide important clues revealing the very basis of memory deficits in diabetes.

Animals↗
PubMed1996

Developmental changes in depolarization-mediated AMPA receptor modifications and potassium-induced long-term potentiation.

In the present study, we examined the KCl-induced increase in [3H] amino-3-hydroxy-5-methylisoxazole-4-propionate ([3H]AMPA) binding in telencephalic synaptoneurosomes and potentiation of synaptic transmission (KLTP) in hippocampal slices during development in rats. As previously reported, KCI-induced depolarization of telencephalic synaptoneurosomes resulted in a 40 +/- 5% increase in [3H]AMPA binding to membrane fractions in adult rats (3 months old). KCI-induced increase in [3H]AMPA binding was reduced to 24 +/- 5% and 15 +/- 5% at postnatal days (PND) 25-30 and PND 15-20 respectively, and was only 6 +/- 5% at PND 5-10. KLTP in area CA1 of hippocampus was most pronounced in adult slices (40 +/- 5%), and was reduced to 30 +/- 5% in slices prepared from PND 25-30 animals; KCI-induced LTP was absent in CA1 hippocampal slices prepared from PND 5-10 animals (3 +/- 5%). The decrease in KCI-induced changes in AMPA receptor binding in young animals was also associated with an altered capacity of the bee venom peptide, mellitin (a phospholipase A2 (PLA2) activator), to increase [3H]AMPA binding in synaptoneurosomes. The smaller effect of mellitin on [3H]AMPA binding in young animals was not due to a decreased ability of this peptide to release [3H]arachidonate from synaptoneuro-somes. The parallel modifications in the extent of depolarization-induced change in AMPA receptor binding and excitatory synaptic transmission during development further support the hypothesis that alterations in AMPA receptor properties may play a critical role in synaptic plasticity.

Age Factors↗
PubMed1996

Speech compensation to structural modifications of the oral cavity.

Acoustic and perceptual analyses of vowels, stops, and fricatives produced with and without an artificial palate were conducted. Recordings were made both immediately upon insertion of the palate and following a 15-min adaptation period. Results of the acoustic analyses revealed significant alterations in the fricative spectra under conditions of perturbation with fewer, if any, changes in the vowels and stop consonants. Perceptual data confirmed these patterns and provided evidence of possible improvements in compensation over time. The data are compared to our previous studies of speech sound articulation under bite-block conditions. Differences between adaptation to modifications of oral structure (artificial palate) and oral function (jaw fixation by a bite block) are considered.

Adult↗
PubMed1995

Melittin increases AMPA receptor affinity in rat brain synaptoneurosomes.

Recent experimental evidence suggests that phospholipase-induced changes in binding properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors account for the increase in synaptic response observed in long-term potentiation (LTP). In the present study, we report that treatment of rat telencephalic synaptoneurosomes with the bee venom peptide melittin, a potent activator of endogenous phospholipases, increased [3H]AMPA binding to the AMPA receptor. The action of melittin was concentration-dependent (EC50 value = 10 micrograms/ml) and did not require the presence of extracellular calcium. Saturation kinetic experiments revealed that the increase in [3H]AMPA binding produced by melittin was due to an enhancement in the affinity of the AMPA receptor, an effect markedly reduced by the phospholipase A2 (PLA2) inhibitor bromophenacyl bromide (BPB). In contrast to BPB, inhibitors of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism did not interfere with the melittin-induced increase in [3H]AMPA binding. In neonatal synaptoneurosomes, the effect of melittin on [3H]AMPA binding was significantly reduced when compared to adult synaptoneurosomes, an effect which is consistent with the observation that LTP is not present in very young animals. The results indicate that activation of endogenous phospholipases may be an important mechanism in the regulation of AMPA receptor properties in LTP.

Aging↗