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Biomedical subjects

J Vamecq

Publications and source records attributed to J Vamecq.

At least 19 recordsLinked to original sources
PubMed2000

Antioxidant actions of ovothiol-derived 4-mercaptoimidazoles: glutathione peroxidase activity and protection against peroxynitrite-induced damage.

4-Mercaptoimidazoles derived from the naturally occurring antioxidants, ovothiols, were tested for their glutathione peroxidase-like (GSH Px-like) activity and protection against peroxynitrite-induced damage. All the thiol compounds displayed similar significant GSH Px-like activities, which are however weaker than that of the reference compound, ebselen. The inhibitions of the peroxynitrite-dependent oxidation of Evans blue dye and dihydrorhodamine 123 showed that the thiol compounds substituted on position 5 of the imidazole ring were nearly as effective as ebselen while the C-2 substituted ones were less effective. Both assays corroborate the large superiority of mercaptoimidazoles over glutathione as inhibitors of peroxynitrite-dependent oxidation.

Antioxidants↗
PubMed2000

Synthesis and anticonvulsant and neurotoxic properties of substituted N-phenyl derivatives of the phthalimide pharmacophore.

A series of compounds including 4-amino (1), 3-amino (2), 4-nitro (3), 2-methyl-3-amino (4), 2-methyl-3-nitro (5), 2-methyl-4-amino (6), 2-methyl-4-nitro (7), 2-methyl-5-amino (8), 2-methyl-5-nitro (9), 2-methyl-6-amino (10), 2-methyl-6-nitro (11), 2,6-dimethyl (12), 2-methyl-3-carboxy (13), 2-methoxycarbonyl (14), 2-methyl-4-methoxy (15), 2,4-dimethoxy (16), 2-chloro-4-amino (17), and 2-chloro-4-nitro (18) N-phenyl substituents of phthalimide were evaluated along with N-[3-methyl-(2-pyridinyl)]phthalimide (19), N-(3-amino-2-methylphenyl)succinimide (20), and phenytoin for anticonvulsant and neurotoxic properties. Initial screening in the intraperitoneal (ip) maximal electroshock-induced seizure (MES) test and the subcutaneous pentylenetetrazol-induced seizure (scPtz) test in mice led to the selection of 1, 2, 4, 10, 12, 17, and 19 for oral MES evaluation in rats. The resultant ED(50) values for 4, 10, 17, and phenytoin were 8.0, 28.3, 5.7 and 29.8 mg/kg, respectively. In the batrachotoxin affinity assay, IC(50) values for 17 and phenytoin were 0.15 and 0.93 microM, respectively, and in the recently validated magnesium deficiency-dependent audiogenic seizure test, ED(50) values of 5.2 and 23 mg/kg were obtained for 17 and phenytoin, respectively. Electrophysiology studies on compound 17 point out its ability to (i) potentiate GABA-evoked current responses with a failure to directly activate the GABAA receptor and (ii) to affect, at 100 microM excitatory non NMDA, but not NMDA, receptors with a 25% block of kainate-evoked response. Electrophysiology measurements on voltage-gated sodium channels in N1E-115 neuroblastoma cells confirm voltage-dependent block of these channels by compound 17. In view of its interaction with multiple ion channels, one would predict that compound 17 might be active in a wide range of seizure models.

Administration, Oral↗
PubMed2000

Evolutionary aspects of peroxisomes as cell organelles, and of genes encoding peroxisomal proteins.

Peroxisomes are present in most eukaryotic cell types, and have different enzymatic content and metabolic functions throughout the life scale. The endosymbiotic origin of these DNA-devoid organelles is supported by evolutionary data concerning genes encoding not only most peroxisomal proteins, but also several transcriptional factors regulating their expression such as peroxisome proliferator-activated receptors.

Animals↗
PubMed2000

Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction.

Disorders of neuronal migration in cerebral cortex are associated with neurological impairments, including mental retardation and epilepsy. Their causes and pathophysiology remain largely unknown, however. In patients with Zellweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration. Analysis of Pxr1-/- mice revealed that the migration defect was caused by altered N-methyl-D-aspartate (NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenomenon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome metabolism and NMDA receptor efficacy.

Animals↗
PubMed1999

Medical significance of peroxisome proliferator-activated receptors.

Peroxisome proliferator-activated receptors (PPAR) were discovered in 1990, ending 25 years of uncertainty about the molecular mechanisms of peroxisome proliferation. Subsequently, PPARs have improved our understanding of adipocyte differentiation. But there is more to PPARs than solving a puzzle about an organelle (the peroxisome) long considered an oddity, and their medical significance goes beyond obesity too. Enhanced PPAR type alpha expression protects against cardiovascular disorders though the role of enhanced PPARgamma expression seems less favourable. PPAR mechanisms, mainly via induction of more differentiated cell phenotypes, protect against some cancers. The differentiation of many cell types (hepatocyte, fibroblast, adipocyte, keratinocyte, myocyte, and monocyte/macrophage) involves PPARs, and these nuclear receptors are now attracting the attention of many medical specialties and the pharmaceutical industry.

Adipocytes↗
PubMed1999

Design, anticonvulsive and neurotoxic properties of retrobenzamides. N-(Nitrophenyl)benzamides and N-(aminophenyl)benzamides.

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.

Administration, Oral↗
PubMed1998

Anticonvulsant activity and interactions with neuronal voltage-dependent sodium channel of analogues of ameltolide.

Fifteen compounds related to ameltolide (LY 201116) were studied for (i) anticonvulsant potential in the maximal electroshock-induced seizures (MES) and the subcutaneous pentylenetetrazol (sc Ptz) tests in mice and rats and (ii) interactions with neuronal voltage-dependent sodium channels. Compounds were chosen ranging in anticonvulsant activity in mice from very active to inactive. The active compounds were defined as those protecting 50% of the animals at doses between 10 and 50 micromol/kg and inactive compounds as those protecting 50% of the animals at doses greater than 1 mmol/kg. The series studied included three N-(2,6-dimethylphenyl)benzamides (compounds 1, 2 (ameltolide), and 3), three N-(2,2,6, 6-tetramethyl)piperidinyl-4-benzamides (compounds 4, 5, 6), one phenylthiourea (compound 7), five N-(2,6-dimethylphenyl)phthalimides (compounds 8, 9, 10, 13, and 14), two N-phenylphthalimide derivatives (compounds 11 and 12), and one N-(2,2,6, 6-tetramethyl)piperidinyl-4-phthalimide (compound 15). Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. After inital screening in mice, compounds 1, 2, 3, 5, 8, 9, 10, 13, and 14 were selected for further testing in rats. Anticonvulsant ED50s (effective doses in at least 50% of animals tested) of compounds in the MES test were determined in rats dosed orally and amounted to 52 (1), 135 (2), 284 (3), 231 (8), 131 (9), 25 (10), 369 (13), 354 (14), and 121 (PHT) micromol/kg, compound 5 presenting with an ED50 value higher than 650 micromol/kg. In our hands, the apparent IC50s (inhibitory concentrations 50) of compounds toward binding to rat brain synaptosomes of [3H]batrachotoxinin-A-20alpha-benzoate were 0.25 (1), 0.97 (2), 0.35 (3), 25.8 (5), 161.3 (8), 183.5 (9), 0.11 (10), 1.86 (13), 47.8 (14), and 0.86 (PHT) microM. The relationship between the activity in the MES test and the capacity to interact in vitro with neuronal voltage-dependent sodium channels and the fact that the IC50 values obtained in the in vitro test are close to the brain concentrations at which anticonvulsant activities are reported to occur for ameltolide strongly suggest that the anticonvulsant properties of most compounds tested could be a direct result of their interaction with the neuronal voltage-dependent sodium channel.

Administration, Oral↗
PubMed1998

Magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice: a nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties.

A great many animal models for audiogenic seizures have been described. The extent to which these models may provide insight into neuroscience fields such as abnormal locomotor behavior (wild running), seizures and anticonvulsants, and neuroinsults and neuroprotectors is examined here by our study of magnesium deficiency-dependent audiogenic seizures (MDDASs) in adult mice. MDDASs were induced in all of the eight tested adult murine strains and are presented as a sequence of four successive components (latency, wild running, convulsion, and recovery phase periods). Compared with several classic seizure tests, the nutritional MDDAS model responded to low doses of prototype antiepileptic drugs (AEDs), including phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), valproic acid (VPA), ethosuximide (ESM), and diazepam (DZP). Modulation by AEDs of the four components of MDDAS indicated that this seizure test was discriminatory, distinguishing between phenytoinergic (PHT, CBZ), GABAergic (PB, VPA, DZP), and ethosuximide (ESM) compounds. Suitability of the MDDAS test for evaluation of neuroprotective compounds was also examined: it showed partial (melatonin) and complete (WEB2170, an anti-PAF agent) reduction of recovery phase by non-anticonvulsant doses of test compounds. These neuroprotective responses were compared with neuroprotective potentials determined in a model of neonatal cerebral injury induced by focal injection of ibotenate (a glutamate analog). WEB2170 and melatonin reduced the size of lesions in white matter, but only WEB2170 protected cortical plate against ibotenate-induced lesions. In addition to the original neuroprotective behavior of WEB2170, studies on the neuroprotectors also supported GABAergic anticonvulsant activity of melatonin in the MDDAS test.

Acoustic Stimulation↗
PubMed1998

Metabolic studies in a patient with severe carnitine palmitoyltransferase type II deficiency.

Here we report on a patient with severe ("non-classic") carnitine palmitoyltransferase type II (CPT II) deficiency. Hypoglycemia prompted by an infectious episode and associated with non-ketotic dicarboxylic aciduria orientated diagnosis towards beta-oxidation deficiency disorders. Blood carnitine levels revealed a secondary carnitine deficiency that was responsive to oral L-carnitine supplementation. Blood acylcarnitine profiles were abnormal and included acetyl (C2:0), butyryl/isobutyryl (C4:0), isovaleryl/2-methylbutyryl (C5:0), hexanoyl (C6:0), myristoyl (C14:0), palmitoyl (C16:0), hexadecenoyl (C16:1), oleyl (C18:1) and stearoyl (C18:0) carnitine. In urine, excess excretion of dicarboxylylcarnitines, mainly dodecanedioylcarnitine, was noticed. Upon carnitine supplementation, C8 to C12 fatty acylcarnitines, with decanoylcarnitine as well as C10 to C14 dicarboxylylcarnitines being prominent, were observed in urine. Biochemical measurements disclosed a severe reduction of mitochondrial CPT II activity (7% of normal values). Correlations of metabolic findings in the patient and physiological roles of CPT II are briefly discussed.

Carnitine↗
PubMed1998

Anticonvulsant phenytoinergic pharmacophores and anti-HIV activity--preliminary evidence for the dual requirement of the 4-aminophthalimide platform and the N-(1-adamantyl) substitution for antiviral properties.

This work is aimed at further exploring the concept that phenytoin-related compounds might present with an anti-HIV potential. We screened for anti-HIV activity, selected compounds whose structural design rests on pharmacophores successfully shown to convey phenytoinergic anticonvulsant activity. We determined the corresponding anticonvulsant protective doses in mice via the i.p. route of administration using the maximal electroshock seizure test (a test in which the anticonvulsant activity of phenytoin is well expressed). Firstly, 4-aminophthalimide pharmacophores were utilized with either N-(2,6-dimethyl)phenyl or N-(1-adamantyl) substitutions. While the former was found to be highly potent, the latter was devoid of significant activity. Secondly, the pharmacophores N-(2,6-dimethylphenyl)phthalimide and N-(1-adamantyl)phthalimide were compared for antiviral (antiHIV-1 and antiHIV-2) properties in CEM (human T-lymphocyte) cells infected with HIV-1 or HIV-2 strains. Various phthalimide C4-substitutions (H, NO2, NH2, Cl, CH3, OCH3, COOH) of these pharmacophores were studied. From this set of experiments, 4-amino-N-(1-adamantyl)phthalimide emerged with EC50 (effective concentration-50) values of 16 and 27 microM against HIV-1 and HIV-2, respectively. The CC50 (cytostatic concentration-50) of this compound was 30 microM. Thirdly, the N-(2,6-dimethylphenyl) and N-(1-adamantyl) substitutions of the 4-aminobenzamide pharmacophore (another known phenytoinergic anticonvulsant platform) were shown to be devoid of anti-HIV activities. A similar negative result was obtained for amantadine. Taken as a whole, the present data indicate that both the 4-aminophthalimide pharmacophore and N-(1-adamantyl) substitutions are required for anti-HIV properties. Molecular modeling studies further provide clues for this dual requirement.

Adamantane↗
PubMed1998

Effects of Lorenzo's Oil on peroxisomes in healthy mice.

We investigated peroxisomal alterations in mice treated with different doses of Lorenzo's Oil (a therapy for X-linked adrenoleukodystrophy patients) for up to 100 days. Hepatic erucic acid levels were already significantly increased 2.2-fold and 2.6-fold in mice treated with 10% and 20% Lorenzo's Oil for 21 days, respectively. No lipidosis was found in liver, myocardium and kidney of any of the treated mice. While hepatic catalase, lauroyl-CoA oxidase and glycolate oxidase, and renal catalase activities were not induced by either diet, myocardial catalase activity was increased in most groups. This suggests that the mechanism of the effect of Lorenzo's Oil in X-linked adrenoleukodystrophy patients may not be a direct effect on the peroxisomes.

Acyl-CoA Dehydrogenase↗
PubMed1998

Peroxisome-proliferating effects of fenoprofen in mice.

We report on hepatic effects obtained in vivo by treating mice with different doses of fenoprofen, an arylpropionic acid previously shown to inhibit in vitro peroxisomal very long chain fatty acid oxidation. A strong and dose-related induction of peroxisomal palmitoyl-CoA oxidase, and of carnitine acyltransferase and acyl-CoA hydrolase activities was recorded in liver homogenates of mice fed diets supplemented with different contents [0.01, 0.05, 0.1, or 1% (w/w)] of fenoprofen for 6 d. Peroxisomal glycolate oxidase and mitochondrial butyryl-CoA, octanoyl-CoA, and palmitoyl-CoA dehydrogenases were unaffected or increased. Hepatic catalase activity was significantly increased in mice fed the diet with 0.05 and 0.1% fenoprofen but, surprisingly, was not stimulated in mice fed the 1% fenoprofen-containing diet. A time-related but unequal induction of acyl-CoA oxidases and catalase was observed with the 0.1% fenoprofen diet: at 21 d of treatment, the induction of lignoceroyl-CoA and palmitoyl-CoA oxidase activities were five-fold stronger than that of catalase activity. In mice treated with 1% fenoprofen for up to 6 d, only acyl-CoA oxidase activities were found to be significantly increased. Morphometric analysis of the liver peroxisomes in mice treated with 0.1% fenoprofen evidenced an increase in size, volume density, and surface density along with a reduced ratio between perimeter and area of the peroxisomal profiles. No morphological marker for very long chain fatty acid deposition could be detected in livers from fenoprofen-treated animals. Our findings clearly demonstrate that fenoprofen acts as a peroxisome proliferator in the liver of mice and do not support the occurrence of in vivo reduction of very long chain fatty acid oxidation in liver from treated animals.

Animals↗
PubMed1997

Anticonvulsant and neurotoxicological properties of 4-amino-N-(2-ethylphenyl)benzamide, a potent ameltolide analogue.

A well documented study on the anticonvulsant properties of 4-amino-N-(2-ethylphenyl)benzamide (4-AEPB) is here provided. Initial screening in mice dosed intraperitoneally and rats dosed orally indicated that 4-AEPB is active against maximal electroshock-induced seizures (MES), but does not protect animals against subcutaneous pentylenetetrazole (sc Ptz)-induced seizures. Quantitative evaluation of anti-MES activity and neurotoxicity of 4-AEPB given intraperitoneally to mice provided ED50 and TD50 values amounting to 28.6 and 96.3 mumol/kg respectively, resulting in a protective index (PI = TD50/ED50) equal to 3.36. Further quantitative evaluation in rats dosed orally indicated that the respective ED50 and TD50 values for 4-AEPB were 29.8 and more than 1,530 mumol/kg, resulting in a very high PI value of over 51. Comparison anticonvulsant properties and neurotoxicity of 4-AEPB with those previously reported in the literature for two 4-aminobenzamide derivatives, 4-amino-N-(2,6-dimethylphenyl)benzamide (or ameltolide, an antiepileptic drug prototype developed by Eli Lilly), and phenytoin, underlines the value of 4-AEPB for future pharmacological development. In this perspective, an additional favorable element is represented by the ability of 4-AEPB to increase the seizure threshold in the intravenous Ptz seizure threshold test in mice dosed intraperitoneally. Molecular modeling studies show that the translocation of one carbon unit in the isomerization of the 2,6-dimethylphenyl moiety of ameltolide to the 2-ethylphenyl counterpart succeeds in maintaining the conformational low energy presentation adopted by ameltolide, providing clues as to why the 4-AEPB here described is an anticonvulsant agent derived from the 4-aminobenzamide pharmacophore platform as potent as ameltolide.

Administration, Oral↗
PubMed1997

Effect of vitamin E on antioxidant enzymes, lipid peroxidation products and glomerulosclerosis in the rat remnant kidney.

In rats with five-sixth nephrectomy (remnant kidney), glomerulosclerosis was significantly reduced by dietary administration of vitamin E (alpha-tocopherol) during 11 and 16 weeks after reduction of nephron number. The activity of catalase and the production of H2O2 in remnant kidney cortex homogenate were not influenced by the vitamin E diet; however, the activities of glutathione peroxidase and superoxide dismutase were significantly increased (up to 140 and 180%, respectively, after 16 weeks). Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentrations, was decreased in cortex homogenates and in urine. Though the extent of the effect of vitamin E on antioxidant enzyme levels and lipid peroxidation is small, the important reduction of glomerulosclerosis is in favor of dietary supplementation with vitamin E.

Animals↗
PubMed1997

Carvedilol protects against glomerulosclerosis in rat remnant kidney without general changes in antioxidant enzyme status. A comparative study of two beta-blocking drugs, carvedilol and propanolol.

Nephron loss leads to increased production of reactive oxygen intermediates. We measured the effect of carvedilol, a beta-blocking drug with radical scavenging properties, on renal function, glomerulosclerosis, antioxidant enzyme status and in vivo hydrogen peroxide (H2O2) production in rats with chronic renal failure caused by 5/6 nephrectomy (remnant kidney) and compared results to data obtained with propranolol, a beta-blocking drug without scavenging characteristics. Carvedilol and propranolol were administered during 11 weeks following reduction of nephron number. Kidneys were examined using enzymatic and histological techniques. Both carvedilol and propranolol decreased systolic blood pressure. Compared to propranolol, carvedilol offered some additional beneficial effects on renal function, particularly with regard to glomerulosclerosis. Lipid peroxidation, evaluated by malonaldehyde and 4-hydroxynonenal concentration in cortex homogenates, was decreased in carvedilol-treated rats only. Superior beneficial effect of carvedilol treatment is not linked to a significant up-regulation of the activities of the remnant kidney antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase) or to a decreased in vivo H2O2 production.

Adrenergic beta-Antagonists↗
PubMed1996

Metabolic studies in twin brothers with 2-methylacetoacetyl-CoA thiolase deficiency.

We report clinical and biological investigations in two patients (twin brothers) with 2-methylacetoacetyl-CoA thiolase deficiency. Main clinical features included important staturo-ponderal delay, frequent infectious rhinopharyngitis episodes and an acute metabolic acidosis at the age of 4 years, this metabolic decompensation being adequately halted by bicarbonate supplementation. Since that age, patients developed rather favorably, however, with persistence of the staturo-ponderal delay. Organicaciduria typical of 2-methylacetoacetyl-CoA thiolase deficiency was recorded consisting of excessive excretion of tiglylglycine, 2-methyl-3-hydroxybutyrate, 3-hydroxyisovalerate, 2-methylglutaconate, adipate and 2-methylacetoacetate. Blood carnitine levels were altered in patients with increased total and esterified carnitine concentrations and enhanced acyl/free carnitine ratios. Determination of acylcarnitine profiles showed that patients excreted excessive amounts of several acylcarnitines in urine including propionyl, butyryl, isobutyryl, isovaleryl, 2-methylbutyryl and tiglyl-carnitine, the latter acylcarnitine being prominent with, in one of the patients, occurrence of a previously undescribed isomer of this carnitine ester, possibly 2-ethylacrylyl-carnitine. Excretion of these acylcarnitines in urine was increased in response to L-carnitine although, as a whole, this therapy resulted in a less important stimulation of esterified carnitine removal in urine from patients than in the case of supplemented controls. Biochemical investigations on cultured skin fibroblasts confirmed 2-methylacetoacetyl-CoA thiolase deficiency. Through the present report on this rare disease in two siblings, we would like to underline that acylcarnitines can be used in the diagnosis of 2-methylacetoacetyl-CoA thiolase deficiency, a view supported by acylcarnitine profiles further determined in another patient with proven oxothiolase deficiency, adding this pathology to the list of beta-oxidation disorders that may be screened successfully through determination of acylcarnitine profiles in body fluids.

Acetyl-CoA C-Acyltransferase↗
PubMed1996

Acylcarnitine removal in a patient with acyl-CoA beta-oxidation deficiency disorder: effect of L-carnitine therapy and starvation.

Carnitine levels and acylcarnitine profiles in a patient with mild multiple acyl-CoA dehydrogenase deficient beta-oxidation were compared with control results. Whereas blood and urine total carnitine levels were moderately decreased, blood esterified carnitine levels in the patient were about 2-fold higher than in controls. Urinary acylcarnitine profiles presented with a larger variety of carnitine esters than in controls and included propionylcarnitine, butyrylcarnitine, 2-methylbutyrylcarnitine, hexanoylcarnitine and octanolycarnitine. Total carnitine levels in body fluids were similarly affected by chronic oral L-carnitine administration in patient and controls. By contrast, esterified carnitine level increase was 2-fold more important in controls than in patient. Whereas no qualitative changes in urinary acylcarnitine profiles were induced by L-carnitine therapy in controls, several alterations of these profiles were observed in the patient. The effect of starvation on metabolites was also studied, especially beta-oxidation rates assessed by free fatty acids to 3-hydroxybutyric acid ratios in blood from the patient in the untreated and L-carnitine treated states. In the L-carnitine-supplemented patient, the effect of starvation on the time course of carnitine levels and acylcarnitine profiles could also be documented. The ability of chronic oral L-carnitine administration to remove relatively less important amounts of acylcarnitines in the patient than in controls is further discussed, as well as qualitative alterations of acylcarnitine profiles induced by this therapy in the pathological condition.

Acyl-CoA Dehydrogenase↗