PubMed Health⌕ Search

Biomedical subjects

F X Coudé

Publications and source records attributed to F X Coudé.

17 recordsLinked to original sources
PubMed1993

Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates.

Compounds possessing neurotrophic properties may represent a possible treatment for neurodegenerative disorders such as Alzheimer's disease. SR 57746A, 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,5,6- tetrahydropyridine hydrochloride, is a new compound with neurotrophic activity in a number of in vitro preparations. The neurotrophic effects of this compound have been evaluated in vivo using four distinct rat models of neurodegeneration: transient global ischaemia produced by a four-vessel occlusion; septohippocampal lesion produced by injection of vincristine sulphate into the medial septum; sciatic nerve crushing; and acrylamide-induced peripheral neuropathy. Rats were administered vehicle or 2.5-10 mg/kg p.o. SR 57746A, after initiation of the degenerative process, then once daily for 10 days in the first two models, 16 days in the third and 26 days in the fourth model. Median scores for ischaemia-induced neuronal damage were reduced by 30-40% by SR 57746A treatment in hippocampal CA1, CA2, and CA3 regions, and in the dorsal striatum. Twelve days after intraseptal vincristine administration, there was a marked loss of septohippocampal cholinergic neurons, as indicated by reduced choline acetyltransferase activity in both the septum and hippocampus. SR 57746A dose-dependently reversed this reduction in both areas. These results were confirmed by histoenzymological evaluation of hippocampal acetylcholinesterase content. SR 57746A also reversed the loss of hippocampal choline acetyltransferase induced by intraseptal vincristine in marmosets. Behavioral deficits in these models (exploratory behaviour in the former and short-term social memory in the latter) were also significantly reduced by SR 57746A treatment. In the sciatic crush model, sensorimotor function improved more rapidly in rats treated with 10 mg/kg SR 57746A. In this same model, SR 57746A (10 mg/kg/day) also significantly increased the length of regenerated nerve eight days after the crush, as measured using the pinch test. Finally, SR 57746A retarded the onset, reduced the amplitude and accelerated the recovery of acrylamide-induced peripheral neuropathy. Thus, SR 57746A possesses notable neurotrophic activity in a variety of neurodegenerative models in vivo, suggesting that the compound may possess therapeutic potential for the treatment of neurodegenerative diseases.

Acetylcholinesterase↗
PubMed1984

Potentiation by ammonia of the metabolic effects of pent-4-enoate in isolated rat hepatocytes.

The metabolic effects of pent-4-enoate were studied in isolated rat hepatocytes; 1 mM-pent-4-enoate did not significantly inhibit gluconeogenesis from lactate, alanine and glycerol, but significantly decreased glucose synthesis from pyruvate. The addition of 1 mM-NH4Cl led to a drastic inhibition of glucose synthesis from all these substrates. In hepatocytes incubated with 10 mM-alanine and 1 mM-oleate, pent-4-enoate at 0.05-1 mM slightly inhibited glucose synthesis and ketogenesis. The addition of ammonia resulted in a dramatic potentiation of the metabolic effects of pent-4-enoate. Half-maximum effect of ammonia was observed at 0.2 mM concentration. Concomitant cellular concentrations of ATP and acetyl-CoA were also decreased by the addition of ammonia, as were lactate/pyruvate ratio and beta-hydroxybutyrate/acetoacetate ratio. These data suggest that ammonia seriously interferes with the cellular metabolism of pent-4-enoate and leads to a dramatic potentiation of its effects.

Acetyl Coenzyme A↗
PubMed1984

Hudson memorial lecture. Neonatal management of organic acidurias. Clinical update.

Therapeutic guidelines have been obtained from a retrospective review of 41 patients affected with organic acidaemias, 16 patients with neonatal maple syrup urine disease (MSUD), 11 methylmalonic acidaemia, (MMA) seven propionic acidaemias (PA) and seven isovaleric acidaemias (IVA), and by comparing this personal series with similar reported cases. The emergency treatment of these organic acidurias in the neonate has to main goals: toxin removal and anabolism. Anabolism is always promoted by early diet therapy. The best method of toxin removal depends on the nature of the defect; peritoneal dialysis with exchange transfusions or multiple or prolonged exchange transfusions in MSUD and in PA, diuresis and exchange transfusions in MMA and glycine supplementation in IVA. Vitamin supplementation (thiamine 20 mg, biotin 10 mg, B12 2 mg and riboflavin 100 mg) should be tried in all cases although the neonatal forms of these defects are very rarely vitamin responsive. Additional treatments such as carnitine or insulin may prove to be useful.

Acids↗
PubMed1983

Action of the antiepileptic drug, valproic acid, on fatty acid oxidation in isolated rat hepatocytes.

Valproate at 0.1 to 5 mM strongly inhibited oxidation of 1-(14C)-palmitate in isolated rat hepatocytes. Valproate at the same concentrations markedly decreased ketogenesis from 1 mM oleate. Valproate in a dose up to 5 mM did not significantly affect cellular concentration of ATP but lowered beta-hydroxybutyrate/acetoacetate and lactate/pyruvate ratios which paralleled its effect on ketogenesis. Moreover concomitant acetyl-CoA levels were drastically decreased by valproate. From this it may be concluded that inhibition of fatty acid oxidation by valproate results in reduced production of two carbons units and a drop of NADH/NAD+ ratio in rat hepatocyte. This suggests that valproate seriously interferes with beta-oxidation of physiological long-chain fatty acids.

Animals↗
PubMed1983

Characterization of enzymatic deficiencies of branched chain amino-acid catabolism in human fibroblasts by genetic complementation.

Leucine and Isoleucine metabolism in cultured skin fibroblasts from patients with leucinosis, beta-Ketothiolase deficiency, propionic, methylmalonic and isovaleric acidemia, was compared with that in normal fibroblasts. A simple assay was developed using (U14C) Isoleucine and (U14C) Leucine as substrates. Radioactive incorporation into protein aminoacids were measured. The (U14C) branched chain aminoacid incorporation into proteins provides an estimation of the protein synthesis and the incorporation ratio (14C) Aspartate + (14C) Glutamate/(14C) branched chain aminoacid, measures the integrity of the metabolic pathway. Complementation tests permits to characterize the genetic defect. The incorporation ratio was significantly decreased in blocked pathways, namely in leucinosis and isovaleric acidemia in the presence of (U14C) Leucine and in Leucinosis, beta-Ketothiolase deficiency, propionic and methylmalonic acidemia in the presence of (U14C) Isoleucine. There was a significant restoration of activity in mutant strains with distinct genetic defects after polyethylene-glycol fusion. This assay provides a valuable tool to screen for enzymatic deficiencies of branched chain aminoacid catabolism.

Acetyl-CoA C-Acyltransferase↗
PubMed1983

Biotin dependent carboxylase activities in normal human and multicarboxylase deficient patient fibroblasts: relationship to the biotin content of the culture medium.

Three mitochondrial carboxylase activities can be depleted in skin fibroblasts from patients with the neonatal form of multiple carboxylase deficiency when the biotin content of the culture medium is lowered to 25 nmol/l. On the other hand this depletion can be achieved in control fibroblasts or in fibroblasts from patients with the late onset form of the deficiency when avidin (50 U/l) is added to the culture medium. The kinetics of the carboxylase activity decrease are nevertheless identical for control and for both types of fibroblasts. After depletion, control and late onset form fibroblasts recover their carboxylase activities at the same rate, whereas fibroblasts with the neonatal form of deficiency need longer times or higher concentrations of biotin to restore their carboxylase activities. These results are consistent with previous hypotheses concerning the origin of both forms of the deficiency. In addition, this technique provides a convenient access to human apocarboxylases, i.e. substrates for in vitro holocarboxylase synthetase investigation.

Biotin↗
PubMed1982

Biotin-responsive immunoregulatory dysfunction in multiple carboxylase deficiency.

The immunoregulatory system has recently been shown to require prostaglandins (PG) for its activation in man. We report here an impairment of immunoregulatory function, due to defective PGE monocytic production, in a 12-month-old boy with multiple carboxylase deficiency (MCD). The abnormal immune-response was corrected in vitro by adding PGE to the medium. Moreover, PGE deficiency and immunoregulatory dysfunction responded to biotin administration in vivo. It is suggested that the PGE deficiency in MCD could result from an impaired activity of a biotin enzyme, acetyl CoA carboxylase, since the product of this enzyme reaction, malonyl CoA, is required for prostaglandin synthesis.

Biotin↗
PubMed1982

Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation.

A number of recently described inherited disorders interfere with the oxidation of fatty acids. In these disorders at least three different metabolic steps may be affected: (1) transport of long chain fatty acids into the mitochondria as in carnitine deficiency and carnitine palmitoyl transferase deficiency (CPT); (2) multiple acyl CoA dehydrogenase deficiency or glutaric aciduria type II (GAII) due presumably to a defective common electron transfering flavoprotein or iron sulfur flavoprotein; (3) specific long or medium chain fatty acyl CoA dehydrogenase deficiency as in inherited dicarboxylic aciduria. In order to develop a system for the detection and the study of the consequences of defects such as these on the oxidation of fatty acids, we investigated the metabolism of oleate (18 carbons), octanoate (eight carbons) and butyrate (four carbons) in intact cultured fibroblasts from patients with CPT deficiency, GAII, and dicarboxylic aciduria. In CPT deficient cells there was a markedly deficient ability to oxidize [1-14C] and [U-14C] oleate (19 and 5% of normal, respectively), whereas oxidations of [1-14C] octanoate and [1,4-14C] succinate were significantly increased (150 and 222%, respectively), and [1-14C] butyrate oxidation was normal. GAII cells displayed a nearly complete defect in the oxidation of [1-14C] and [U-14C] oleate (8 and 1%, respectively), as well as of [1-14C] octanoate and [1-14C] butyrate (8 and 5% of normal, respectively). The oxidation of [1,4-14C] succinate by GAII cells was normal. Cells from a patient with dicarboxylic aciduria showed a significant reduction in [14CO2] production from [U-14C] oleate (57%) and [1-14C] octanoate (31%) and a normal oxidation of [1-14C] oleate, [1-14C] butyrate, and [1,4-14C] succinate. These observations are consistent with available information on the normal metabolism of fatty acids in liver and muscle and also with the hypothesis about the molecular localization of the defects in GAII and inherited dicarboxylic aciduria. They demonstrate that intact cultured skin fibroblasts represent a reliable and convenient model for the investigation of fatty acid oxidation in man. Many aspects of the human acyl CoA dehydrogenases and their physiologic functions remain unknown, among them the problem of their acyl chain length specificity. Studies in cultured fibroblasts from patients with presumed mutations affecting the metabolism of fatty acids provide a means for the elucidation of these defects and at the same time give information on normal metabolic functions. It appears likely that a number of previously unrecognized defects in this area of metabolism remain to be found. The availability of a model system for their study in cultured fibroblasts should facilitate their discovery.

Carnitine O-Palmitoyltransferase↗
PubMed1982

[Heterogeneity of leucinosis. Correlations between clinical manifestations, protein tolerance and enzyme deficiency].

Maple syrup urine disease (MSUD) is an inborn error of branched-chain aminoacid (BCAA) catabolism due to a defect of BC ketoacid decarboxylation. Beside the classical form of the disease, general variant forms have been recently reported. From our personal experience in 21 patients consisting of 14 patients with classical MSUD and 7 patients with "variant" forms (1 intermittent, 2 subacute forms, 1 lipoamide dehydrogenase deficiency and 3 composite heterozygotes), we tried to correlate clinical features with protein tolerance and enzyme activity. All classical forms share an acute neonatal presentation, with a low leucine tolerance (m +/- SD = 465 +/- 88 mg per day), and a very low enzyme activity (m +/- SD = 2.5 +/- 1.5% of controls), mild variations being consistent with a possible polyallelism within this group. All "variant" forms share a late onset with a reasonable leucine tolerance (2-3 grams per day) and a fair enzyme activity, ranging from 7 to 20% of controls. However, no strict correlation could be found between the severity of the outcome and the extent of the residual enzyme activity, since acute episodes or chronic deterioration occurred even in "variants", irrespective of the level of their enzyme activity. Finally, our data suggest that variant forms could result from a composite heterozygotism, combining heterozygotism for the gene of classical MSUD and heterozygotism for a "petite" mutation, undetectable when isolated. The occurrence of classical MSUD and "variant" forms of the disease within a single family of our series further supports this hypothesis.

Adolescent↗