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B Marescau

Publications and source records attributed to B Marescau.

At least 55 records · Page 3Linked to original sources
PubMed1992

Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals.

Guanidino compound levels were quantitatively determined in serum, urine, liver, kidney, and brain of man and of some ureotelic animals. The guanidino compounds were separated over a cation exchange resin, using sodium citrate buffers, and detected with the fluorescence ninhydrin method. Species-specific differences in the levels of some guanidino compounds in the studied ureotelic animals are shown. alpha-Keto-delta-guanidinovaleric acid is a naturally occurring guanidino compound in ureotelic animals, and is not restricted to the pathobiochemistry of hyperargininemic patients. The fasting serum levels observed in beagles are the same as those found in hyperargininemic patients. In serum, liver, and kidney, the homoarginine, beta-guanidinopropionic acid, and gamma-guanidinobutyric acid levels are the highest in rats. The last two compounds have the highest levels of the studied guanidino compounds, with the exception of creatinine, in kidney. Specific high levels of gamma-guanidinobutyric acid and argininic acid are found in brain of rabbits.

Animals↗
PubMed1992

Behavioral toxicity of guanidinosuccinic acid in adult and young mice.

Guanidinosuccinic acid (GSA), a guanidino compound found to be greatly increased in uremia, was administered by intraperitoneal (i.p.) injection to adult albino mice and to young mice 7, 14 and 21 days old. Epileptogenic and toxic properties were assessed and GSA brain levels following i.p. injection were determined. In adult mice, GSA induced long-lasting generalized clonic and clonic-tonic convulsions in a dose-dependent manner with a CD50 (and 95% confidence interval) of 363 (287-458) mg/kg (n = 35), and an LD50 of 579 (445-756) mg/kg. The CD50 of GSA corresponded with a brain concentration of 56 nmol/g tissue. Electrocorticographic recording in five adult mice revealed epileptiform discharges (spikes, spike-waves, and polyspike-waves) which appeared concomitant with the convulsions. When young mice were i.p. injected with a (for adults) subconvulsive dose of GSA (250 mg/kg), an age-dependent decrease was noted in GSA-induced convulsions and in the resulting brain concentration. The presented findings suggest that GSA could be an important uremic toxin which could contribute to the epileptic symptomatology in uremia.

Age Factors↗
PubMed1992

Chemical models of epilepsy with some reference to their applicability in the development of anticonvulsants.

This paper reviews chemical models of epilepsy and their relevance in the identification and characterization of anticonvulsants. For each convulsant we discuss possible modes of administration, clinical type(s) of seizures induced, proposed mechanism(s) of epileptogenesis and, where available, responsiveness of the induced seizures to anticonvulsants. The following compounds are reviewed: pentylenetetrazol, bicuculline, penicillin, picrotoxin, beta-carbolines, 3-mercaptopropionic acid, hydrazides, allylglycine; the glycine antagonist strychnine; gamma-hydroxybutyrate; excitatory amino acids (glutamate, aspartate, N-methyl-D-aspartate, quisqualate, kainate, quinolinic acid); monosubstituted guanidino compounds, metals (alumina, cobalt, zinc, iron); neuropeptides (opioid peptides, corticotropin releasing factor, somatostatin, vasopressin); cholinergic agents (acetylcholine, acetylcholinesterase inhibitors, pilocarpine); tetanus toxin; flurothyl; folates; homocysteine and colchicine. Although there are a multitude of chemical models of epilepsy, only a limited number are applied in the routine screening of potential anticonvulsants. Some chemical models have a predictive value with regard to the clinical profile of efficacy of the tested anticonvulsants. Some chemical models may contribute to a better understanding of possible mechanisms of epileptogenesis.

Animals↗
PubMed1992

Clinical and pathophysiological aspects of neurological complications in renal failure.

A review of the neurological complications presenting in uremia and an account of their presumed pathophysiology is given. With the introduction of different dialytic procedures during the last twenty years, the incidence and severity of neurological complications have declined. Nevertheless, some disturbances related to the uremic syndrome fail to respond to dialytic therapy and these therapeutic measures may even be responsible for the appearance of some new abnormalities. The clinical manifestations of uremic encephalopathy and polyneuropathy are presented. The review of the presumed pathophysiology of these syndromes illustrates the still existing controversies. Nevertheless, some promising new lines of research are reviewed. In addition, some complications of uremic treatment, including dialysis disequilibrium syndrome and dialysis encephalopathy are presented.

Brain Diseases, Metabolic↗
PubMed1992

Molecular genetic study of human arginase deficiency.

We have explored the molecular pathology in 28 individuals homozygous or heterozygous for liver arginase deficiency (hyperargininemia) by a combination of Southern analysis, western blotting, DNA sequencing, and PCR. This cohort represents the majority of arginase-deficient individuals worldwide. Only 2 of 15 homozygous patients on whom red blood cells were available had antigenically cross-reacting material as ascertained by western blot analysis using anti-liver arginase antibody. Southern blots of patient genomic DNAs, cut with a variety of restriction enzymes and probed with a near-full-length (1,450-bp) human liver arginase cDNA clone, detected no gross gene deletions. Loss of a TaqI cleavage site was identified in three individuals: in a homozygous state in a Saudi Arabian patient at one site, at a different site in homozygosity in a German patient, and in heterozygosity in a patient from Australia. The changes in the latter two were localized to exon 8, through amplification of this region by PCR and electrophoretic analysis of the amplified fragment after treatment with TaqI; the precise base changes (Arg291X and Thr290Ser) were confirmed by sequencing. It is interesting that the latter nucleotide variant (Thr290Ser) was found to lie adjacent to the TaqI site rather than within it, though whether such a conservative amino acid substitution represents a true pathologic mutation remains to be determined. We conclude that arginase deficiency, though rare, is a heterogeneous disorder at the genotypic level, generally encompassing a variety of point mutations rather than substantial structural gene deletions.

Amino Acid Sequence↗
PubMed1991

Effect of ammonium acetate-induced hyperammonemia on metabolism of guanidino compounds.

Guanidino compounds are synthesized from arginine in various tissues such as liver, kidney, brain, and skeletal muscle. Guanidino compounds such as arginine and creatine play an important role in nitrogen metabolism, whereas other guanidino compounds such as guanidinosuccinic acid and alpha-N-acetylarginine are known toxins. In order to understand the changes in the metabolism of guanidino compounds during ammonia toxicity, we investigated the effect of hyperammonemia induced by an ammonium acetate injection on the levels of guanidino compounds in plasma, liver, kidney, and brain of rats. Control animals were injected with an equal volume of saline. Blood and tissues were removed 1 h following ammonium acetate or saline injection and guanidino compounds were analyzed by high-performance liquid chromatography. Plasma and kidney levels of guanidinosuccinic acid were significantly elevated in rats challenged with ammonium acetate. Brain alpha-N-acetylarginine levels were also significantly higher in rats injected with ammonium acetate as compared to those in controls. Our results suggest that guanidinosuccinic acid and alpha-N-acetylarginine may play an important role in hyperammonemia.

Acetates↗
PubMed1991

Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture.

The effects of arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (guanidino compounds that were found to be increased in hyperargininemia) were evaluated on responses to gamma-aminoburtyric acid (GABA) and glycine (Gly) on mouse neurons in primary dissociated cell culture. GABA and Gly were applied iontophoretically and intracellular microelectrode recording techniques were used. The guanidino compounds rapidly and reversibly inhibited both GABA and Gly responses. The guanidino compounds inhibited GABA responses in a concentration-dependent manner and inhibited Gly responses at a concentration of 10 mM. Argininic acid was the most potent in reducing inhibitory amino acid responses, followed in decreasing potency by alpha-keto-delta-guanidinovaleric acid, homoarginine and arginine. The guanidino compounds were equally potent in decreasing Gly and GABA responses. Co-application of CGS 9896, a benzodiazepine receptor antagonist, did not antagonize the guanidino compound-induced inhibition of GABA responses. These findings suggest that the guanidino compounds inhibited responses to the inhibitory neurotransmitters GABA and Gly by blocking the chloride channel. This effect might underlie the in vivo epileptogenicity of some of the guanidino compounds and might contribute to the pathogenesis of seizures in hyperargininemia.

Animals↗
PubMed1991

Guanidino compound metabolism in arginine-free diet induced hyperammonemia.

Guanidino compounds, intermediates of arginine metabolism, are altered in many pathological conditions especially those involving the urea cycle. Arginine and creatine play an important role in nitrogen metabolism whereas other guanidino compounds such as guanidinosuccinic acid and N-acetylarginine are toxins. Our objective was to investigate the relationship between guanidino compounds and hyperammonemia. Young and adult ferrets were fed a single meal of either an arginine-containing diet (ACD) or an arginine-free diet (AFD). Guanidino compounds were determined by HPLC in the plasma, liver, kidney and brain 3 h after feeding the specified diet. Only young ferrets fed AFD developed hyperammonemia. Plasma and kidney arginine was decreased whereas guanidinosuccinic acid was increased in young ferrets fed AFD. Hepatic creatine and kidney and brain guanidinoacetic acid were significantly decreased in this group. These results indicate that AFD-induced hyperammonemia produced decreased methylation activity in the liver and transamidination activity in kidney. Elevated guanidinosuccinate levels coupled with deficient hepatic creatine synthesis may play a role in the pathophysiology of hyperammonemia.

Ammonia↗
PubMed1990

Serum guanidino compound levels and clearances in uremic patients treated with continuous ambulatory peritoneal dialysis.

Guanidino compounds are increased in uremia and have been implicated as uremic toxins. The serum concentrations of 13 guanidino compounds and the clearances of 10 guanidino compounds were determined in 15 steady-state uremic patients treated with continuous ambulatory peritoneal dialysis. Guanidino compounds were determined using liquid cation-exchange chromatography with a sensitive fluorescence detection method. Standardized dialysis procedures were performed, including an overnight and a 3-hour dwell period. Guanidino compound levels did not significantly differ at the end of an overnight or a 3-hour exchange, indicating a steady-state blood chemistry for these substances in chronic ambulatory peritoneal dialysis. High levels were found for guanidinosuccinic acid, creatinine, guanidine and methylguanidine, while creatine and homoarginine levels were lower than in controls. Guanidinosuccinic acid, creatinine and methylguanidine reached levels associated with toxic effects in vitro. Significantly different clearances were found ranging from 4.02 +/- 1.08 ml/min for arginine to 7.94 +/- 2.76 ml/min for creatine during a 3-hour exchange.

Adult↗
PubMed1990

Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: follow-up of guanidino compound levels during therapy.

The aim of this collaborative study was to investigate whether guanidino compound analyses in the biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, alpha-keto-delta-guanidino-valeric acid, argininic acid, and N-alpha-acetylarginine levels of all the hyperargininemic patients are higher than the normal range. Similar increases were seen for the urinary excretion of alpha-keto-delta-guanidinovaleric acid and argininic acid. Untreated hyperargininemic patients have the highest guanidino compound levels in cerebrospinal fluid. However, even under therapy, the arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid, and argininic acid levels in cerebrospinal fluid are still increased. Protein restriction alone is not sufficient to normalize the hyperargininemia, but protein restriction together with supplementation of essential amino acids with or without sodium benzoate decreases further the arginine levels. However, whereas the argininemia can be normalized, the catabolites of arginine are still increased. We conclude that the urinary amino acid levels may remain normal in hyperargininemia, whereas consistent increases of the guanidino compounds are observed. Thus, guanidino compound analyses can be used as a complementary biochemical diagnostic parameter for hyperargininemia. Although the argininemia can be normalized by therapy, the levels of the catabolites of arginine are still elevated.

Adolescent↗
PubMed1990

Epilepsy and the GABA-hypothesis a brief review and some examples.

A brief review is given with regard to the GABAergic alterations in experimental and genetic models of epilepsy and human epilepsy, illustrating, among others, that agents exist, both convulsants and anticonvulsants, that are capable of interacting with GABA's synthesis, storage, extraneuronal release, presynaptic reuptake, postsynaptic destruction and activation. The so-called "GABA-hypothesis" of epilepsy implies that a reduction of GABA-ergic inhibition results in epilepsy while an enhancement of GABAergic inhibition results in an antiepileptic effect. The examples presented, in support of the "GABA-hypothesis", concern the effects of some exogenous [pentylenetetrazol (PTZ) and methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)] and some endogenous convulsants on the postsynaptic GABAA receptor. The studied endogenous convulsants were the guanidino compounds which are known to increase in uremia and hyperargininemia. PTZ and DMCM dose-dependently reduced GABA responses on mouse neurons in cell culture. The benzodiazepine receptor antagonist CGS 9896 antagonized the DMCM- but not the PTZ-induced inhibition of GABA-responses. The guanidino compounds guanidine, methylguanidine, creatinine, guanidinosuccinic acid (increased in uremia) and arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (increased in hyperargininemia) decreased both GABA- and GLY-responses. The guanidino compounds were equally potent in decreasing GABA- and GLY-responses and CGS 9896 did not antagonize the guanidino compound-induced inhibition of GABA responses. The presented results indicate that the studied convulsants inhibit GABAergic inhibition through interaction with distinct sites at the postsynaptic GABAA receptor. The demonstrated effect might, in agreement with the "GABA-hypothesis", underlie the epileptogenicity of these compounds in animal models and might have pathophysiological importance in uremia and hyperargininemia.

Animals↗
PubMed1989

Hyperargininemia, epilepsy and the metabolism of guanidino compounds.

Patients with hyperargininemia have an arginase deficiency which leads to blockade of the urea cycle in the last step with several clinical symptoms. Owing to the arginase deficiency this patients accumulate arginine which leads to eventual alternative yet unknown pathways of arginine metabolism. These clinical and biochemical findings intensified the research on guanidino compounds. It has been shown that most of the guanidino compounds are epileptogenic. Therefore we investigated the levels of 12 guanidino compounds in serum and brain of audiogenic sensitive rats. The changes of some guanidino compounds in serum and brain will be discussed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Effects of alpha-keto-delta-guanidinovaleric acid on inhibitory amino acid responses on mouse neurons in cell culture.

The experimentally proven convulsant alpha-keto-delta-guanidinovaleric acid (alpha-K-delta-GVA) was applied to mouse spinal cord neurons in primary dissociated cell culture to assess its effects on postsynaptic gamma-aminobutyric acid (GABA)- and glycine (GLY)-responses. Intracellular microelectrode recording techniques were used. alpha-K-delta-GVA reversibly inhibited both GABA- and GLY-responses in a concentration-dependent manner. The effect of alpha-K-delta-GVA on GABA-responses was not antagonized by co-application of the benzodiazepine receptor antagonist CGS 9896. The results suggest that alpha-K-delta-GVA inhibited responses to the inhibitory neurotransmitters GABA and GLY by blocking the chloride channel. This action might underlie the convulsant effect of this compound in rabbit. The possible pathophysiological importance of alpha-K-delta-GVA in hyperargininemic patients is discussed.

Animals↗
PubMed1987

Guanidino compounds in serum and cerebrospinal fluid of non-dialyzed patients with renal insufficiency.

Twelve guanidino compounds were determined in simultaneously sampled serum and cerebrospinal fluid of eight non-dialyzed patients with renal insufficiency. Liquid cation exchange chromatography with a highly sensitive fluorescence detection method was used. In patients with serum urea levels about 10 times higher than in controls, the levels of guanidinosuccinic acid, creatinine, guanidine and methylguanidine, in serum as well as in cerebrospinal fluid, are at least 10 times higher than in control subjects. The levels of argininic acid and N-alpha-acetylarginine (in serum) and gamma-guanidinobutyric acid (in cerebrospinal fluid) are slightly increased (less than 10 X). The levels of the other guanidino compounds are close to normal values. A significant positive correlation exists between the guanidinosuccinic acid, creatinine and guanidine levels in serum and cerebrospinal fluid. The accumulation of several experimentally proven toxic guanidino compounds could contribute to the complex nervous system symptomatology and the hematological complications seen in renal insufficiency.

Aged↗
PubMed1987

Serum guanidino compound levels and the influence of a single hemodialysis in uremic patients undergoing maintenance hemodialysis.

Guanidino compounds are increased in uremia and are highly suspected to be uremic toxins. The serum levels of 11 guanidino compounds and the influence of a single hemodialysis were evaluated in 30 steady-state uremic patients undergoing maintenance hemodialysis. Guanidino compound levels were detected using liquid cation exchange chromatography with a highly sensitive fluorescence detection method. Highly standardized dialysis procedures were performed. Before hemodialysis, high levels were found for guanidinosuccinic acid, N-alpha-acetylarginine, argininic acid, creatinine, gamma-guanidinobutyric acid, guanidine and methylguanidine. Guanidinosuccinic acid reached levels associated with toxic effects in vitro. After hemodialysis, although lowered, guanidinosuccinic acid, creatinine, guanidine and methylguanidine were still markedly increased. No differences in the percent decrease, during a single hemodialysis, of the studied compounds were found using different membranes such as cellulose acetate, cuprophane and polyacrylonitrile membranes. Substantial differences, however, in the percent decrease of the different guanidino compounds were found, ranging from 25 +/- 13% for arginine to 74 +/- 7.5% for guanidinosuccinic acid. Data reported here show that guanidino compounds are raised in serum of uremic patients undergoing maintenance hemodialysis, before as well as after a single hemodialysis, while substantial differences in the percent decrease of the different guanidino compounds are found.

Adult↗
PubMed1986

Guanidino compounds in uraemic dialysed patients.

The concentrations of guanidino compounds in blood are raised in uraemic patients and may have toxic effects. The concentrations of 13 guanidino compounds in serum were measured in 29 patients with chronic renal failure treated by chronic intermittent haemodialysis using liquid cation exchange chromatography with a highly sensitive fluorescence detection method. For taurocyamine we used another column system. Substantial increases in guanidinosuccinic acid, creatine, N-alpha-acetylarginine, creatinine, guanidine and methylguanidine were found. The values obtained for taurocyamine and beta-guanidinoproprionic acid were much lower than those reported by others: a much smaller increase was observed for beta-guanidinoproprionic acid and taurocyamine was only doubled in 4 of 29 uraemic patients. The concentrations of other guanidino compounds such as arginine and guanidinoacetic acid were normal. No differences were found between the polycystic renal disease, the chronic glomerulonephritis and the interstitial nephritis subgroups.

Adult↗