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Biomedical subjects

A G Chapman

Publications and source records attributed to A G Chapman.

At least 73 records · Page 4Linked to original sources
PubMed1984

Anticonvulsant activity of intracerebroventricularly administered valproate and valproate analogues. A dose-dependent correlation with changes in brain aspartate and GABA levels in DBA/2 mice.

Valproate and the branch-chain valproate analogues, 2-propyl-hexanoate and 2-ethyl-hexanoate, block sound-induced seizures in DBA/2 mice following their intracerebroventricular administration, the ED50 values for the suppression the clonic phase of the seizures being 6.0, 5.0, and 10.2 mumoles respectively. The straight-chain analogues, butyrate and pentanoate , have no anticonvulsant activity. Systemic administration of branched-chain valproate analogues has previously shown a progressive increase in the anticonvulsant activity of the analogues with an increase in the chain-length of the molecules. This relationship is abolished when the same analogues are injected directly into the ventricles. The icv administration of the 2 straight-chain, inactive analogues produces no effect on brain aspartate and GABA levels (with the exception of a butyrate-induced 34% rise in forebrain GABA level). There is a dose-dependent decrease in aspartate levels in cerebellum and forebrain (up to 45-55% reduction), and a dose-dependent increase in GABA levels in forebrain (up to 30-75% rise) 30 min after the icv administration of the 3 anticonvulsant branched-chain fatty acids. 2-Propyl-hexanoate does not affect the cerebellar GABA level significantly, while valproate and 2-ethyl-hexanoate administration produce 20-40% increases in cerebellar GABA levels.

Animals↗
PubMed1984

Changes in regional neurotransmitter amino acid levels in rat brain during seizures induced by L-allylglycine, bicuculline, and kainic acid.

Changes in amino acid concentrations were studied in the cortex, cerebellum, and hippocampus of the rat brain, after 20 min of seizure activity induced by kainic acid, 47 mumol/kg i.v.; L-allylglycine, 2.4 mmol/kg i.v.; or bicuculline, 3.27 mumol/kg i.v. in paralysed, mechanically ventilated animals. Metabolic changes associated with kainic acid seizures predominate in the hippocampus, where there are decreases in aspartate (-26%), glutamate (-45%), taurine (-20%), and glutamine (-32%) concentrations and an increase in gamma-aminobutyric acid (GABA) concentration (+ 26%). L-Allylglycine seizures are associated with generalized decreases in GABA concentrations (-32 to -54%), increases in glutamine concentrations (+10 to +53%), and a decrease in cortical aspartate concentration (-14%). Bicuculline seizures, in fasted rats, are associated with marked increases in the levels of hippocampal GABA (+106%) and taurine (+40%). In the cerebellum, there are increases in glutamine (+50%) and taurine concentrations (+36%). These changes can be explained partially in terms of known biochemical and neurophysiological mechanisms, but uncertainties remain, particularly concerning the cerebellar changes and the effects of kainic acid on dicarboxylic amino acid metabolism.

Allylglycine↗
PubMed1984

Evaluation of anticonvulsant drugs in DBA/2 mice with sound-induced seizures.

The syndrome of sound-induced seizures in DBA/2 mice is described. Protection against seizure responses is provided by intraperitoneal administration of conventional anticonvulsant drugs with benzodiazepines being the most potent, and valproate, ethosuximide and trimethadione the least potent. Protection is also provided by intracerebroventricular administration of anticonvulsant drugs. GABAergic agents, antagonists of excitation due to dicarboxylic amino acids, alpha 2-noradrenergic agonists, and dopamine agonists all provide protection against the seizure responses. There is, however, no conclusive biochemical evidence that the syndrome is attributable to a defect in one or more of these neurotransmitter systems.

Acoustic Stimulation↗
PubMed1983

Uptake of a novel anticonvulsant compound, 2-amino-7-phosphono-[4,5-3H]heptanoic acid, into mouse brain.

The time course of radioactivity in plasma, liver and brain is described following the intraperitoneal injection of 2-amino-7-phosphono-[4,5-3H]heptanoic acid in mice. Using high performance liquid chromatography of dansylated extracts of mouse brain the radioactivity attributable to 2-amino-7-phosphono-[4,5-3H]heptanoic acid has been determined at 0.25-180 min after injection. The time course, with a peak concentration at 30 min, declining markedly between 90 and 180 min, corresponds to the anticonvulsant action.

2-Amino-5-phosphonovalerate↗
PubMed1983

Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content.

Ten analogues of valproic acid (substituted butyric, pentanoic and hexanoic acids) were tested for anticonvulsant activity against audiogenic seizures in DBA/2 mice. There is a consistent correlation between the structure of these branched-chain fatty acids and their anticonvulsant potency, the larger molecules being the more active. There is also a strong correlation between the anticonvulsant potency of these compounds and their ability to reduce cerebral aspartate levels. Cerebral GABA levels are elevated by most, but not all, of the actively anticonvulsant valproate analogues.

Acoustic Stimulation↗
PubMed1983

Effect of 2-amino-7-phosphonoheptanoic acid on regional brain amino acid levels in fed and fasted rodents.

2-Amino-7-phosphonoheptanoic acid, an antagonist of excitation caused by dicarboxylic amino acids with a selective action on N-methyl-D-aspartate receptors, has been administered in an anticonvulsant dose (1 mmol/kg i.p.) to fed or fasted rats and mice. The drug impaired motor activity in fasted mice. Glucose and amino acids were determined in dissected regions of brain fixed by microwave irradiation. Glucose content was low in the brains of fasted rats and mice but was restored to normal (fed) concentration 45 min after the administration of 2-amino-7-phosphonoheptanoic acid in fasted mice. In fed animals, 2-amino-7-phosphonoheptanoic acid did not change brain aspartate concentration. In fasted animals, aspartate concentration was raised in most brain regions. In fasted rats and mice, 2-amino-7-phosphonoheptanoic acid significantly increased glutamine in rat cortex and mouse striatum, decreased glutamate content in rat striatum, and decreased aspartate concentration in all regions except mouse cortex and striatum. GABA levels were significantly decreased in rat striatum and hippocampus. These changes are consistent with an increased synaptic release of glutamate and aspartate following blockage of their post-synaptic action at selected sites.

2-Amino-5-phosphonovalerate↗
PubMed1983

Cortical GABA turnover during bicuculline seizures in rats.

The rate of cortical gamma-aminobutyric acid (GABA) turnover was estimated by determining the rate of GABA accumulation following inhibition of GABA transaminase by gamma-vinyl-GABA (1.5 g/kg, i.v.) in paralysed, ventilated rats. During 1 h of bicuculline-induced seizures (1.2 mg/kg, i.v.) the rate of accumulation of cortical GABA level is approximately threefold greater than in the control group receiving gamma-vinyl-GABA alone, suggesting that the GABA shunt activity increases in parallel with the increase in overall cortical metabolic rate observed during bicuculline seizures. Pretreatment with gamma-vinyl-GABA did not affect the bicuculline-induced changes in other major cortical amino acids.

Aminocaproates↗
PubMed1982

Acute effects of sodium valproate and gamma-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids.

Amino acid concentrations have been determined in rat brain regions (cortex, striatum, cerebellum, and hippocampus) by HPLC after administration of acute anticonvulsant doses of sodium valproate (400 mg/kg, i.p.) and gamma-vinyl-GABA (1 g/kg, i.p.). After valproate administration the GABA level increases only in the cortex; aspartic acid concentration decreases in the cortex and hippocampus, and glutamic acid decreases in the hippocampus and striatum and increases in the cortex and cerebellum. There are no changes in the concentrations of glutamine, taurine, glycine, serine, and alanine following valproate administration. Only the GABA level increases in all the regions after gamma-vinyl-GABA administration. Cortical analyses 2, 4 and 10 minutes after pulse labeling with 2-[14C]glucose, i.v., show no change in the rate of cortical glucose utilization in the valproate treated group. The rate of labeling of glutamic acid is also unchanged, but the rate of labeling of GABA is reduced following valproate administration. After gamma-vinyl-GABA administration there is no change in the rate of labeling of GABA. These biochemical findings can be interpreted in terms of a primary anticonvulsant action of valproate on membrane receptors with secondary effects on the metabolism of amino acid neurotransmitters. This contrasts with the primary action of gamma-vinyl-GABA on GABA-transaminase activity.

Amino Acids↗
PubMed1981

The effect of diazepam on the cerebral metabolic state in rats and its interaction with nitrous oxide.

It has previously been shown in rats that diazepam alone has no effect on the cerebral metabolic rate (CMRO2) but that it interacts with nitrous oxide to produce a 40 per cent reduction in the CMRO2 value. In the present study, the effect of sedative doses of diazepam on the cerebral energy state, glycolysis, citric acid cycle, and amino acid metabolism in rats was determined in the presence and absence of a simultaneous administration of 70 per cent nitrous oxide, 45 s to 30 min after the diazepam injection. The metabolic response was very similar in the two groups despite the differences in metabolic rates of oxygen consumption. There were no changes in the cortical concentrations in ATP, ADP, AMP, phosphocreatine and creatine. The brain glycogen concentration was elevated during diazepam sedation, whereas brain glucose levels remained close to normal values except at 30 min after administration of diazepam alone, when the glucose level showed a 30 per cent increase. The onset of diazepam sedation was associated with an inhibition of glycolysis at the phosphofructokinase step in both groups. The reduced pyruvate concentration subsequently leads to a reduction in the pool size of the citric acid cycle intermediates. The concentrations of alanine and glutamate decreased during the period of diazepam sedation, while those of aspartate and glutamine increased. GABA and ammonia concentrations remained unchanged. Based on the cerebral metabolic response, the onset of diazepam sedation appears to be associated with an inhibition of rate of metabolism (glycolysis), both in the presence and absence of nitrous oxide. In that respect, diazepam has a metabolic profile similar to barbiturates.

Amino Acids↗
PubMed1981

The metabolism of purine and pyrimidine nucleotides in rat cortex during insulin-induced hypoglycemia and recovery.

Brains of paralysed rats with insulin-induced hypoglycemia were frozen in situ after spontaneous EEG activity had been absent for 5 or 15 min ("coma"). Recovery (30 min) was achieved in a different group of rats by administering glucose after a 30-min coma period. Purine and pyrimidine nucleotides, nucleosides and free bases were determined in the cortical extracts by high pressure liquid chromatography (HPLC). The ATP values obtained with the HPLC method were in excellent agreement with those obtained using standard enzymatic/fluorometric techniques, while values for ADP and AMP obtained with the HPLC method were significantly lower. Comatose animals showed a severe (40-80%) reduction in the concentrations of all nucleoside triphosphates (ATP, GTP, UTP and CTP) and a simultaneous increase in the concentrations of all nucleoside di- and monophosphates, including that of IMP. The adenine nucleotide pool size decreased to 50% of control level. The concentrations of the nucleosides adenosine, inosine, and uridine increased 50- to 250-fold, while the concentrations of the purine bases, xanthine and hypoxanthine, rose 2- and 30-fold, respectively. There were no increases in the concentrations of adenine, guanine, or xanthosine. Following glucose administration there was a partial (ATP, UTP and CTP) or almost complete (GTP) recovery of the nucleoside triphosphate levels. During recovery, the levels of nucleoside di- and monophosphates and of adenosine decreased to values close to control; the rise in the inosine level was only partially reversed, and the concentrations of hypoxanthine and xanthine rose further. The adenine nucleotide pool size was only partially restored (to 67% of control value). The adenine nucleotide pool size was not increased by i.p. injection of adenosine or adenine under control condition, or during the posthypoglycemic recovery period.

Adenine↗
PubMed1981

Adenylate energy charge in Escherichia coli CR341T28 and properties of heat-sensitive adenylate kinase.

Escherichia coli strain CR341T28 will not grow at temperatures above 34 degrees C in liquid medium, and the adenylate kinase of this strain is heat sensitive. When a culture was shifted from a permissive (30 degrees C) to a nonpermissive (36 degrees C) temperature, the adenylate energy charge fell from 0.9 to 0.2, with a concurrent decrease in the number of viable cells and in the specific activity of adenylate kinase. When cultures of the temperature-sensitive strain were grown at temperatures above 30 degrees C, the adenylate energy charge, the specific activity of adenylate kinase, and the growth rate were lower than the corresponding parameters for the parental strain. By isotopic labeling of the adenine nucleotides in vivo, it was determined that increasing growth temperatures between 30 and 34 degrees C for the heat-sensitive strain resulted in a decrease in the adenosine triphosphate-to-adenosine monophosphate and adenosine triphosphate-to-adenosine diphosphate ratios. Between 26 and 30 degrees C the adenosine triphosphate-to-adenosine diphosphate ratio was essentially normal in the temperature-sensitive strain, but the adenosine triphosphate-to-adenosine diphosphate ratio was decreased. The adenylate ratios in the parental strain did not change between 30 and 34 degrees C. The adenylate kinase mass action ratio for each strain was essentially constant under all growth conditions. When assayed at 30 degrees C, the affinities of the enzyme from the mutant strain were somewhat lower than those of the parent adenylate kinase. The mutant enzyme also did not exhibit the substrate inhibition that was observed at high adenosine monophosphate concentrations with the parental enzyme. An increase in the assay temperature from 30 degrees to 40 degrees C had little or no effect on the Km values determined for the parental adenylate kinase, but caused the Km values determined for the mutant adenylate kinase to increase by a factor of two or more.

Adenosine Diphosphate↗