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Biomedical subjects

S L Lowe

Publications and source records attributed to S L Lowe.

At least 19 recordsLinked to original sources
PubMed1992

Effect of psychotropic drugs on excitatory amino acids in patients undergoing psychosurgery for depression.

Samples of ventricular CSF were taken from 52 consecutive patients admitted for psychosurgery for intractable depression. Concentrations of asparagine, aspartate, glutamine, glutamic acid, and serine were determined. Glutamate and aspartate concentrations, implicated in excitotoxic brain damage, were not affected by various types of psychotropic drug treatment. Serine, a modulator of glutamate responses, was significantly elevated in samples from subjects receiving antidepressants. These subjects responded poorly to the operation. Psychotropic drugs are unlikely to be neurotoxic. Nevertheless, antidepressants may influence excitatory neurotransmission.

Adult↗
PubMed1991

Terminal coma affects messenger RNA detection in post mortem human temporal cortex.

In situ hybridization histochemistry has been used to study the amount of M1 muscarinic receptor mRNA in temporal cortex from subjects with Alzheimer's disease and other neurodegenerative disorders, where the duration of terminal coma was known. Total polyadenylated mRNA and glutamate decarboxylase activity were also measured. Both muscarinic receptor mRNA and enzyme activity showed a significant decline with increasing duration of terminal coma, but were not related to diagnosis. Polyadenylated mRNA signal did not show an association with coma. These data indicate the need to consider the nature of the terminal illness in post mortem studies of mRNA as well as for neurochemical research.

Alzheimer Disease↗
PubMed1991

Characterisation of the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex in human brain.

[3H]Glycine binding and glycine modulation of [3H]MK-801 binding have been used to study the glycine allosteric site associated with the N-methyl-D-aspartate receptor complex in postmortem human brain. The effect of glycine on [3H]MK-801 binding appeared sensitive to duration of terminal coma, and possibly postmortem delay. Thirty percent of the binding occurred in a subfraction of brain tissue and did not show enhancement by glycine and glutamic acid. [3H]Glycine binding to a subfraction free from this component was studied and showed high specific binding. KD and Bmax values showed considerable intersubject variability which did not appear to be due to demographic features or to tissue content of amino acids with an affinity for this site. The pharmacological characteristics of binding in this subfraction and a correlation between Bmax values and the maximal enhancement of [3H]MK-801 binding by glycine are consistent with [3H]glycine binding occurring to an N-methyl-D-aspartate receptor complex associated site. Further support for this is provided by a significantly lower Bmax value for [3H]glycine binding in subjects with Alzheimer's disease and reduced glycine enhancement of [3H]MK-801 binding. However, the effect of perimortem factors makes it difficult to confidently attribute this solely to a disease-related change in the receptor. The possible role of the glycine allosteric site in the treatment of neuropsychiatric disorders is discussed.

Aged↗
PubMed1990

Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease.

There is little information about major constituents of the brain in Alzheimer's disease. In the case of amino acids most of the previous data are contradictory. These have been interpreted in an anatomic and neurotransmitter as well as a metabolic context. To help clarify this, the contents of 14 amino acids and ethanolamine were determined in samples of neocortex from diagnostic craniotomies of 15 demented patients (10 with Alzheimer's disease) and other neurosurgical procedures (57 patients, 18 with intractable depression). A comprehensive survey of the effects of possible complicating factors on the concentrations of amino acids showed that artefacts were few; this was in contrast to a post mortem series of brains (16 with Alzheimer's disease and 16 controls; six regions assayed). We have used the ante mortem data to provide the basis for an accurate comparison of amino acid values between Alzheimer and control samples. In Alzheimer's disease, the mean contents of many amino acids were slightly higher (sum of the increases of those significantly affected was 15 nmol/mg protein) whereas glutamate content alone was significantly reduced (by 16 nmol/mg protein). This was not a feature of depression or a group of patients with other dementias. Glutamate content of Alzheimer samples was related to pyramidal neuron density in cortical layer III. These alterations were detected relatively early during the course of Alzheimer's disease and are considered to be due to loss of corticocortical glutamatergic association pathways.

Alzheimer Disease↗
PubMed1990

Influence of tetrahydro-9-aminoacridine on excitatory amino acid release.

Alzheimer's disease may be associated with an early and clinically relevant degeneration of some cortical excitatory amino acid-releasing neurons. Tetrahydro-9-aminoacridine (tacrine) might be an effective drug for the treatment of the disease. Various pharmacological paradigms (in rats) related to amino acid release are shown here to be modified both in vivo and in vitro by the drug. These effects are only observed with high concentrations, so it is unlikely that tacrine acts through amino acid release in humans.

Amino Acids↗
PubMed1990

Clinical correlations of the neurobiological changes of aging.

Increasing age is associated with increased risk of developing both dementia and depression; both conditions appear to be associated with structural changes in the cerebral cortex. In depression, there was evidence for regional alterations in cortical neurons either as a result of the disease or its treatment. In Alzheimer's disease, a key change is likely to be either shrinkage or loss of corticocortical pyramidal neurones which probably use glutamate as their transmitter. The putative pathogenic role of glutamate and energy metabolism, as well as an approach to treatment of symptoms are outlined.

Aged↗
PubMed1989

Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem.

The concentrations of 3 putative neurotransmitters (glutamate, aspartate and gamma-aminobutyrate), 4 related amino acids and 5 non-transmitter-related amino acids have been measured in neurosurgical samples (frontal cortex) from patients with intractable depression and controls. In addition, the glutamate receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified in human brain and measured in these samples. There were no changes in the concentrations of amino acids in depressed patients compared to control with the exception of aspartic and homocysteic acids which were elevated in a sub-group of patients with depression compared to control. The Ca2+-dependent release (K+-stimulated) of putative neurotransmitters has been demonstrated for the first time from brain tissue of depressed patients. Glutamate release was unaltered from the control value. Aspartate values showed unexplained variability but it's release and that of gamma-aminobutyrate were elevated in some depressed subjects. These results do not support the hypothesis of reduced amino acid function in depressive illness.

Aged↗
PubMed1989

Extracellular concentrations of aspartate and glutamate in rat neostriatum following chemical stimulation of frontal cortex.

Extracellular concentrations of excitatory amino acids in the neostriatum of anaesthetized rats were studied by in vivo microdialysis and the influence of chemical stimulation of the neocortex assessed. Administration of gamma-aminobutyric acid (GABA) antagonists to the neocortex evoked an increase in the extracellular concentration of aspartate (to 315 and 210% of basal values for microinfusion and topical application, respectively), but not of extracellular glutamate. Such selectivity was also found in response to N-methyl-D-aspartate (NMDA, 348% increase in extracellular aspartate concentration). Yet co-administration of NMDA with GABA antagonists increased the extracellular concentration of glutamate (to 278% of basal values) as well as aspartate (to 611% of basal values). The results suggest that either the activated neurons are hypoglycemic or hypoxic, or that aspartate is the major neurotransmitter of corticostriatal neurons.

Animals↗
PubMed1989

Reduced glycine stimulation of [3H]MK-801 binding in Alzheimer's disease.

The novel N-methyl-D-aspartate receptor channel ligand (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine maleate ([3H]MK-801) has been utilized to label this receptor in human brain tissue. Characteristics of [3H]MK-801 binding to well-washed membranes from 17 control subjects and 16 patients with Alzheimer's disease were determined in frontal, parietal, and temporal cerebral cortex and cerebellar cortex. In control tissue the pharmacological specificity of the binding of this substance is entirely consistent with the profile previously reported for rat brain. Binding could be stimulated by the addition of glutamic acid to the incubation medium; addition of glycine produced further enhancement which was not prevented by strychnine. The specificity of the effects of these and other amino acids on the binding was the same as in the rat. In Alzheimer's disease significantly less binding was observed in the frontal cortex under glutamate- and glycine-stimulated conditions. This appears to be associated with a reduced affinity of the site whereas the pharmacological specificity of the site remained unchanged. The effect did not appear to be due to differences in mode of death between Alzheimer's disease and control subjects and is unlikely to be related to factors for which the groups were matched. In contrast, binding was not altered in the absence of added amino acids and presence of glutamate alone. These results imply that in the cerebral cortex the agonist site and a site in the cation channel of the receptor are not selectively altered, but that their coupling to a strychnine-insensitive glycine recognition site is impaired.

Aged↗
PubMed1988

Topographical distribution of neurochemical changes in Alzheimer's disease.

Biochemical indices of cortical nerve cells affected in Alzheimer's disease have been proposed (excitatory dicarboxylic amino acid, EDAA, sodium-dependent carrier; phosphate-activated glutaminase activity; serotonin type 2 recognition site; somatostatin-like immunoreactivity). These and the content of EDAAs and two related amino acids, and choline acetyltransferase (ChAT) activity have been measured in up to 13 areas of cerebral cortex and the cerebellar cortex from 16 patients with Alzheimer's disease and 17 controls. Reduction of the index of the serotonin recognition site, somatostatin content and another biochemical index of interneurones coincide and indicate a rather unexpected focal loss of such neurones from the parietal lobe. No unequivocal measure of the integrity of pyramidal neurones could be established as the content of no amino acid was reduced, the index of the EDAA carrier showed evidence of change in few brain regions and glutaminase activity was subject to unexplained variability. ChAT activity alone closely paralleled a previous report of the distribution of morphological degeneration. The results are discussed in relation to therapy and positron emission tomography.

Aged↗
PubMed1988

Gamma-aminobutyric acid concentration in brain tissue at two stages of Alzheimer's disease.

The concentration of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), was measured in the cerebral cortex obtained at diagnostic craniotomy from 10 patients with Alzheimer's disease of 3 yrs mean duration and 6 patients with other causes of dementia, and from 31 subjects undergoing other neurosurgical procedures (for which removal of apparently normal tissue was necessary). GABA content of 5 areas of the cerebral cortex and the cerebellar cortex was measured postmortem in the brains of 23 Alzheimer and 19 control subjects and 5 patients with other causes of dementia. Fourteen of these specimens, including 7 from patients with Alzheimer's disease of 8 yrs mean duration, were obtained within 3 h of death. These were processed in a similar manner to the neurosurgical specimens and are regarded also as fresh tissue samples. The remaining 33 specimens are regarded as conventional postmortem samples as the mean interval of death to autopsy was 21 h. GABA concentration in conventional autopsy specimens from Alzheimer subjects was not reduced as compared with controls in either cingulate or cerebellar cortex. In the inferior parietal cortex, agonal status confounded this comparison. The concentration was reduced in superior parietal, frontal and temporal cortex but there is a possibility that agonal state also confounded these comparisons. There was no deficit in GABA concentration in fresh cortical tissue from Alzheimer patients except for the temporal lobe from autopsy specimens. The content of somatostatin-like immunoreactivity was, like GABA, found to be comparable to control in some groups of Alzheimer specimens. It is argued that the deficits in autopsy samples and lack of change in surgical specimens is likely to be due to the duration of illness at the time of sampling. Losses of choline acetyltransferase activity were observed in all groups of Alzheimer specimens in all areas of brain studied. The data are consistent with other results which suggest that cholinergic under-activity is most closely related to the clinical course of Alzheimer's disease.

Aged↗
PubMed1988

Evidence of glutamatergic denervation and possible abnormal metabolism in Alzheimer's disease.

Excitatory dicarboxylic amino acids previously have been ascribed several functions in the brain. Here their total concentration and proposed neurochemical markers of neurotransmitter function have been measured in brain from patients with Alzheimer's disease (AD) and controls. Specimens were obtained antemortem (biopsy) approximately 3 years after emergence of symptoms and promptly (less than 3 h) postmortem some 10 years after onset. Early in the disease a slight elevation in aspartic acid concentration of cerebral cortex was observed in the patients with AD. A reduction in glutamic acid concentration of a similar magnitude was found. It is argued that this, together with a decrease in CSF glutamine content and lack of change in the phosphate-activated brain glutaminase activity of tissue, reflects an early metabolic abnormality. Later in the disease evidence of glutamatergic neurone loss is provided by the finding that in many regions of the cerebral cortex the Na+-dependent uptake of D-[3H]aspartic acid was almost always lowest in AD subjects compared with control when assessed by a method designed to minimise artifacts and epiphenomena. Release of endogenous neurotransmitters from human brain tissue postmortem did not appear to have the characteristics of that from human tissue antemortem and rat brain.

Aged↗
PubMed1987

Somatostatin content and release measured in cerebral biopsies from demented patients.

Somatostatin-like immunoreactivity (SLIR) has been assayed in frontal and temporal cortex obtained at diagnostic craniotomy and post-mortem from patients with histologically verified Alzheimer's disease. SLIR content was not significantly different from controls in the frontal and temporal lobes, except in the temporal cortex post-mortem. The K+-stimulated release of endogenous SLIR from tissue prisms ('mini-slices') prepared from neocortex obtained at diagnostic craniotomy from Alzheimer patients was not below the control values. Indices of cholinergic varicosities in similar samples from the frontal and temporal lobes are reduced; accordingly, somatostatin does not seem to be as prominently involved in these regions. Patients with Alzheimer's disease underwent neuropsychological assessment shortly before sampling the temporal lobe. Scores for WAIS full scale and the verbal subscale and the Token Test (measure of language comprehension) significantly correlated with the SLIR content; mean values (fmole/mg protein) were 817, 1468 and 1363 for aphasic and non-aphasic Alzheimer patients and controls, respectively. Ventricular fluid obtained from Alzheimer patients during surgery, did not have a significantly different SLIR content compared to controls. SLIR contents of ventricular fluid and neocortex from demented patients, without any specific histological changes in the sample obtained at diagnostic craniotomy, were also not significantly different from controls. Previously, we have shown that these demented patients, as well as those with histologically verified Alzheimer's disease, have a reduced SLIR content of lumbar fluid so it seems that somatostatin neurones located outside the frontal and temporal lobes are affected relatively early in the disease process.

Aged↗
PubMed1975

The subunit structure of phosphoglucose isomerase from bakers' yeast.

Bakers' yeast phosphoglucose isomerase was studied by both chemical and physical methods to determine its submit structure. Gel filtration in 6 M guanidine HCl as well as acrylamide gel electrophoresis of sodium dodecyl sulfatedentured phosphoglucose isomerase showed two speices corresponding to one-half and one-fourth of the preparative molecular weight of 119,400 determined by equilibrium centrifugation. Further centrifugation studies showed that the enzyme could be completely dissociated to species of 30,000 molecular weight. Peptide maps of tryptic hydrolysates of denatured and chemically modified enzyme showed that the protein is composed of four identical or nearly identical sub-units. The results of amino acid analysis, except half-cystine content, were compatible with identical subunits. The appearent partial specific volume and extinction coefficient were also determined.

Amino Acid Sequence↗