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Biomedical subjects

J W Pettegrew

Publications and source records attributed to J W Pettegrew.

At least 19 recordsLinked to original sources
PubMed1996

Phosphocreatine-dependent glutamate uptake by synaptic vesicles. A comparison with atp-dependent glutamate uptake.

ATP-dependent uptake of glutamate into synaptic vesicles has been well documented. Stimulation of glutamate uptake into synaptic vesicles by other high-energy phosphates has not been described. In this paper, we examine the stimulation of phosphocreatine (PCr)-induced glutamate uptake and determine whether this stimulation is secondary to conversion of PCr to ATP. We found the following. 1) PCr stimulates glutamate uptake into synaptic vesicles in the absence of added ATP. 2) At a glutamate concentration of 50 microM, no concentration of added ATP could produce the degree of stimulation seen in the presence of PCr. 3) 0.5 mM iodoacetamide completely inhibits synaptic vesicle creatine kinase activity but does not inhibit PCr-stimulated glutamate uptake. 4) PCr-dependent glutamate uptake, unlike ATP-dependent uptake, is not magnesium- or chloride-dependent. 5) 0.5 mM N-ethylmaleimide, a selective H+-ATPase inhibitor, completely inhibits ATP-dependent glutamate uptake but only slightly inhibits PCr-dependent glutamate uptake. 6) PCr-dependent glutamate uptake is sensitive to valinomycin, a K+/H+ translocator, whereas the ATP-dependent uptake is not. Therefore, it appears that in addition to the well-known ATP-dependent glutamate uptake system, there is a previously unreported PCr-dependent glutamate uptake system in synaptic vesicles. The total glutamate uptake by synaptic vesicles is likely the sum of both ATP- and PCr-dependent glutamate uptake.

Adenosine Triphosphate↗
PubMed1996

Molecular membrane interactions of a phospholipid metabolite. Implications for Alzheimer's disease pathophysiology.

Alzheimer's disease is characterized by changes in phospholipid metabolism leading to a perturbation in the levels of phosphomonoesters, including L-Phosphoserine (L-PS). These early changes in lipid metabolism may result in a defect in membrane bilayer structure, leading to increased rates of beta-amyloid formation. To investigate the effect of L-PS on membrane lipid bilayers, small angle x-ray diffraction and high resolution differential scanning calorimetry (DSC) approaches were used with liposomes composed of lecithin and cholesterol. A one-dimensional electron density profile of a control dimyristoyl phosphatidylcholine (DMPC)/cholesterol lipid bilayer with a unit cell dimension of 52 A at 37 degrees C was generated from the x-ray diffraction data. Following incubation with 2.0 mM L-PS, a broad decrease in electron density +/- 4.12A from the lipid bilayer center was observed concomitant with an increase in the width of the phospholipid headgroup electron density and a 3A reduction in lipid bilayer width. The interactions of L-PS with DMPC lipid bilayers were concentration-dependent, highly affected by cholesterol content and reproduced in egg phosphatidylcholine/cholesterol liposomes. DSC analysis showed that millimolar (1.0-5.0 mM) L-PS levels decreased the phase transition cooperative unit size of DMPC liposomes in a highly concentration-dependent manner which was significantly greater in preparations containing 10 mol% cholesterol. These data provide direct evidence that phosphomonoester levels modulate the biophysical properties of the membrane lipid bilayer which may, in turn, lead to altered structure/function relationships in AD.

Alzheimer Disease↗
PubMed1996

Phospholipid metabolism in Alzheimer's disease and in a human cholinergic cell.

There is evidence available suggesting that membrane alterations occur in Alzheimer's disease including the metabolism of membrane phospholipids. We have quantitated in vitro the phospholipase D activity of homogenates from Alzheimer's disease brain tissue. There was a significant increase of this enzyme activity as compared to controls. Amyloid beta protein is the predominant protein of the characteristic senile plaques found in Alzheimer's disease. Treatment of LA-N-2 cells, a human cholinergic neuroblastoma clone, with amyloid beta protein results in an activation of phospholipases A, C and D.

Alzheimer Disease↗
PubMed1996

A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease.

A 1-year, double-blind, placebo-controlled, randomized, parallel-group study compared the efficacy and safety of acetyl-L-carnitine hydrochloride (ALCAR) with placebo in patients with probable Alzheimer's disease (AD). Subjects with mild to moderate probable AD, aged 50 or older, were treated with 3 g/day of ALCAR or placebo (1 g tid) for 12 months. Four hundred thirty-one patients entered the study, and 83% completed 1 year of treatment. The Alzheimer's Disease Assessment Scale cognitive component and the Clinical Dementia Rating Scale were the primary outcome measures. Overall, both ALCAR- and placebo-treated patients declined at the same rate on all primary and most secondary measures during the trial. In a subanalysis by age that compared early-onset patients (aged 65 years or younger at study entry) with late-onset patients (older than 66 at study entry), we found a trend for early-onset patients on ALCAR to decline more slowly than early-onset AD patients on placebo on both primary endpoints. In addition, early-onset patients tended to decline more rapidly than older patients in the placebo groups. Conversely, late-onset AD patients on ALCAR tended to progress more rapidly than similarly treated early-onset patients. The drug was very well tolerated during the trial. The study suggests that a subgroup of AD patients aged 65 or younger may benefit from treatment with ALCAR whereas older individuals might do more poorly. However, these preliminary findings are based on past hoc analyses. A prospective trial of ALCAR in younger patients is underway to test the hypothesis that young, rapidly progressing subjects will benefit from ALCAR treatment.

Acetylcarnitine↗
PubMed1995

Biological correlates of slow wave sleep deficits in functional psychoses: 31P-magnetic resonance spectroscopy.

Deficits in slow wave sleep (SWS) are consistently seen in schizophrenia and related psychotic disorders. However, the pathophysiological significance of this finding is uncertain. In 19 patients with psychotic illness, sleep and 31P-magnetic resonance spectroscopy (MRS) studies were carried out before the patients began medication treatment. Polysomnographic studies were carried out in 2-3 consecutive nights. MRS studies were performed with a surface coil and a depth-resolved pulse sequence focusing on the dorsal prefrontal cortex. Phosphomonoesters were correlated with visually scored delta and Stage 4 sleep, as well as with automated delta wave counts. An inverse relation was also seen between negative symptoms scores and SWS. The association between decreases brain anabolic processes (reflected by decreased PME) and decreased SWS may be related either to processes of accelerated aging or to developmentally mediated alterations in cortical synaptic pruning, postulated to underlie the pathophysiology of functional psychoses.

Adult↗
PubMed1995

A comparison of stereology and segmentation techniques for volumetric measurements of lateral ventricles in magnetic resonance imaging.

Lateral ventricular volumes were measured on magnetic resonance imaging (MRI) scans by independent raters in 18 subjects (11 psychotic patients and 7 healthy control subjects) with two different approaches: a point-counting stereological (PCS) technique and a computerized technique based on segmentation algorithms. The correlation between the two techniques was very high (r = 0.96), and phantom studies showed good validity for both approaches. These findings and the technical simplicity of the PCS technique support its potential use for MRI morphometric measurements.

Cerebral Ventricles↗
PubMed1995

Structural determinants of activity at the GABAB receptor. A comparison of phosphoethanolamine and related GABA analogs.

Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and the GABAB partial agonist 3-aminopropylphosphonic acid, phosphoethanolamine binds very poorly to GABAB receptors (IC50 = 7.5 +/- 0.8 mM). In this study, we examined whether the marked decrease in binding affinity associated with the presence of an ester oxygen in place of the alpha-CH2 group of GABAergic compounds also occurred in sulfonates and used high resolution solution NMR and molecular mechanics calculations to determine the structural basis of this decrease in activity. The sulfonate analog of GABA, 3-amino-propylsulfonic acid, became > 2500-fold less potent when the alpha-CH2 was replaced by an ester oxygen. Structural studies showed that the active alpha-CH2 compounds (GABA, 3-aminopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a fully extended conformation. The inactive compounds, phosphoethanolamine and ethanolamine-O-sulfate, exist in a gauche conformation around the C beta-C gamma bond. This study, which suggests conformational differences, may explain how PE can be so efficiently excluded from GABAB receptors, despite being present in millimolar concentrations in brain. Exclusion of phosphoethanolamine from GABAB receptors may be an important physiologic control mechanism in the regulation of inhibitory neurotransmission.

Crystallography, X-Ray↗
PubMed1995

Inactivity of phosphoethanolamine, an endogenous GABA analog decreased in Alzheimer's disease, at GABA binding sites.

Phosphoethanolamine (PE) is a metabolite of the phospholipid metabolism which is decreased in Alzheimer's disease brain. PE shows a strong structural similarity to the inhibitory neurotransmitter, GABA, and the GABAB receptor partial agonist, 3-amino-propylphosphonic acid. The ability of PE to compete for binding to GABAA and GABAB binding sites was investigated. GABAA sites were studied using [3H]SR-95531 and [3H]muscimol. GABAB sites were studied using [3H]GABA in the presence of isoguvacine to saturate GABAA sites. Total [3H]GABA binding was also examined. PE showed little activity at any of the GABA binding sites investigated. PE was most potent at GABAB sites, but the IC50 of 7.5 +/- 0.75 mM was considerably higher than its maximal physiologic concentration of approximately 1.5 mM. The efficient exclusion of PE from GABA binding sites may be an important physiologic mechanism in the control of inhibitory neurotransmission. The structural basis for this exclusion is discussed in reference to the GABAB partial agonist 3-amino-propylphosphonic acid.

Alzheimer Disease↗
PubMed1995

Magnetic resonance spectroscopy and its application to aging and Alzheimer's disease.

This is a review of magnetic resonance (MR) spectroscopy and its application to aging and Alzheimer's disease (AD). Examinations of perchloric acid extracts of AD brain tissue by MR spectroscopy reveal elevated levels of phosphomonoesters, phosphodiesters, and glutamate accompanied by reduced levels of N-acetyl-L-aspartate compared with extracts from controls. These metabolicalterations may be an indication of accelerated membrane phospholipid metabolism, glutamate neurotoxicity, and neuronal loss in AD brain that is not seen in normal aging. In vivo 31P MR spectroscopy studies of AD indicate that levels of phosphomonoesters are elevated early in the course of AD, which may be a causative molecular neuropathologic event. In vivo MR spectroscopy is a powerful technique to investigate the molecular neuropathology of the disease, to follow the progression of AD, and to assess the efficacy of experimental therapies.

Adolescent↗
PubMed1994

NMR identification of the formic acid-modified residue in Alzheimer's amyloid protein.

The beta/A4-amyloid protein (beta/A4) and many synthetic fragments of this protein have proved to be very difficult to solubilize, leading to the use of relatively harsh chemical methods, most notably, formic acid. This treatment has previously been shown to cause a covalent modification of this peptide. In this study, one- and two-dimensional NMR techniques are used to show that the nature of this covalent modification is formation of a formate ester to a serine residue. This finding is consistent with our previously reported kinetic studies of formic acid-induced modification of beta/A4 and further illustrates the potential danger of solubilizing fragments of beta/A4 in formic acid. Alternative methods of solubilization are discussed.

Amino Acid Sequence↗
PubMed1993

Alterations of selected enzymes of phospholipid metabolism in Alzheimer's disease brain tissue as compared to non-Alzheimer's demented controls.

Previous studies have demonstrated elevated brain levels of phosphomonoesters in early stages of Alzheimer's disease and elevations of phosphodiesters later in the disease. In addition, preliminary quantitative analyses of the phospholipids of Alzheimer's brain reveals either decreases in some phospholipids or elevations followed by decreases in others. This study quantitated the activities of selected enzymes involved in phospholipid and choline metabolism and demonstrated elevated glycerol-3-phosphorylcholine phosphodiesterase and decreased choline kinase activities in Alzheimer's disease brain. The former could provide an enzymatic mechanism for the increased phosphorylcholine found in Alzheimer's disease brain.

Aged↗
PubMed1993

Erythrocyte membrane phospholipids in psychotic patients.

Thin layer chromatography and laser densitometry were used to examine erythrocyte membrane phospholipid composition in 13 medication-free patients with schizophrenia or schizoaffective disorder and 11 healthy control subjects. The patient group had significantly decreased levels of phosphatidylethanolamine and a significant increase in sphingomyelin. The patient group also showed a trend toward decreased levels of phosphatidylinositol bisphosphate. Levels of phosphatidylcholine and lysophosphatidylcholine did not significantly differ between groups. There were no significant effects of age, body mass index, or gender on any of the phospholipid parameters. The observed alterations may point to abnormalities in key membrane-related functions, including signal transduction and ion transport.

Adult↗
PubMed1993

Frontal lobe metabolism and cerebral morphology in schizophrenia: 31P MRS and MRI studies.

The relation between frontal lobe membrane phospholipid metabolism as measured by 31Phosphorus magnetic resonance spectroscopy (31P MRS) and cerebral morphology as measured on magnetic resonance images (MRI) was examined in nine first episode neuroleptic naive schizophrenic patients. Total corpus callosal area was significantly correlated with phosphodiester concentration. When examined separately, this relation was confined to the rostral quartile (genu) of the corpus callosum. The pathophysiological significance of this finding is discussed in relation to neurodevelopmental hypotheses of schizophrenia.

Adult↗
PubMed1993

31P nuclear magnetic resonance spectroscopy: neurodevelopment and schizophrenia.

A number of studies have demonstrated alterations in the structure and function of the frontolimbic system in some schizophrenic patients. Recent in vivo phosphorus-31 nuclear magnetic resonance studies of the dorsal prefrontal cortex in neuroleptic-naive, first-episode schizophrenic patients and matched controls have shown evidence of alterations in membrane phospholipid and energy metabolism. The membrane alterations observed in the schizophrenic patients are compatible with either premature aging or altered timing and exaggeration of regressive events occurring during normal brain development. These molecular changes may precede onset of clinical symptoms and brain structural changes in schizophrenia and suggest fresh approaches to the pathogenesis and treatment of this illness.

Adult↗
PubMed1992

Molecular insights into schizophrenia.

A number of studies have demonstrated alterations in the structure and function of the frontal cortex in some schizophrenic patients. The possible etiology and pathogenesis of these abnormalities are unknown, but genetic and developmental causes are frequently mentioned. Recent in vivo 31P NMR studies of the dorsal prefrontal cortex have been conducted in eleven neuroleptic naive, first episode schizophrenic patients and compared with normal controls of comparable age, educational level and parental educational level. The findings in the schizophrenic patients are different from those of normal IQ adult autistic patients of comparable age and Alzheimer's patients but similar to normal elderly controls. These studies show decreased frontal lobe utilization of adenosine triphosphate in the schizophrenic patients which suggests a hypoactive dorsal prefrontal cortex. In addition, indices of membrane phospholipid metabolism are altered in the schizophrenic patients. However, the findings in the schizophrenic patients are quite similar to those observed in normal elderly controls and to those that normally occur to a lesser degree during adolescence. The phospholipid alterations observed in the schizophrenic patients are compatible with either premature aging or altered timing and exaggeration of the regressive events which occur during normal brain development. The changes in high-energy phosphate metabolism observed in the schizophrenic patients may prove to be state dependent, but the changes in membrane phospholipid metabolism could be related to molecular changes that precede the onset of clinical symptoms and brain structural changes in schizophrenia. These findings suggest new avenues of thinking about the pathogenesis and treatment of schizophrenia.

Aging↗