31P-NMR study of brain phospholipid structures in vivo

doi:10.1016/0005-2760(91)90102-N

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism

Volume 1085, Issue 2, 11 September 1991, Pages 257-264

Biochimica et Biophy...

https://doi.org/10.1016/0005-2760(91)90102-N Get rights and content

Abstract

³¹P-NMR has been used extensively for the study of cytosolic small molecule phosphates in vivo and phospholipid structures in vitro. We present in this paper a series of studies of the brain by ³¹P-NMR, both in vivo and in extracts, showing the information that can be derived about phospholipids. ³¹P-NMR spectra of mouse brain at 73 mHz are characterised by almost a complete absence of the large phosphodiester peak in comparison to equivalent spectra at 32 mHz. Proton decoupled spectra in vivo, and spectra of extracts, show that the phosphodiester peak observed in 32 mHz spectra in vivo is mainly due to phospholipid bilayers. Homogenates of quaking and control mouse brains, and of bovine grey matter, show another narrower phosphodiester peak possibly from small phospholipid vesicles. This peak is increased in intensity in the affected mice. These experiments demonstrate the presence of three major components contributing to the phosphodiester resonance: bilayer phospholipids, more mobile phospholipids, and the freely soluble cytosolic molecules glycerophosphocholine and glycerophosphoethanolamine. These NMR methods for non-invasive investigation of phospholipid structures in the brain might be extended to studies of patients with membrane involved diseases such as multiple sclerosis.

References (27)

E.P. Kennedy et al.
J. Biol. Chem.
(1956)
M. Barany et al.
Lancet
(1985)
D.J. Hayes et al.
J. Neurol. Sci.
(1985)
P.R. Cullis et al.
Biochim. Biophys. Acta
(1980)
G.R. Bartlett
J. Biol. Chem.
(1959)
J. Seelig
Biochim. Biophys. Acta
(1978)
R. Gonzalez-Mendez et al.
J. Magn. Reson.
(1984)
P.R. Cullis et al.
Biochim. Biophys. Acta
(1977)
G. Hauser et al.
Biochem. Biophys. Res. Comm.
(1971)
G.K. Radda et al.

G.K. Radda et al.

Magn. Reson. Quart.

(1989)

E.P. Kennedy

T. Glonek et al.

J. Neurochem.

(1982)

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Citation Excerpt :
The NMR-visible phospholipid derivatives, glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), were found to contribute to the PDE resonance. Subsequent studies indicated that additional contributions to the PDE spectral profile could arise from broad, field-dependent signals of mobile phospholipid head groups [155–159]. As these phospholipids are involved in the metabolism of phosphatidylserine, the major building block of human cell membranes, these findings triggered interest in investigating human tumors by 31P MRS to find out if the levels of PME and PDE could be used to assess tumor malignancy and response to therapy.
Many years of research and development culminated in the establishment of phosphorous-31 (³¹P) magnetic resonance spectroscopy (MRS) as a powerful tool in the characterization of cancer microenvironment. ³¹P MRS provides vital information on cancer bioenergetics, phospholipid biosynthesis, and pH, which latter is linked to tumor vasculature and oxygen consumption. Changes in cancer microenvironment during tumor progression or in response to therapy will result in changes in these biomarkers, which manifest itself as alterations in the localized ³¹P MR spectrum. Moreover, as the ³¹P MR spectra represent metabolism rather than morphology, changes in tumor microenvironment can be observed at an early stage. Thus, ³¹P MRS localized or imaged (MRSI) to the tumor is a powerful tool in the assessment of tumor therapy response. The combination of magnetic resonance imaging (MRI) with ³¹P MRSI is expected to improve cancer treatment by personalizing therapy and minimizing adverse effects, enabling better patient care. Here, we review state-of-the-art ³¹P MRSI as a noninvasive tool to assess unique relevant biomarkers from cancer in patients in vivo.
Probing phospholipid dynamics by electrospray ionisation mass spectrometry
2007, Progress in Lipid Research
Recent advances in electrospray ionisation mass spectrometry (ESI-MS) have greatly facilitated the analysis of phospholipid molecular species in a growing diversity of biological and clinical settings. The combination of ESI-MS and metabolic labelling employing substrates labelled with stable isotopes is especially exciting, permitting studies of phospholipid synthesis and turnover in vivo. This review will first describe the methodology involved and will then detail dynamic lipidomic studies that have applied the stable isotope incorporation approach. Finally, it will summarise the increasing number of studies that have used ESI-MS to characterise structural and signalling phospholipid molecular species in development and disease.
Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate
2003, Psychiatry Research - Neuroimaging
Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton ¹H-MRS, and a decrease in the β-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus ³¹P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9±2.2; body mass index=22.9±1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both ¹H- and ³¹P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. ¹H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm×2 cm×2 cm) proton MRS PRESS sequence in the left frontal lobe. ³¹P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased β-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (¹H and ³¹P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.
31P-spectroscopy of frontal lobe in schizophrenia: Alterations in phospholipid and high-energy phosphate metabolism
2002, Schizophrenia Research
Studies using ³¹P-magnetic resonance spectroscopy (MRS) reported on abnormalities in frontal lobe metabolism in schizophrenia. The most consistent findings were a reduction in the resonances of phosphomonoesters (PME) and/or increased phosphodiesters (PDE), which are, respectively, the precursors and the metabolites of membrane phospholipids, thus suggesting an accelerated phospholipid metabolism in the disease. Other studies reported increased high-energy phosphates (ATP—adenosine triphosphate and PCr—phosphocreatine) in schizophrenia, reflecting decreased use of energy in the frontal lobe. We investigated 53 schizophrenic patients (DSM-IV) and 35 healthy controls. Eighteen from these patients were drug naı̈ve and the remaining 35 were drug-free for an average of 6 months. Phospholipid metabolism and high-energy phosphates were assessed in the left frontal lobe using ³¹P-MRS. Psychopathological evaluation was done with the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms Rating Scale (NSRS). Neuropsychological evaluation was performed with the Wisconsin Card Sorting Test (WCST), Stroop Test and Wechsler Adult Intelligence Scale. Drug-naı̈ve patients showed reduced PDE in the left frontal lobe compared to controls and to previously medicated patients (p<0.05). No differences among the three groups were found regarding the other spectroscopy parameters. In healthy controls, but not in schizophrenics, a negative (and probably physiological) correlation was found between PME and PDE (p<0.01). In schizophrenic patients, ATP was correlated with negative symptoms and with neuropsychological impairment (p<0.01). The lack of a correlation between PME and PDE, as well as the reduction of PDE in schizophrenia, suggest a disrupted phospholipid metabolism in the disease, albeit on a contrary direction of that reported in literature. The relationships of ATP with negative symptoms and neuropsychological deficit suggest an alteration of energetic demand in the frontal lobe of schizophrenic patients, which is in line with the hypofrontality hypothesis of the disease.
Phospholipid abnormalities in postmortem schizophrenic brains detected by 31P nuclear magnetic resonance spectroscopy: A preliminary study
2001, Psychiatry Research - Neuroimaging
It has been hypothesized that schizophrenia arises from cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism. We have used high resolution, in vitro ³¹P nuclear magnetic resonance (NMR) to characterize the PLs in left frontal cortex (gray matter) of postmortem brain from four schizophrenics and five controls. High resolution ³¹P NMR spectra were obtained in an organic-solvent system to resolve PL classes (headgroups) and in a sodium-cholate, aqueous dispersion system to resolve phosphatidylcholine (PC) molecular species. Multivariate analysis which included the major PC molecular species and phosphatidylinositol (PI) showed a significant difference between schizophrenics and controls. Analysis of specific interactions showed that the PI was significantly higher in the schizophrenic group than in the control group. There were no differences between the two groups for other individual PL classes, or for individual PL subclasses determined by the linkage type at the sn-1 position on glycerol. There was a trend for total PL content to be higher in schizophrenics than in controls. There was no evidence for elevated lysophosphatidylcholine or lysophosphatidylethanolamine in schizophrenia. The intensity of the PC peak representing molecular species with one saturated and one unsaturated (one or two double bonds) acyl chain was higher for the schizophrenic group than for the control group. Although these results are not in complete agreement with previous studies, they support the idea that PL abnormalities occur in the brain in schizophrenia and that fatty acid metabolism may be abnormal.
Molecular insights into neurodevelopmental and neurodegenerative diseases
2000, Brain Research Bulletin
Magnetic resonance spectroscopy (MRS) is a non-invasive physical technique that is routinely used to determine the quantity and structure of organic molecules in solution. Technical advances that have expanded the usefulness of this technique include: (1) high resolution MRS to identify and quantify individual molecules present in complex mixtures of tissue extracts; (2) in vivo MRS techniques to non-invasively monitor metabolites in humans; (3) stucture determination of proteins of moderate size; and (4) improved structure characterization of solids and liquid crystals, such as the detection of phase changes in membranes. The focus of this review is on the first two technical advances mentioned above. The strengths of MRS as a research tool to investigate molecular alterations in disease states include ease of sample preparation, minimum sample manipulation, avoidance of the preparation of derivatives, and the ability to analyze an unfractionated sample. The strengths of MRS in the clinic are its ability to measure neuronal metabolite levels non-invasively in humans and its potential for disease diagnosis, monitoring disease progression, and assessing the efficacy of experimental therapies.

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^∗: Present address: Biological NMR Centre, Department of Biochemistry, University of Leicester, Leicester LE1 7RH, U.K.

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Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism

Abstract

References (27)

J. Biol. Chem.

Lancet

J. Neurol. Sci.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochim. Biophys. Acta

J. Magn. Reson.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Comm.

Magn. Reson. Quart.

J. Neurochem.

Cited by (48)

<sup>31</sup>P MRSI Studies in Patients with Cancer

Probing phospholipid dynamics by electrospray ionisation mass spectrometry

Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate

<sup>31</sup>P-spectroscopy of frontal lobe in schizophrenia: Alterations in phospholipid and high-energy phosphate metabolism

Phospholipid abnormalities in postmortem schizophrenic brains detected by <sup>31</sup>P nuclear magnetic resonance spectroscopy: A preliminary study

Molecular insights into neurodevelopmental and neurodegenerative diseases

Regular paper31P-NMR study of brain phospholipid structures in vivo

Abstract

J. Biol. Chem.

Lancet

J. Neurol. Sci.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochim. Biophys. Acta

J. Magn. Reson.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Comm.

Magn. Reson. Quart.

J. Neurochem.

Regular paper
³¹P-NMR study of brain phospholipid structures in vivo