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Role of Phospholipase A2 in the Modulation of Membrane Markers Observed by 1H and 31P MRS in Brain Diseases

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Role of Phospholipase A2 in the Modulation of Membrane Markers Observed by 1H and 31P MRS in Brain Diseases Role of Phospholipase A2 in the Modulation of Membrane Markers Observed by 1H and 31P MRS in Brain Diseases Yvan BOULANGER1, Abdesslem KHIAT1, Martin LABELLE1 1Hôpital Saint-Luc du CHUM, Département de radiologie, Montréal, Qc Canada; Introduction In schizophrenia, the Cho signal has been reported to remain The choline (Cho) signal detected by 1H MRS and the unchanged (6), to decrease (7) or to increase (8). Cerebral 31P MRS phosphomonoester (PME) and phosphodiester (PDE) signals detected has also revealed both increasing and decreasing PDE and PME levels by 31P MRS in the brain arise from several metabolites which are (9, 10). In a recent study, a negative correlation could be established precursors or degradation products of membrane phospholipids. The between the elevation of the PDE levels and the reduction of highly- major constituents of the Cho signal are phosphocholine (PCho) and unsaturated fatty acid concentrations in erythrocyte membranes, glycerophosphocholine (GPCho) and minor contributions are provided confirming the role of PLA2 in that disease (11). by free choline, acetylcholine, cytidine diphosphate choline and Many studies have reported increased Cho levels in brain tumors but betaine. PCho and GPCho are precursor and degradation product, their PDE levels are usually reduced and their PME levels increased respectively, of the membrane phospholipids phosphatidylcholine (12). Measurements of PLA2 activity show a stimulation in tumors (PtdCho), plasmalogen-choline and sphingomyelin-choline (Fig. 1). (13). In that case, the increased Cho is not attributable only to a The PME signal observed by 31P MRS is constituted of PCho but also stimulation of PLA2 activity since the PME signal is increased. It has of phosphoethanolamine and precursors of other phospholipids. been determined that both PCho and phosphoethanolamine GPCho contributes to the PDE signal along with corresponding concentrations are elevated in tumors (12). A stimulation of both degradation products of other phospholipids. phospholipase C (PLC) and phospholipase D (PLD) have been In a recent study on the effects of Cushing´s syndrome on the brain reported in tumor cells (14, 15). In addition, data suggest that the (1), our research group has been able to suggest that a decrease in the phosphorylcholine cytidyltransferase (PChoCT) enzyme could be Cho signal could be explained by an inhibition of phospholipase A2 inhibited, preventing the biosynthesis of PtdCho (12). Therefore, in (PLA2) or phospholipase D by the excessive cortisol production tumors, the increase in Cho levels is still attributable to a perturbation occurring in that disease. This explanation was based on previous of the PtdCho metabolism but in this case, other enzymes and choline reports of phospholipase inhibition by such molecules (2). Numerous transport seem to play a more significant role than PLA2. studies have reported changes in the Cho, PME and PDE signal Discussion intensities and PLA2 activity in various brain diseases. This lead us to Combining the results of 1H MRS, 31P MRS and enzyme assays, it examine the relationship between variations of these membrane has been possible to demonstrate that PLA2, which catalyzes the first markers measured by MRS and phospholipase activity in step of the PtdCho phospholipid breakdown, is one of the main neuropathologies. enzymes contributing to the variation of the Cho signal observed by 1H MRS in brain pathologies. In most cases, the Cho signal is increased due to a stimulated PLA2 activity. When inhibitors of the enzyme are present, such as glucocorticoids, the Cho signal is found to decrease. PLA2 is however not the only enzyme affecting the Cho signal intensity as demonstrated by the brain tumor results. References (1) Khiat, A. et al. (2000) Brain Res. 862, 301-307. (2) Kol, S. et al. (1998) Mol. Cell. Endocrinol. 137, 117-125. (3) Ross, B.D. et al. (1996) Dig. Dis. 14 (Suppl. 1), 30-39. (4) Taylor-Robinson, S.D. et al. (1999) Liver 19, 389-398. (5) Cabré, E. et al. (1992) JPEN J. Parenter. Enteral Nutr. 16, 359- 363. (6) Deicken, R.F. et al. (2000) Am. J. Psychiatry 157, 644-647. (7) Maier, M. et al. (1995) Psychol. Med. 25, 1201-1209. (8) Fujimoto, T. et al. (1996) Biol. Psychiatry 40, 14-18. (9) Pettegrew, J.W. et al. (1991) Arch. Gen. Psychiatry 48, 563-568. (10) Volz, H.P. et al. (1998) Biol. Psychiatry 44, 399-404. (11) Richardson, A.J. et al. (2000) ISMRM Meeting, Denver CO. (12) Podo, F. (1999) NMR Biomed. 12, 413-439. Fig. 1. Metabolic pathways and transport mechanism susceptible (13) Voelkel-Johnson, C. et al. (1996) J. Immunol. 156, 201-207. to affect the intensities of the Cho, PME and PDE MRS signals in (14) Moscat, J. et al. (1989) Biochem. Soc. Trans. 17, 988-991. the brain. (15) Carnero, A. et al. (1994) Oncogene 9, 1387-1395. Methods 1H and 31P MRS data from more than 100 published studies were Table 1. Representative examples of brain disease studies reviewed for 20 major brain diseases showing effects on the brain Cho, PME or PDE signals. Articles reporting changes in PLA2 activity or reporting effects on the Cho, PME and PDE MRS signals and on the activity of other enzymes involved in phospholipid metabolism PLA2 activity caused by these diseases were also reviewed (15 articles). When Cho PME PDE PLA2 Refs. contradictory results were reported, they were considered as equally activity valid. Cushing ↓ ↓ 1, 2 Results syn- Table 1 presents results from selected studies of brain diseases drome where Cho, PME, PDE and PLA2 are affected. Hepatic ↓ ↓ ↓ ↓ 3-5 In hepatic encephalopathy, the Cho signal is reduced (3). If this encepha- reduction is due to an inhibition of the PLA2 enzyme activity, a lopathy reduction of the PDE signal should be measured by 31P MRS and this Schizo- ↓ - ↑ ↓ ↑ ↑ ↓ ↑ 6-11 has indeed been reported (4). Concomitantly, a reduction of the PME phrenia signal is measured, indicating that the phospholipid synthesis is also Brain ↑ ↑ ↓ ↓ 12-15 reduced (4). Additional support for the inhibition of PLA2 is provided tumors by measurements of highly unsaturated fatty acid concentrations in the plasma which are reduced as a result of reduced PLA2 activity (5). Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 998 Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 998 .
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