Arachidonic acid and the brain

Abstract

Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A(2) (PLA(2)) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA(2) or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA(2) were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA(2) and COX-1 expression, whereas AA-selective cPLA(2), sPLA(2), and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.

Figures

FIGURE 1

Model of brain AA cascade. AA, found at the sn-2 position of a phospholipid, is liberated by activation (star) of PLA2 at the synapse. A fraction of the liberated AA is converted to bioactive eicosanoids. The remainder diffuses to the endoplasmic reticulum while bound to a fatty acid binding protein (FABP), from where it is converted to arachidonoyl-CoA by acyl-CoA synthetase with the consumption of 2 ATP, then reesterified by an acyltransferase. Unesterified AA in the endoplasmic reticulum exchanges freely and rapidly with unesterified nonprotein-bound unesterified AA in plasma, into which labeled AA (AA*) has been injected. Equations for calculating incorporation coefficients k*, rates Jin, and turnover of AA are shown in right lower corner. Adapted from Rapoport and Bosetti (26).

FIGURE 2

Prolongation of DHA half-life in brain by dietary (n-3) PUFA deprivation. [4,5-3H]DHA was injected into the brain after deprivation for 15 wk, and radioactivity from the tracer was followed in phospholipids for 60 d, from which half-lives t½ were calculated. Jloss was calculated from half-lives as illustrated in the figure. The deprivation prolonged the DHA half-life from 33 to 90 d. Adapted from DeMar et al. (14).

FIGURE 3

Fifteen weeks of dietary (n-3) PUFA deprivation decreased rat frontal cortex iPLA2 and COX-1 protein but increased sPLA2, cPLA2, and COX-2 protein. Protein measured relative to actin. Adapted from Rao et al. (25).

FIGURE 4

Horizontal brain images of incorporation coefficients k* for DHA and AA in healthy human volunteers, obtained with PET. Values of k* are corrected for partial volume errors. Plasma concentration of unesterified DHA was 2.63 ± 1.17 μmol/L for left scan; of unesterified AA, 3.8 ± 1.7 μmol/L for right scan. Rates of whole-brain daily consumption are given in the inset. Adapted from J. C. Umhau, W. Zhou, R. E. Carson, S. I. Rapoport, A. Polozova, J. Demar, N. Hussein, A. K. Bhattacharjee, K. Ma, G. Esposito, S. Majchrzak, P. Herscovitch, W. C. Eckelman, K. A. Kurdziel, and N. Salem, Jr, unpublished material and Giovacchini et al. (30).