Modulation of Arachidonate Turnover in Cerebral Phospholipids

Abstract

The effects of the neurotransmitters NE and 5HT on the turnover of AA in cerebral PL were investigated in slices of rat brain cortex. Incorporation of 3[H]-AA into individual PL was first analyzed in accordance with a closed two-compartmental model. Apparent rates of deacylation and reacylation as well as sizes of the metabolically active PL-bound AA pools were calculated. It was found that rates of reacylation of individual PL varied markedly, while deacylation rates remained within a relatively narrow range. The rate of PI acylation was found to be the most rapid, while the rate of PS acylation was the slowest observed. The pool of PL-bound AA that is readily accessible to deacylation-reacylation processes was distributed differentially among the various PL, with more than 50% of this pool in PI; but only 0.75% of the PI content was associated with this pool. Both NE and 5HT enhanced the incorporation of 3[H]-AA into PI in a dose-related manner, while they attenuated its incorporation into other PL. Pharmacological studies indicated that the neurotransmitter effects were not mediated by known NE or 5HT receptors and that a functional presynaptic reuptake system was not required for these effects. The observed effects did not appear to be related to the formation of hydrogen peroxide by the action of MAO on the neurotransmitter. Examination of the structure-activity relationships indicated that the presence of two hydroxyl groups in the aromatic ring was needed for attenuating 3[H]-AA incorporation into PC, whereas an active catechol nucleus with an additional hydroxyl group in the beta position of the side chain appeared to enhance 3[H]-AA incorporation into PI. Results obtained with the phospholipase A-2 inhibitor mepacrine and the acyltransferase inhibitor THC suggest that NE attenuates PL acylation by activating phospholipase A-2, but it concomitantly enhances PI acylation by selectively stimulating a PI-specific arachidonyl transferase via mechanisms that have not yet been elucidated.