RAPID REGULATION OF NEURITE OUTGROWTH AND RETRACTION BY PHOSPHOLIPASEA(2)-DERIVED ARACHIDONIC-ACID AND ITS METABOLITES

Arachidonic acid and lipoxygenase metabolites have been proposed to ac t as retrograde synaptic messengers and as early mediators of neuronal injury, but few studies have analyzed their roles in controlling neur ite behavior within a time window of minutes to hours. Phospholipase A (2) inhibitors (BPB, ONO-RS-082, quinacrine and AACOCF(3)) and the lip oxygenase inhibitor AA861 delayed the initial outgrowth of NG108-15 ce ll neurites on laminin. Inhibitors of diacylglycerol lipase (RHC 80267 ), cyclooxygenase (indomethacin) and free radicals (N-acetyl cysteine and vitamin E) did not produce similar effects. Phospholipase A(2) and lipoxygenase inhibitors also prevented acute neurite retraction in re sponse to lysophosphatidic acid and eight other agents tested. and dec reased F-actin staining at cell margins. Conversely, exogenous arachid onic acid (1 mu M) enhanced the responses of neurites in outgrowth and retraction assays. Phospholipase A, and lipoxygenase pathways appear to have a general role in maintaining the ability of neurites to respo nd rapidly to external stimuli, possibly via regulating the ability of the cytoskeleton to remodel.