The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A2 knockout mouse

We examined brain phospholipase A(2) (PLA(2)) activity and the expression of enzymes metabolizing arachidonic acid (AA) in cytosolic PLA(2) knockout (cPLA(2)(-/-)) mice to see if other brain PLA(2) can compensate for the absence of cPLA(2) alpha and if cPLA(2) couples with specific downstream enzymes in the eicosanoid biosynthetic pathway. We found that the rate of formation of prostaglandin E-2 (PGE(2)), an index of net cyclooxygenase (COX) activity, was decreased by 62% in the cPLA(2)(-/-) compared with the control mouse brain. The decrease was accompanied by a 50-60% decrease in mRNA and protein levels of COX-2, but no change in these levels in COX-1 or in PGE synthase. Brain 5-lipoxygenase (5-LO) and cytochrome P450 epoxygenase (cyp2C11) protein levels were also unaltered. Total and Ca2+-dependent PLA(2) activities did not differ significantly between cPLA(2)(-/-) and control mice, and protein levels of type VI iPLA(2) and type V sPLA(2), normalized to actin, were unchanged. These results show that type V sPLA(2) and type VI iPLA(2) do not compensate for the loss of brain cPLA(2) alpha, and that this loss has significant downstream effects on COX-2 expression and PGE(2) formation, sparing other AA oxidative enzymes. This suggests that cPLA(2) is critical for COX-2-derived eicosanoid production in mouse brain.