Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain

Background Carbamazepine is a mood stabilizer used as monotherapy or as an adjunct to lithium in the treatment of acute mania or the prophylaxis of bipolar disorder. Based on evidence that lithium and valproate, other mood stabilizers, reduce brain arachidonic acid turnover and its conversion via cyclooxygenase to prostaglandin E2 in rat brain, one possibility is that carbamazepine also targets the arachidonic acid cascade. Methods To test this hypothesis, carbamazepine was administered to rats by intraperitoneal injection at a daily dose of 25 mg/kg for 30 days. Results Carbamazepine decreased brain phospholipase A2 activity and cytosolic phospholipase A2 protein and messenger RNA levels without changing significantly protein and activity levels of calcium-independent phospholipase A2 or secretory phospholipase A2. Cyclooxygenase activity was decreased in carbamazepine-treated rats without any change in cyclooxygenase-1 or cyclooxygenase-2 protein levels. Brain prostaglandin E2 concentration also was reduced. The protein levels of other arachidonic acid metabolizing enzymes, 5-lipoxygenase and cytochrome P450 epoxygenase, were not significantly changed nor was the brain concentration of the 5-lipoxygenase product leukotriene B4. Conclusions Carbamazepine downregulates cytosolic phospholipase A2-mediated release of arachidonic acid and its subsequent conversion to prostaglandin E2 by cyclooxygenase. These effects may contribute to its therapeutic actions in bipolar disorder.