Arachidonic acid is released in brain from the sn-2 position of phospholipids, following the activation of phospholipase A2. Phospholipase A2 is coupled a number of neurotransmitter receptors, and can be activate via G proteins when these receptors are occupied. Arachidonic acid and its bioactive eicosanoids, such as prostaglandins, are important second messengers in the brain rat regulate a large number of functional processes. (1) Both lithium and valproic acid are used to treat patients with bipolar disorder, but the mechanisms of action of these drugs are not understood. Chronically administered valproic acid, an anticonvulsant used to treat bipolar disorder, reduced turnover of arachidonic acid in brain phospholipids of awake rats, and reduced the plasma unesterified arachidonic acid concentration. The reduction of turnover was somewhat smaller than the reduction caused by chronically administered lithium, suggesting that the arachidonic acid cascade is a target for different drugs effective against bipolar disorder. (2) Lithium's reduction of arachidonic acid turnover in rat brain phospholipids was accompanied by its reduced transcription of multiple genes, some of which regulate expression of enzymes in the arachidonic acid cascade. Lithium specifically downregulated gene expression (the mRNA level) of an arachidonate selective cytosolic phospholipase A2 (cPLA2), secondarily reduced the activity and protein levels of cyclooxygenase (COX)-2, and the brain concentration of prostaglandin E2, an arachidonate metabolite produced via COX-2. Although cPLA2 phosphorylation is necessary for its activation, lithium did not alter the fractional phosphorylation of cPLA2, consistent with it only affecting gene transcription of this enzyme. (3) Based on evidence that both lithium and valproic acid target the arachidonic acid cascade, and on other data that n-3 fatty acids which inhibit arachidonic acid metabolism are therapeutic in bipolar disorder, we proposed that inhibitors of COX-2, nonsteroidal anti-inflammatory drugs (NSAIDs) would be therapeutic in bipolar disorder. (4) Brain phospholipid metabolism and kinetics were examine in a phospholipase A2 knockout mouse, as a model for downregulation of the enzyme found with lithium. Arachidonic acid concentrations and turnover rates in the phospholipids were markedly reduced, and compensatory changes were noted in docosahexaenoic acid. (5) It has been postulated that lithium acts in bipolar disorder inhibiting myoinositol monophosphatase, reducing the brain concentration of myoinositol and thus reducing turnover of the phosphatidylinositide cycle. No method is available to measure phosphatidylinositide cycle in vivo to test this hypothesis. As a first step to do this, we developed a method and mathematical model to measure phosphatidylinositide turnover in cultured cortical neurons, using deuterated myoinositol with mass spectrometry. Half-lives of 10 hours for phosphatidylinositol were estimated from the measurements.
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