A mathematical model was used to derive equations to examine incorporation into and half-lives of long chain fatty acids within brain phospholipids under in vivo conditions. In rats, the model was combined with quantitative autoradiography and biochemical analysis to examine these parameters with saturated [9,10-3H]palmitic acid ([3H]PAM) and unsaturated [1-14C]arachidonic acid ([14C]AA) and [1-14C]docosahexaenoate acid ([14C]DHA). Kinetic parameters were determined after we developed a method to measure specific activity relative to plasma fatty acid specific activity of brain acyl-CoA, the precursor for incorporation of fatty acids into brain phospholipids. Low values for this dilution factor indicated marked recycling of fatty acids within phospholipids (e.g. half-life of 40 min for arachidonate in phosphatidylinositol). This recycling reflects activity of phospholipase A2 in signal transduction, and could be inhibited by manoalide, a specific inhibitor of this enzyme. Fatty acid incorporation into brain occurs at the level of brain synapses, as shown following fractionation of brain. Ischemia contributes to release of fatty acids and an increased level of arachidonyl-CoA via activation of phospholipases, products which contribute to neuronal death. Chronic sensory deprivation is associated with reduced membrane remodeling and signal transduction, as measured with the fatty acid method. The method was extended to monkeys following the synthesis of fatty acids labeled with carbon-11, and using positron emission tomography (PET).
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