of work: A mathematical model was used to derive operational equations for examining incorporation and turnover of fatty acids within individual brain phospholipids under in vivo conditions in animals and humans. In rats, the model was combined with quantitative autoradiography and biochemical analysis to examine these parameters with the saturated palmitic acid (PAM) and the unsaturated arachidonic (AA) and docosahexaenoate acid (DHA). We refined the model by thorough analysis of phospholipid metabolic precursor pools. We applied the model to a number of systems in which membrane homeostasis was acutely or chronically perturbed. Chronic treatment of rats with lithium chloride was shown to alter the metabolism of the three fatty acids in brain phospholipids. Fractionation of brain membranes after arecoline stimulation indicated rapid turnover of DHA in synaptosomes. Manoalide, an irreversible inhibitor of phospholipase A2, prevented the massive arecoline-stimulated increase of radiolabeled AA incorporation into brain phospholipids. The incorporation of radiolabeled AA and DHA showed significant reductions following brain ischemia. Seizures induced in a kindled rat model showed increased incorporation of labeled PAM in specific brain regions. Rates of fatty acid incorporation were shown to be independent of cerebral blood flow. An inhibitor of fatty acid oxidation increased the fraction of labeled PAM that entered brain lipids. We used the model to define radiolabeled fatty acid imaging of the brain by positron emission tomography (PET). [1-11C]fatty acids were synthesized and gave incorporation coefficients in monkeys comparable to those in rats. A PET protocol was initiated on Alzheimers and control subjects using [1-11C] fatty acids.
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