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. We refined the model by developing a method to rapidly analyze specific activities of the brain acyl-CoA pool, the precursor pool for fatty acid incorporation into phospholipids. Chronic lithium, at a brain level considered to be therapeutic in humans with bipolar disorder, did not significantly alter net incorporation rates or turnover of docosahexaenoic acid (DHA) in brain phospholipids. However, chronic lithium decreased the turnover of arachidonic acid (AA) within brain phospholipids by up to 80% and attenuated phospholipase A2 (PLA2) activity. The lack of effect of lithium on DHA recycling and turnover suggests that a target for lithiums therapeutic action is an AA- selective PLA2. Lithium also decreased brain mRNA and protein levels of PLA2. Positron emission tomography (PET) studies were conducted in human subjects consistent with this proposal using [1-11C]AA, to image signal transduction in vivo in humans in health and disease. Initial studies demonstrated clear imaging of brain gray matter areas by tracer, with increased uptake in visual areas associated with activation PLA2-mediated brain. Additionally, initial PET studies showed that [1-11C]palmitate can be used to image neuroplastic phospholipid changes in the human brain, provided that methyl palmoxirate, an inhibitor of mitochondrial beta-oxidation of long chain fatty acids, is first administered. This drug was shown to be safe and an IND has been awarded for its use with PET. We also used our fatty acid model to study brain phospholipid metabolism in rats deprived of DHA for three generations. We could demonstrate in these rats abnormal recycling of this critical fatty acid within brain phospholipids, consistent with reduced performance on maze tests. Additionally, rats with a unilateral lesion of the substantia nigra are considered an animal model for Parkinson disease. In such rats, our fatty acid method combined with quantitative autoradiography demonstrated upregulation of PLA2-mediated cortical signaling involving dopaminergic D2 receptors, on the side ipsilateral to the lesion, consistent with current theories accounting for motor dysfunction in Parkinson disease. In addition, we extended the multicompartmental approach of our fatty acid method to quantify turnover of the myoinositol base in phosphoinositides of cultured mouse cortical neurons. To do this, we quantified uptake of deuterated myoinositol using mass spectrometry, from the tissue culture bath into the cell myoinositol and phophoinositide pools, as a function of time. In intact rodents this myoinositol method should allow comparison of turnover rates of fatty acids and the myoinositol base in phosphoinositides, in relation to neuroplasticity and brain function and activities of both PLA2 and phospholipase C. Finally, based on measurements of phospholipid kinetics, we calculated that phospholipid metabolism in brain consumes at least 25% of the net amount of ATP consumed by the brain as a whole. This high rate of energy consumption argues for very important roles of phospholipids in brain function and structure. - brain,phospholipids,imaging,energy,lithium, phospholipase,signaling,neuroplasticity,positron emission tomography,arachidonic acid - Human Subjects
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