National Institute on Aging
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Brain Physiology and Metabolism Section |
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Stanley I. Rapoport, M.D., Chief Senior Investigator |
Overview: The Brain Physiology and Metabolism Section (BPMS) studies brain phospholipid metabolism in intact animals and humans, as well as synaptic integrity and function in aging and Alzheimer's disease. Methods involve in vivo tracer studies, chemical analytical techniques quantitative autoradiography, and positron emission tomography (PET). Studies are related to neuroplasticity and signal transduction, central action of drugs, and nutritional regulation of brain fatty acid metabolism. |
(1) Brain Phospholipid Metabolism in Signal Transduction and Neuroplasticity: Radiolabeled long chain fatty acids are injected intravenously into awake rodents. By mathematical modeling, rates of incorporation into brain phospholipids, recycling and half lives are determined. Short half-lives (minutes to hours) and high turnover rates within brain phospholipids reflect their active participation in signal transduction and membrane modeling. Brain incorporation from plasma of labeled arachidonic acid, an important second messenger, is increased in response to cholinergic and dopaminergic agonists in rat models of Alzheimer's disease (chronic unilateral lesion of nucleus basalis) and Parkinson disease (chronic unilateral lesion of substantia nigra), respectively, reflecting upregulation of phospholipase A2 mediated signal transduction. Upregulated signaling may be imaged in the human brain using positron emission tomography (PET) and [C11]arachidonic, and may help in the early diagnosis and understanding disease mechanisms of neurodegenerative disorders. |
The fatty acid model can elucidate targets for centrally acting drugs with indeterminate modes of action. For example, the model has shown that lithium, used to treat manic depressive (bipolar) disorder reduces turnover of arachidonate within brain phospholipids by 80%, by downregulating gene expression (mRNA level) and enzyme activity of an arachidonic-specific phospholipase A2. Other antibipolar disorder drugs, valproic acid and carbamazepine, have effects like lithium on brain arachidonic acid metabolism, suggesting that this metabolism is a common target for such drugs. With this information, we may design drugs less toxic and with a wider therapeutic window than lithium for treating bipolar disorder. The model has demonstrated that the brain responds to nutritional deficiency of the polyunsaturated essential fatty acid, docosahexaenoic acid, by reducing its turnover and metabolism within brain phospholipids, thus helping to retain it. |
(2) Imaging Signal Transduction in the Human Brain:: In vivo imaging methods involving positron emission tomography (PET) were developed to examine brain blood flow and arachidonic and docosahexaenoic acid metabolism at rest and during activation in healthy subjects in relation to age, and in patients with Alzheimer's disease or chronic alcoholism. An activation, or stress test, was shown to quantify changes in signal transduction in relation to dementia progression in Alzheimer's disease, and to be effective in studying activation involving the fatty acids. |
Investigators: |
Brain Physiology and Metabolism Section Building 9, Room 1S126 9 Memorial Drive, MSC 0947 Bethesda, MD 20892-7511 |
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