OMEGA-3 FATTY ACIDS AND THE CEREBRAL CIRCULATION
Principal Investigator: EARL ELLIS
Abstract: Epidemiologic research and laboratory investigations have led others to propose that the omega-3 (n-3 fatty acids in fish oil reduce the incidence of coronary heart disease. The same epidemiologic studies suggests that populations consuming increased amounts of n-3 fatty acids also have increased cerebrovascular disease. Our objective is to determine whether dietary enrichment with n-3 fatty acids affects the brain circulation. The n-3 fatty acids are known to affect platelet cyclooxygenase metabolism of arachidonic acid (AA), resulting in decreased formation of thromboxane A2, which is pro-aggregatory and a vasoconstrictor. Some evidence suggests that fish oils also alter formation of the vasodilator prostaglandins (PGs) E2 and I2. The brain and brain microvessels form these dilator PGs and their formation can be stimulated by acetylcholine, bradykinin, and hypoxia plus hypercapnia. In the neonatal animal, inhibition of PG formation reduces cerebral blood flow and compromises the ability of the brain to increase blood flow in response to hypoxia plus hypercapnia. PG inhibition also reduces intraparenchymal hemorrhage in premature infants and decreases free radical damage to cerebral arterioles following brain injury in animals. Our pilot data suggest the that n-3 fatty acid eicosapentaenoic acid (EPA) is metabolized by brain tissue and that it produces less arteriolar dilation compared to AA. Also, another n-3 fatty acid, docosahexaenoic acid (DHA), does not itself affect cerebral arteriolar diameter but does reduce dilation produced by EPA and AA. These findings, along with the previous literature concerning prostaglandins and the cerebral circulation, suggest that dietary n-3 modification of the arachidonic acid cascade in the brain or brain vasculature may alter the response of the brain circulation to normal or pathophysiologic challenges. We wish to test the hypothesis that long term dietary enrichment with n-3 fatty acids alters in vivo platelet aggregation, prostaglandin formation and cyclooxygenase-dependent microvascular reactivity in the brain. Another hypothesis we will examine is that brain and brain microvessels can metabolize the n-3 fatty acids EPA and DHA by the cyclooxygenase and lipoxygenase enzyme system. To test these hypotheses we will employ acute and chronic cranial windows in rabbits, which allow microscopic assessment of reactivity and the collection of CSF for PG analysis by RIA. In vivo aggregation will be examined in mice using a microscope and the light plus dye technique to induce platelet aggregation. Metabolism in brain slices and isolated cortical microvessels will be studied with the use of radiolabeled tracers, HPLC and GC/MS. These studies will provide a basis for determining if n-3 fatty acids have potentially beneficial effects or may exacerbate undesirable phenomena in the brain vasculature. The proposed aims are consistent with our long term goal of understanding how polyunsaturated fatty acids affect brain function and brain blood flow.
Funding Period: 1988-12-01 - 1994-11-30
more information: NIH RePORT