Upsala journal of medical sciences. Supplement最新文献

The brain has generally been viewed as an organ resistant to structural changes induced by exogenous factors. Research has shown, however, that the brain responds to changes in diet by altering neurotransmitter synthesis thereby shifting neuroendocrine controls over a variety of physiological events. Research from our lab utilizing an animal model indicates that the fatty acid constituents and synthesis of brain structural lipid in membranes undergoing turnover can be altered by changing the composition of dietary fat. The balance of n-6 to n-3 fatty acid fed influences brain phospholipid fatty acid composition, phosphatidylethanolamine methyltransferase activity and rate of phosphatidylcholine biosynthesis via the CDP-choline pathway. It may be concluded that biosynthetic control mechanisms regulating synthesis of brain structural lipid, in particular phosphatidylcholine, respond to exogenous factors and represent a normal physiological response by the brain. This response may conceivably be used as a mechanism for therapeutic treatment of disorders involving degeneration of brain structural lipid.

An in vivo labeling procedure was used to probe the dynamic turnover of mouse brain phospholipids and to evaluate the response of these phospholipids toward decapitation ischemic insult. Within 4 hr after intracerebral injection of [32P]-ATP, the label was effectively incorporated into all phospholipids and uniquely in all subcellular membrane fractions examined. With respect to age, synaptosomes isolated from the 27-month-old mice group showed a higher incorporation of label into polyphosphoinositides and phosphatidic acids and a lower incorporation into the neutral phospholipids than the 10-month-old group. The increase in labeling of these phospholipids with age seems to reflect the increase in basal level of substrates for phosphorylation of phosphoinositol 4-phosphate and diacylglycerols. The increase in substrate level is probably related to a decrease in metabolic turnover of the lipids underlying the phosphoinositide cycle. Decapitation ischemic insult is known to result in a rapid time-dependent breakdown of the polyphosphoinositides in brain. However, a comparison of the ischemia-induced breakdown of polyphosphoinositide between the 10 and 27 month-old groups did not reveal obvious age differences in the rate of their disappearance.

Ethanol interacts with brain cell membranes because of its lipid solubility. This perturbation alters the biophysical properties of the membranes. During chronic ethanol treatment, the cell membranes become resistant to the perturbing effects of ethanol, suggesting changes in the lipid composition. The most consistently found effect on lipid composition after chronic ethanol exposure has been an increase in oleic acid proportions of glycerophospholipids. There are also different changes in specific glycerophospholipids. The polyunsaturated fatty acids, docosahexaenoic acid in phosphatidylserine and arachidonic acid in phosphatidylethanolamine, were decreased. On the other hand, in phosphatidylcholine the saturated fatty acid palmitic acid was decreased after chronic ethanol exposure. Other changes found in brain after ethanol exposure are increased concentrations of acidic phospholipids and formation of abnormal phospholipids in which ethanol itself is a part of the molecule. Some of the changes found may be a result of adaptive mechanisms occurring in order to counteract the different biophysical effects of ethanol.

Docosahexaenoic acid (DHA), the major biosynthetic product of the omega-3 family of fatty acids, is uniquely concentrated in the retina and synaptic membranes. In the perinatal period of life, when the bulk of synaptogenesis and photoreceptor biogenesis takes place, large requirements of DHA may be met first by the placenta and then by maternal milk. Linolenic acid (LLA), the precursor of DHA, is the most prevalent fatty acid of the omega-3 series in the stomach contents of newborn mice. In this study we have investigated the fate of radiolabeled LLA and DHA injected intraperitoneally in developing postnatal mouse. Our results show that radiolabeled LLA was taken up by the liver and DHA was synthesized; at 72 hrs post-injection about 90% of the label had been converted to DHA. Since there was a time-dependent buildup of radiolabeled DHA in blood plasma with negligible early uptake of LLA by the brain and retina, we hypothesize that the liver may secrete lipoproteins containing DHA and that this process is regulated by the nervous tissue.

The epidemiological and biochemical evidence supporting a role of dietary lipids in Multiple Sclerosis is reviewed. The published controlled trials of omega six Polyunsaturated Fatty Acids including 172 patients with Acute Remitting Multiple Sclerosis are discussed and the results of recent study with omega three Polyunsaturated Fatty Acids in a Double Blind controlled study involving 312 patients are presented. It appears that there is a trend suggesting that the addition of omega six and omega three Polyunsaturated Fatty Acids to the diet of patients with Multiple Sclerosis results in a reduction of the severity and frequency of relapses and in a mild overall benefit in a two year period.

Increased platelet membrane fluidity, as determined by the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH), appears to be a stable, inherited trait that identifies a prominent subgroup of patients with Alzheimer's disease with distinct clinical features. Evidence bearing on the clinical and biological significance of this genetic source of clinical heterogeneity in Alzheimer's disease is presented.

THE CHEMISTRY OF THE BRAIN: The brain and nervous system is characterised by a heavy investment in lipid chemistry which accounts for up to 60% of its structural material. In the different mammalian species so far studied, only the 20 and 22 carbon chain length polyenoic fatty acids were present and the balance of the n-3 to n-6 fatty acids was consistently 1:1. The difference observed between species, was not in the chemistry but in the extent to which the brain is developed. This paper discusses the possibility that essential fatty acids may have played a part in it evolution. THE ORIGIN OF AIR BREATHING ANIMALS: The first phase of the planet's existence indulged in high temperature reactions in which oxygen combined with everything feasible: from silicon to make rocks to hydrogen to make water. Once the planet's temperature dropped to a point at which water could condense on the surface allowing chemical reactions to take place in it. The atmosphere was at that time devoid of oxygen so life evolved in a reducing atmosphere. Oxygen was liberated by photolysis of water and as a by-product of the blue-green algae through photosynthesis. When the point was reached at which oxidative metabolism became thermodynamically possible, animal life evolved with all the principle phyla establishing themselves within a relatively short space of geological time. (Bernal 1973). DHA and nerve cell membranes DHA AND NERVE CELL MEMBRANES: From the chemistry of contemporary algae it is likely that animal life evolved in an n-3 rich environment although not exclusively so as smaller amounts of n-6 fatty acids would have been present. A key feature of the first animals was the evolution of the photoreceptor: in examples of marine, amphibian and modern mammalian species, it has been found to use docosahexaenoic acid (DHA) as the principle membrane fatty acid in the phosphoglycerides. It is likely that the first animals did so as well. Coincidentally, the synaptic membranes involved in signal transduction also use high proportions of n-3 fatty acids. However, the n-6 fatty acids also find a place, in the inositol phosphoglyceride (IPG) which appears to be involved with calcium ion transport and hence signal activation and reception. Even in the photoreceptor, the IPG is an arachidonic acid rich phosphoglyceride. THE EVOLUTION OF MAMMALS AND THE LARGE BRAIN: The dominance of n-3 fatty acids in the food chain, persisted until the end of the Cretaceous period when the flowering plants followed on the disappearance of the giant cycads and ferns. A new set of species, the mammals, then evolved with a requirement for n-6 fatty acids for reproduction. This dependance was coincident with the flowering plants which for the first time produced protected seeds: these introduced a rich source of n-6 fatty acids. The brain size of the mammals tended to be relatively larger (that is in relation to body size) by comparison with the previous reptilian or egg laying systems. Thi

Saturated and monounsaturated fatty acids are mainly synthetized in the brain, but some of them could originate from the diet; in contrast polyunsaturated fatty acids are derived from dietary linoleic and linolenic acid. Saturated fatty acid biosynthesis occurs via three main pathways in mammalian cells. One is de novo synthesis of fatty acids from acetyl-CoA via malonyl-CoA; this system has been isolated in soluble form (the soluble system) from various animal tissues including brain. The second and third pathways involve elongation: in the mitochondrial system, acetyl CoA is the principal substrate in extracts from all organs, even brain; in the microsomal system, however, malonyl-CoA acts as donor of the 2 carbon fragments. In vivo studies in brain have shown that very long chain fatty acids are synthesized by elongation rather than by a than by a de novo mechanism. Feeding animals with oils that have a low n-3 acid content (linolenic series) results in all brain cells and organelles reduced amounts of 22:6 n-3 which is compensated for by an increase in 22:5 n-6. The speed of recuperation from these anomalies is extremely slow for brain cells, organelles and microvessels, in contrast with other organs. Essential fatty acids for the brain could be those with very long chains as shown with cell culture. They are probably synthesized in the liver from linolenic acid. They can also be supplied directly by food. During the period of cerebral development there is a linear relation between the n-3 acid content of the brain and that of food until linolenic acid represents approx. 200 mg per 100 g of food (for 1200 mg linoleic acid). A decrease in acids of the linolenic series in the membranes results in a 40% reduction of Na-K-ATPase in nerve terminals and a 20% reduction in 5'-nucleotidase in whole brain homogenate. A diet low in linolenic acid leads to anomalies in the electroretinogram which disappear partially with age, it seriously affects learning tasks. The presence of linolenic acid in the diet confers a greater resistance to certain neurotoxic agents.