Dietary asparagine and brain development
Newburg, David Stephen
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Dietary asparagine was found to be required for optimal growth in the young rat. To investigate this phenomenon, diets were formulated with L-amino acids so as to contain asparagine, aspartic acid, glutamine and/or glutamic acid in all the possible combinations. These diets were fed to weanling rats for three weeks and, of the four amino acids, only asparagine was found to be essential for optimal growth; this requirement persisted regardless of the presence or absence of any dietary combination of these related amino acids. In selected dietary groups, the unbound asparagine levels were measured in various tissues over an eight-day period: muscle asparagine levels were reduced for asparagine-deprived animals over the entire period studied, while brain levels were decreased only after seven days of dietary depletion; hepatic levels were unaffected by dietary asparagine deprivation. In a related study, animals that were drastically depleted of asparagine showed decreased protein and DNA synthesis in those organs undergoing "hyperplastic" growth (rapid cellular proliferation), suggesting that asparagine may be rate-limiting to protein synthesis during early periods of dietary asparagine deprivation, thus resulting in irreversible deficits in development. The main purpose of the research for this dissertation has been to determine whether asparagine deprivation also affects the developing brain. An improved system for analyzing neutral brain lipids by means of thin-layer densitometry was developed. Perinatal deprivation was tested by feeding dams asparagine-free diets during various phases of pregnancy and lactation. Those dams deprived during the third trimester of pregnancy delivered fewer pups; furthermore, the brain stems of their pups showed decreased levels of protein and cholesterol, indicating decreased cell size and differentiation. Pups whose dams were deprived during the second or third trimester of lactation weighed less, and the chemical composition of their brains was altered. Lower levels of cholesterol and cerebrosides, suggesting a defect in myelination, were seen in the cerebra and cerebella of pups whose dams were deprived in the third week of lactation, and in the cerebella of those whose deprivation began in the second trimester. Pups of dams deprived during lactation had increased resistance to seizures, and a decreased ability to perform in a learning situation was seen in those whose dams were deprived either in the second or third trimester. The maximal behavioral deficits correlated with decreased levels of myelin lipids in the cerebrum and cerebellum of deprived pups. These results indicate that the most severe effects of asparagine deficiency immediately follow the onset of this dietary deprivation. When such deprivation limits the ability of dams to provide for the increased metabolic demands of their offspring, those tissues of the offspring undergoing the most rapid growth are the most severely affected. On the basis of data from other developing organs, a mechanism is postulated whereby such deprivation affects developing brain: asparagine becomes rate-limiting to protein synthesis that may cause impairment of cellular proliferation in both neuronal and glial populations. Decreased glial proliferation results in impaired myelination. Both the altered behavioral parameters and the chemical changes (cerebrosides, cholesterol, DNA and protein) are indicative of functional abnormalities in the central nervous system. Thus a requirement for dietary asparagine in the rat during pregnancy and lactation, as well as during the weanling period, seems evident, and its omission during periods of rapid brain growth can have serious neurological consequences.
PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact firstname.lastname@example.org.Dissertation (Ph.D.)--Boston University.Vita.Bibliography: leaves 107-118.
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