The proposed research is aimed at examining the hypothesis that several pathways of brain metabolism in developing animals are linked to nutrient availability in brain. Cerebral nutrient supply is a function of substrate transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). These studies propose to quantitate developmental modulations of both BBB transport and brain metabolism of amino acids (leucine, arginine, ornithine), choline, adenosine, lactate and glucose in newborn and suckling rats and rabbits. We hypothesize (i) that brain protein synthesis may be linked to leucine oxidation, (ii) that polyamine production in brain is regulated by BBB transport of ornithine (or arginine), (iii) that brain conversion of choline to lecithin, or adenosine to AMP, is linked to cerebral precursor availability, and (iv) that circulating lactate is an important carbon source in neonatal hypoglycemia. The present work raises the question: should nutrients such as ornithine, choline, adenosine, or lactate, be considered essential nutrients, i.e., blood-derived nutrients, for the developing brain under certain conditions? If so, the proposed studies may provide the rationale for monitoring plasma levels of these nutrients in developing humans. The major methodologies utilized will be (i) the carotid injection technique to both quantitate the Michaelis-Menten kinetics of BBB nutrient transport and to pulse label the brain for metabolic studies, (ii) HPLC and other chromatographic separations of microwave-fixed brain homogenates, and (iii) mathematical modeling procedures using compartmental analysis, or when necessary, non-compartmental methods for data analyses. An added benefit of the proposed studies is that the compartmental analyses are similar in form to clinical investigations of brain metabolism using posicron emission tomography (PET). Therefore, the proposed studies are likely to provide basic scientific information useful for clinical PET studies.
