Prior work from our laboratory has provided the first evidence of a carrier mediated saturable process for the transport of alpha- keto acid analogs of the amino acids across the blood-brain barrier. Our findings indicate that alpha-keto acids share the transport carrier with straight chain monocarboxylic acids and the ketone bodies, acetoacetate and 3-hydroxybutyrate. An general objective that we propose to accomplish is to refine and improve the methods used for analyzing blood-brain barrier transport and inhibition data. We will develop menu-driven computer programs from programs originally developed for the analysis of pharmacological nonlinear dose response curves. These programs will provide for the first time good methods for the rigorous statistical analysis of transport kinetic and inhibition data. Studies will be conducted to assess the transport of alpha-keto acids in the newborn suckling rat since all prior data has been obtained using the adult rat. We are particularly interested in determining if aromatic keto acids will penetrate the barrier of the suckling rat. Other studies will be conducted in the young and adult rat to determine if alpha-hydroxy acid analogs of the amino acids penetrate the barrier and, if so, by what mechanism. We will also fully characterize the kinetics of transport of substrates using the monocarboxylate carrier in the starved animal and in the portacaval shunted rat, conditions which appear to increase and decrease, respectively, the capacity for transport. The role of diet in these alterations will also be studied since our preliminary studies indicate that diet composition may be an important variable. The completion of these studies will place us in the position of having a model carrier system for the blood- brain barrier that may be either induced or repressed. No other blood-brain barrier carrier has been shown to be inducible and repressible for the same substrate. Since a compound that has penetrated the barrier still must be further transported to enter a brain cell and be utilized, we will study the transport of monocarboxylate compounds into the astrocyte, the principal cell type for metabolism of these compounds. A cell culture system has been developed and implemented in the P.I.'s laboratory to carry out these studies. The completion of the studies outlined in this proposal will result in our having the two major transport barriers for monocarboxylate compounds fully characterized and the ability to induce or repress the transport capacity of at least one of them.
| Jerkins, A A; Steele, R D (1988) Diet composition and surgical technique influence the postoperative recovery of portacaval shunted rats. Hepatology 8:855-60 |
