Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats

Neurological dysfunction is common in patients with maple syrup urine disea se (MSUD). However, the mechanisms underlying the neuropathology of this di sorder are poorly known. In the present study. we investigated the effect o f acute hyperleucinemia on plasma and brain concentrations of amino acids. Fifteen-day-old rats were injected subcutaneously with 6 mu mol L-leucine p er gram body weight. Controls received saline in the same volumes. The anim als were sacrificed 30-120 min after injection, blood was collected and the ir brain rapidly removed and homogenized. The amino acid concentrations wer e determined bq HPLC using orthophtaldialdehyde for derivatization and fluo rescence for detection. The results showed significant reductions of the la rge neutral amino acids (LNAA) L-phenylalanine, t-tyrosine, L-isoleucine, L -valine and L-methionine, as well as L-alanine, L-serine and L-histidine in plasma and of L-phenylalanine, L-isoleucine, L-valine and L-methionine in brain, as compared to controls. In vitro experiments using brain slices to study the influence of leucine on amino acid transport and protein synthesi s were also carried out. L-Leucine strongly inhibited [C-14]-L-phenylalanin e transport into brain, as well as the incorporation of the [C-14]-amino ac id mixture. [C-14]-L-phenylalanine and [C-14]-L-lysine into the brain prote ins. Although additional studies are necessary to evaluate the importance o f these effects for MSUD, considering previous findings of reduced levels o f LNAA in plasma and CSF of MSUD patients during crises, it may be speculat ed that a decrease of essential amino acids in brain may lead to reduction of protein and neurotransmiter synthesis in this disorder. (C) 2001 Elsevie r Science Ltd. All rights reserved.