INCREASED KYNURENIC ACID LEVELS AND DECREASED BRAIN KYNURENINE AMINOTRANSFERASE-I IN PATIENTS WITH DOWN-SYNDROME

Excitatory amino acid (EAA) receptors are central to brain physiology and play important roles in learning and memory processes. Kynurenic a cid (KYNA), a metabolite of tryptophan in the brain blocks all three c lassical ionotropic EAA receptors and also serves as an antagonist at the glycine site associated with the N-methyl-D-aspartate receptor (NM DA) complex. We measured the endogenous levels of KYNA and activities of KYNA synthesizing enzymes kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal and temporal c ortex of elderly Down syndrome (DS) patients (aged 46-69 years). Compa red with control specimens (0.21+/-0.06 pmol/mg tissue), the measureme nt of KYNA content revealed a significant 3-fold increase in frontal c ortex of DS patients (0.67+/-0.13 pmol/mg tissue; p less than or equal to 0.01). In temporal cortex KYNA levels were increased by 151% (p le ss than or equal to 0.05) of control (0.41+/-0.09 pmol/mg tissue) Usin g crude cell free homogenate KAT's activities were determined in the p resence of the 1 mM 2-oxoacid as a co-substrate at their pH optima of 10.0 for KAT I and 7.4 for KAT II. KATs activities in the presence of 1 mM pyruvate were 2.79+/-0.52 and 4.55+/-1.98 pmol/mg protein/h for K AT I and 0.98+/-0.07 and 1.09+/-0.14 pmol/mg protein/h for KAT II in f rontal cortex and temporal cortex, respectively. When compared with th e brain samples of controls the activity of KAT I was reduced in front al cortex (9.8+/-2.4%; p less than or equal to 0.01) and temporal cort ex (25.8+/-6.4%) of DS patients, while KAT II levels were within the n ormal range. Measurement of the neuronal, cholinergic marker choline a cetyltransferase (ChAT) in the frontal cortex, revealed a significant reduction (36.6+/-4.3% of control; p less than or equal to 0.01) in DS . Our data demonstrate the involvement of KYNA-metabolism in the cellu lar mechanisms underlying altered cognitive function in patients with DS. Although the localisation of both, KAT I and KAT II is not stated yet the reduction of KAT I may suggest impairment of KYNA metabolism i n neuronal and/or nonneuronal compartments.