alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: Implications for lactate as an energy substrate for neurons

The rates of uptake and oxidation of [U-C-14] lactate and [U-C-14]glucose w ere determined in primary cultures of astrocytes and neurons from rat brain , in the presence and absence of the monocarboxylic acid transport inhibito r alpha -cyano-4-hydroxycinnamate (4-CIN). The rates of uptake for 1 mM lac tate and glucose were 7.45 +/- 1.35 and 8.80 +/- 1.0 nmol/30 sec/mg protein in astrocytes and 2.36 +/- 0.19 and 1.93 +/- 0.16 nmol/30 sec/mg protein i n neuron cultures, respectively. Lactate transport into both astrocytes and neurons was significantly decreased by 0.25-1.0 mM 4-CIN; however, glucose uptake was not affected. The rates of (CO2)-C-14 formation from 1 mM lacta te and glucose were 12.49 +/- 0.77 and 3.42 +/- 0.67 nmol/ hr/mg protein in astrocytes and 29.32 +/- 2.81 and 10.04 +/- 1.79 nmol/hr/mg protein in neu rons, respectively. Incubation with 0.25 mM 4-CIN decreased the oxidation o f lactate and glucose to 57.1% and 54.1% of control values in astrocytes an d to 13.2% and 41.6% of the control rates in neurons, respectively. Preincu bation with 4-CIN further decreased the oxidation of both glucose and lacta te. Studies with glucose specifically labeled in the one and six positions demonstrated that 4-CIN decreased mitochondrial glucose oxidation but did n ot impair the metabolism of glucose via the pentose phosphate pathway in th e cytosol. The lack of effect of 4-CIN on glutamate oxidation demonstrated that overall mitochondrial metabolism was not impaired. These findings sugg est that the impaired neuronal function and tissue damage in the presence o f 4-CIN observed in other studies may be due in part to decreased uptake of lactate; however, the effects of 4-CIN on mitochondrial transport would si gnificantly decrease the oxidative metabolism of pyruvate derived from both glucose and lactate. (C) 2001 Wiley-Liss, Inc.