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

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Abstract
The rates of uptake and oxidation of [U-14C]lactate and [U-14C]glucose were determined in primary cultures of astrocytes and neurons from rat brain, in the presence and absence of the monocarboxylic acid transport inhibitor α-cyano-4-hydroxycinnamate (4-CIN). The rates of uptake for 1 mM lactate 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 in 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 14CO2 formation from 1 mM lactate 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 neurons, respectively. Incubation with 0.25 mM 4-CIN decreased the oxidation of lactate and glucose to 57.1% and 54.1% of control values in astrocytes and to 13.2% and 41.6% of the control rates in neurons, respectively. Preincubation with 4-CIN further decreased the oxidation of both glucose and lactate. Studies with glucose specifically labeled in the one and six positions demonstrated that 4-CIN decreased mitochondrial glucose oxidation but did not impair the metabolism of glucose via the pentose phosphate pathway in the cytosol. The lack of effect of 4-CIN on glutamate oxidation demonstrated that overall mitochondrial metabolism was not impaired. These findings suggest that the impaired neuronal function and tissue damage in the presence of 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 significantly decrease the oxidative metabolism of pyruvate derived from both glucose and lactate.

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