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

Abstract

The rates of uptake and oxidation of [U-(14)C]lactate and [U-(14)C]glucose were determined in primary cultures of astrocytes and neurons from rat brain, in the presence and absence of the monocarboxylic acid transport inhibitor alpha-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 (14)CO(2) 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.

Lactate is a Preferential Oxidative Energy Substrate over Glucose for Neurons in Culture

“…Thus, on this basis, it can be argued that lactate might represent a better oxidative substrate than glucose for neurons, at least in vitro. This conclusion is consistent with numerous other studies performed by measuring CO 2 production on synaptic terminals (McKenna et al, 1993(McKenna et al, , 1994(McKenna et al, , 1998, excised sympathetic ganglia (Larrabee, 1996), brain slices (Fernandez and Medina, 1986;Ide et al, 1969), and cultured neurons (McKenna et al, 2001;Tabernero et al, 1996;Vicario et al, 1991), all of which have shown preferential oxidation of lactate over glucose.…”

Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics

“…Lactate can be used as an oxidative substrate in brain slices (Ide et al, 1969;Fernandez and Medina, 1986), cultured telencephalic neurons (Tabernero et al, 1996;McKenna et al, 2001), aggregated neuronal cultures (Honegger et al, 2002), sympathetic ganglia (Larrabee, 1996), and synaptic terminals (McKenna et al, 1993) and can be preferred to glucose (Bouzier-Sore et al, 2003;Itoh et al, 2003;Smith et al, 2003). In addition, metabolic demands increase neuronal ability to use lactate (Schurr et al, 1999).…”

Glucose is Necessary to Maintain Neurotransmitter Homeostasis during Synaptic Activity in Cultured Glutamatergic Neurons

“…In addition, lactate has been proposed to function as an energy substrate for neurons recovering after glucose deprivation or a hypoxic insult (Fowler, 1993;Schurr et al, 1997a, b, c;Cater et al, 2001). However, much remains controversial and additional experiments seem pertinent to elucidate whether neurons in fact prefer lactate over glucose during synaptic activity (McKenna et al, 2001;Chih et al, 2001a). The present study represents an attempt to shed further light on this important question.…”