Glial–neuronal interactions underlying fructose utilization in rat hippocampal slices

Abstract

Although fructose is commonly used as a sweetener, its effects on brain function are unclear. Using rat hippocampal slices, we found that fructose and mannose, like pyruvate, preserve ATP levels during 3-hours of glucose deprivation. Similarly, fructose and mannose restored synaptic potentials (EPSPs) depressed during glucose deprivation. However, restoration of synaptic responses was slow and only partial with fructose. EPSPs supported by mannose were inhibited by cytochalasin B (CCB), a glucose transport inhibitor, but were not inhibited by α-cyano-4-hydroxycinnamate (4-CIN), a monocarboxylate transport inhibitor, indicating that neurons use mannose via glucose transporters. In contrast, both CCB and 4-CIN depressed EPSPs supported by fructose, suggesting that fructose may be taken up by non-neuronal cells through CCB sensitive hexose transporters and metabolized to a monocarboxylate for subsequent use during neuronal respiration. Supporting this possibility, twenty minutes of oxygen deprivation in the presence of fructose resulted in functional and morphological deterioration whereas oxygen deprivation in the presence of glucose or mannose had minimal toxic effects. These results indicate that neuronal fructose utilization differs from glucose and mannose and likely involves release of monocarboxylates from glia.

Metabolic Communication between Astrocytes and Neurons via Bicarbonate-Responsive Soluble Adenylyl Cyclase

“…Lactate leaves astrocytes via monocarboxylate transporter subtypes 1 and 4 (MCT1 and MCT4) and enters neurons via MCT2 (Debernardi et al, 2003; Pierre et al, 2002). To test the hypothesis that neurons take up the extracellular lactate released as a consequence of high [K + ] ext and thus sAC activation, we utilized α-cyano-4-hydroxycinnamate (4-CIN), an MCT inhibitor that is effective at concentrations under 250 μM in selectively blocking neuronal uptake of exogenous or endogenous lactate in rat hippocampal slices (Erlichman et al, 2008; Izumi and Zorumski, 2009; Schurr et al, 1999). At higher concentrations such as 2 mM, 4-CIN has additional effects by inhibiting pyruvate uptake into mitochondria (Halestrap and Armston, 1984; Izumi et al, 1997; Izumi and Zorumski, 2009).…”

“…To test the hypothesis that neurons take up the extracellular lactate released as a consequence of high [K + ] ext and thus sAC activation, we utilized α-cyano-4-hydroxycinnamate (4-CIN), an MCT inhibitor that is effective at concentrations under 250 μM in selectively blocking neuronal uptake of exogenous or endogenous lactate in rat hippocampal slices (Erlichman et al, 2008; Izumi and Zorumski, 2009; Schurr et al, 1999). At higher concentrations such as 2 mM, 4-CIN has additional effects by inhibiting pyruvate uptake into mitochondria (Halestrap and Armston, 1984; Izumi et al, 1997; Izumi and Zorumski, 2009). In brain slices treated with 4-CIN (100 μM), application of 10 mM [K + ] ext significantly increased extracellular lactate (81.0 ± 6.4 μM, n = 5; + 4-CIN: 121.7 ± 7.0 μM, n = 7 p < 0.001; Figure 5A), suggesting that when neuronal lactate uptake is inhibited by 4-CIN, more lactate is free to diffuse out of the brain slice into the superfusate.…”

Specific regions of the brain are capable of fructose metabolism

“…The issue of fructose metabolism by the brain in vivo has been controversial and elusive, despite knowing for over 50 years that fructose can be metabolized by brain tissue from experiments conducted on cultured brain slices (Chain et al, 1969; Izumi and Zorumski, 2009; Stein and Cohen, 1976; Wada et al, 1998). One reason for this confusion is that accessibility of fructose to brain cells has been difficult to quantify.…”

The human brain produces fructose from glucose

“…Why the human brain produces fructose at such high concentrations compared with the plasma remains unclear. In humans, Glut 5, the principal fructose transporter (33), is present predominantly on microglial cells (34,35), raising the possibility that endogenous fructose production in the brain may alter neuronal and glial interactions.…”