Chloramphenicol decreases brain glucose utilization and modifies the sleep-wake cycle architecture in rats

We studied the effects of chloramphenicol on brain glucose utilization and sleep-wake cycles in rat. After slightly anaesthetized animals were injected with [18F]fluoro-2-deoxy-D-glucose, we acquired time-concentration curves from three radiosensitive beta microprobes inserted into the right and left frontal cortices and the cerebellum, and applied a three-compartment model to calculate the cerebral metabolic rates for glucose. The sleep-wake cycle architecture was analysed in anaesthetic-free rats by recording electroencephalographic and electromyographic signals. Although chloramphenicol is a well-established inhibitor of oxidative phosphorylation, no compensatory increase in glucose utilization was detected in frontal cortex. Instead, chloramphenicol induced a significant 23% decrease in the regional cerebral metabolic rate for glucose. Such a metabolic response indicates a potential mismatch between energy supply and neuronal activity induced by chloramphenicol administration. Regarding sleep-wake states, chloramphenicol treatment was followed by a 64% increase in waking, a 20% decrease in slow-wave sleep, and a marked 59% loss in paradoxical sleep. Spectral analysis of the electroencephalogram indicates that chloramphenicol induces long-lasting modifications of delta-band power during slow-wave sleep.

The cellular bases of functional brain imaging: evidence for astrocyte-neuron metabolic coupling

Pierre Magistretti, Luc Pellerin

Signals detected with functional brain imaging techniques are based on the coupling between neuronal activity and energy metabolism. Positron emission tomography signals detect blood flow, oxygen consumption and glucose utilization associated with neuronal activity; the degree of blood oxygenation is thought to contribute to the signal detected with functional magnetic resonance imaging, whereas magnetic resonance spectroscopy identifies the spatiotemporal pattern of activity-dependent appearance of metabolic in termediates, such as glucose or lactate. Despite the technological sophistication of these brain imaging techniques, the precise mechanisms and cell types involved in coupling and in generating metabolic signals are still debated. Indeed, given the level of resolution achieved with these brain imaging techniques, it has not been feasible to monitor met abolic fluxes between the highly intermingled neuronal, glial, and vascular elements in the intact brain. This obstacle has been overcome in recent years by using purified cellular preparations of neurons and glia. These approaches have suggested a critical role for astrocytes in coupling neuronal activity to energy metabolism. Indeed, astrocytes possess receptors and reuptake sites for a variety of neurotransmitters, including glu tamate. In addition, astrocytic end-feet, which surround capillaries, are enriched in the specific glucose transporter GLUT-1. These features would be expected to allow astro cytes to sense synaptic activity and to couple it with energy metabolism. During activa tion, glutamate is the predominant neurotransmitter released by modality-specific excitatory pathways to a given cortical area; in vitro and in vivo data support a model in which glutamate would stimulate, during activation, an initial glycolytic processing of blood-borne glucose by astrocytes; this glutamate-dependent process would result in a transient lactate overproduction, followed by a recoupling phase during which lactate would be oxidized by neurons. Such a model is consistent with data recently obtained with functional brain imaging techniques

1997

In Vivo Evidence for Lactate as a Neuronal Energy Source

Renaud Jolivet, Pierre Magistretti

Cerebral energy metabolism is a highly compartmentalized and complex process in which transcellular trafficking of metabolites plays a pivotal role. Over the past decade, a role for lactate in fueling the energetic requirements of neurons has emerged. Furthermore, a neuroprotective effect of lactate during hypoglycemia or cerebral ischemia has been reported. The majority of the current evidence concerning lactate metabolism at the cellular level is based on in vitro data; only a few recent in vivo results have demonstrated that the brain preferentially utilizes lactate over glucose. Using voltage-sensitive dye (VSD) imaging, beta-probe measurements of radiotracer kinetics, and brain activation by sensory stimulation in the anesthetized rat, we investigated several aspects of cerebral lactate metabolism. The present study is the first in vivo demonstration of the maintenance of neuronal activity in the presence of lactate as the primary energy source. The loss of the voltage-sensitive dye signal found during severe insulin-induced hypoglycemia is completely prevented by lactate infusion. Thus, lactate has a direct neuroprotective effect. Furthermore, we demonstrate that the brain readily oxidizes lactate in an activity-dependent manner. The washout of 1-[C-11]L-lactate, reflecting cerebral lactate oxidation, was observed to increase during brain activation from 0.077 +/- 0.009 to 0.105 +/- 0.007 min(-1). Finally, our data confirm that the brain prefers lactate over glucose as an energy substrate when both substrates are available. Using [F-18]fluorodeoxyglucose(FDG) to measure the local cerebral metabolic rate of glucose, we demonstrated a lactate concentration-dependent reduction of cerebral glucose utilization during experimentally increased plasma lactate levels.

2011

Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex

Anne Catherine Clerc, João Miguel das Neves Duarte, Rolf Gruetter, Nathalie Just, Gregor Rainer, Sarah Catherine Sonnay

Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ( math formula, p < 0.001) and in astrocytes by 24% ( math formula, p = 0.007). We further observed linear relationships between VNT and both math formula and math formula. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.