Eugene L. Roberts

Energy Substrates for Neurons during Neural Activity: A Critical Review of the Astrocyte-Neuron Lactate Shuttle Hypothesis

Glucose had long been thought to fuel oxidative metabolism in active neurons until the recently proposed astrocyte-neuron lactate shuttle hypothesis (ANLSH) challenged this view. According to the ANLSH, activity-induced uptake of glucose takes place predominantly in astrocytes, which metabolize glucose anaerobically. Lactate produced from anaerobic glycolysis in astrocytes is then released from astrocytes and provides the primary metabolic fuel for neurons. The conventional hypothesis asserts that glucose is the primary substrate for both neurons and astrocytes during neural activity and that lactate produced during activity is removed mainly after neural activity. The conventional hypothesis does not assign any particular fraction of glucose metabolism to the aerobic or anaerobic pathways. In this review, the authors discuss the theoretical background and critically review the experimental evidence regarding these two hypotheses. The authors conclude that the experimental evidence for the ANLSH is weak, and that existing evidence and theoretical considerations support the conventional hypothesis.

Do active cerebral neurons really use lactate rather than glucose

Glucose has long been considered the substrate for neuronal energy metabolism in the brain. Recently, an alternative explanation of energy metabolism in the active brain, the astrocyte-neuron lactate shuttle hypothesis, has received attention. It suggests that during neural activity energy needs in glia are met by anaerobic glycolysis, whereas neuronal metabolism is fueled by lactate released from glia. In this article, we critically examine the evidence supporting this hypothesis and explain, from the perspective of enzyme kinetics and substrate availability, why neurons probably use ambient glucose, and not glial-derived lactate, as the major substrate during activity.

Depth profile of local oxygen tension and blood flow in rat cerebral cortex, white matter and hippocampus

Microregional oxygenation and blood flow were measured in rat cerebral cortical lamina, subcortical white matter and hippocampus. This was done to examine relationships between oxygenation and blood flow at a local level, to determine effects of craniotomy, and to consider whether flow/oxygenation relationships might be predictive of selective vulnerability known to accompany anoxia or ischemia. Blood flow and oxygen tension were measured with closely apposed polarographic microelectrodes. Oxygen tension was highest in white matter, lower in the region of cortical laminae IV-V and lowest in the hippocampus. Blood flow in the hippocampus was higher than that in white matter or laminae IV-V of cerebral cortex. Ratios of blood flow to oxygenation were similar throughout the cortex, higher in white matter but oxygenation in hippocampus was significantly less than expected from measurement of hippocampal blood flow reflecting increased oxygen consumption or relative hypoxia due to increased diffusion distances for oxygen in hippocampus. Comparison of data from closed vs opened skull animals indicated that diffusion of oxygen and hydrogen influenced data to approximately 1000 micron below the cerebral surface.

Calcium-sensitive recovery of extracellular potassium and synaptic transmission in rat hippocampal slices exposed to brief anoxia

We examined the possibility that Ca2+-sensitive inhibition of synaptic transmission following anoxia involves compromise of ion transport activity. Rat hippocampal slices were superfused with artificial cerebrospinal fluids containing different concentrations of CaCl2, and subjected to short anoxia. Durations of anoxia were sufficient to provoke anoxic depolarization, indicated by a sudden rise in extracellular K+ (K+o). Following anoxia, apparent K+ transport was assessed by measuring the magnitude of subnormal K+o (the K+o undershoot) in hippocampal region CA1. Recovery of synaptic transmission 1 h after anoxia was determined by evaluation of the magnitudes of the orthodromically stimulated population spike recorded from CA1 pyramidal cells. K+o undershoots and recovery of synaptic transmission decreased as CaCl2 or the duration of anoxic depolarization increased. These data suggest: (1) that increased artificial cerebrospinal fluid CaCl2 compromised K+ reaccumulation after anoxia; and (2) that ion transport dysfunction may inhibit recovery of synaptic transmission.

The Influence of Age on pH Regulation in Hippocampal Slices Before, During, and After Anoxia

Changes in intracellular and extracellular pH may influence the vulnerability of brain tissue to anoxic or ischemic damage. In the present study, we investigated whether the increased vulnerability of aged brain tissue to anoxic damage is associated with age-related alterations in pH regulation. We obtained evidence for altered pH regulation by measuring concurrent changes in intracellular and extracellular pH before, during, and after anoxia in hippocampal slices from young adult (6–8 months old) and aged (24–27 months old) rats. We found indications of impaired pH regulation in aged hippocampal slices (a) before anoxia, as seen in a lower resting intracellular pH, (b) during anoxia, as seen in a slower decline in extracellular pH, and (c) during recovery after anoxia, as seen in a slower rate of recovery of intracellular pH. Age-related changes in pH regulation may contribute to the faster onset of anoxic depolarization in aged brain tissue during anoxia.

Age-related alterations in energy metabolism contribute to the increased vulnerability of the aging brain to anoxic damage.

Aging increases the vulnerability of brain tissue to anoxia and ischemia. We investigated whether age-related alterations in energy metabolism underlie this increased vulnerability. Energy metabolism was manipulated in hippocampal slices from Fischer 344 rats of ages 6-9 (young adult), 16-19 (middle-aged adult), and 26-29 (aged adult) months by altering glucose concentrations or by using lactate instead of glucose as the metabolic substrate. Extracellular K+ activity (K+o) and synaptic excitability were monitored in stratum pyramidale of hippocampal subfield CA1. Aging diminished how well increasing concentrations of glucose delayed onset of anoxic depolarization and improved postanoxic recovery of K+o homeostasis and synaptic transmission. Hippocampal slices from all age groups responded to anoxia similarly when lactate was present instead of glucose. Also, no age-related differences were seen in normoxic ATP and phosphocreatine levels. These results suggest that an age-related decline in the glycolytic capacity of brain cells contributes to earlier onset of anoxic depolarization and poorer recovery of ion homeostasis and synaptic transmission in aging brain tissue.

Ethnic Differences in Carotid Artery Diameter and Stiffness: The Northern Manhattan Study

OBJECTIVE Race/ethnic differences in carotid arterial function and structure exist among those with cerebrovascular disease, but whether differences persist among healthy populations is unknown. Our objective was to investigate differences in carotid artery diameter and stiffness between race/ethnic groups, and examine whether these race/ethnic differences were age-dependent. METHODS Carotid diameters were assessed by B-mode ultrasound among 1536 participants from the Northern Manhattan Study (NOMAS), and carotid stiffness metrics were calculated. We used multivariable linear regression models to determine the relationship between race/ethnicity and both carotid arterial stiffness and carotid diastolic diameter. RESULTS Mean participant age was 70 ± 9 years (Hispanics = 68 ± 8, blacks = 72 ± 9, and whites = 74 ± 9, p < 0.0001). Mean DDIAM was 6.2 ± 1.0mm (Hispanics = 6.2 ± 0.9 mm, blacks = 6.3 ± 1.0 mm, and whites = 6.3 ± 1.0 mm, p < 0.005) and mean STIFF was 8.7 ± 6.3 (Hispanics = 8.5 ± 5.7, blacks = 9.2 ± 6.2 and whites = 8.9 ± 6.9, p < 0.02). In a model that adjusted for sociodemographics and vascular risk factors including hypertension, diabetes, dislipidemia, renal function, physical acticity and a history of known coronary artery diseases; age was positively associated with greater DDIAM in Hispanics (p < 0.0001) but not among blacks or whites. Older age was associated with greater stiffness among Hispanics (p < 0.0001) and blacks (p < 0.003), but not among whites. CONCLUSIONS We found race/ethnic differences in the association between age and arterial stiffness and diameter, including age-dependent arterial dilation observed in Hispanics that was not observed among blacks or whites.

Comparison of glucose and lactate as substrates during NMDA-induced activation of hippocampal slices

It has been postulated that lactate released from astrocytes may be the preferred metabolic substrate for neurons, particularly during intense neuronal activity (the astrocyte-neuron lactate shuttle hypothesis). We examined this hypothesis by exposing rat hippocampal slices to artificial cerebrospinal fluid containing either glucose or lactate and either N-methyl-D-aspartate, which activates neurons without stimulating astrocytic glucose uptake, or alpha-cyano-4-hydroxycinnamate, which blocks monocarboxylate transport across plasma and mitochondrial membranes. When exposed to N-methyl-D-aspartate, slices lost synaptic transmission and K+ homeostasis more slowly in glucose-containing artificial cerebrospinal fluid than in lactate-containing artificial cerebrospinal fluid. After N-methyl-D-aspartate exposure, slices recovered synaptic transmission more completely in glucose. These results suggest that hippocampal neurons can use glucose more effectively than lactate when energy demand is high. In experiments with alpha-cyano-4-hydroxycinnamate, 500 microM alpha-cyano-4-hydroxycinnamate caused loss of K+ homeostasis and synaptic transmission in hippocampal slices during normoxia. When 200 microM alpha-cyano-4-hydroxycinnamate was used, synaptic activity and intracellular pH in slices decreased significantly during normoxia. These results suggest that alpha-cyano-4-hydroxycinnamate may have blocked mitochondrial oxidative metabolism along with lactate transport. Thus, studies using alpha-cyano-4-hydroxycinnamate to demonstrate the presence of a lactate shuttle in the brain tissue may need reevaluation. Our findings, together with observations in the literature that (1) glucose is available to neurons during activation, (2) heightened energy demand rapidly activates glycolysis in neurons, and (3) activation of glycolysis suppresses lactate utilization, suggests that glucose is the primary substrate for neurons during neuronal activation and do not support the astrocyte-neuron lactate shuttle hypothesis.

Glycolysis and recovery of pottasium ion homeostasis and synaptic transmission in hippocampal slices after anoxia or stimulated pottasium release

The present study was undertaken to determine whether glycolytic energy production was critical to the survival of brain tissue subjected to metabolic stress. Specifically, the contributions of glycolysis (1) to recovery of ion homeostasis after anoxia or high frequency electrical stimulation, and (2) to recovery of synaptic transmission after anoxia, were examined. Energy metabolism in rat hippocampal slices was manipulated by varying glucose concentrations, and by substituting lactate for glucose. Ion transport was slower and recovery of synaptic transmission after anoxia was greatly impeded in the absence of glycolysis. These results support the hypothesis that glycolytic ATP production is tied directly or indirectly to ion transport. The results also suggest that recovery of synaptic transmission following anoxia requires glycolytic ATP.

Rimantadine in Parkinson's disease patients experiencing peripheral adverse effects from amantadine : Report of a case series

We report our experience with 7 consecutive patients with Parkinsons disease (PD) who received rimantadine (the α‐methyl derivative of amantadine) in substitution of amantadine due to peripheral side effects (lower limb edema, livedo reticularis). Mean age was 67.3 ± 5.9 years, the mean disease duration was 13 ± 6.3 years, and mean Hoehn and Yahr stage was 2.2 ± 0.4. A total of 3 patients experienced marked improvement of edema, and 1 patient experienced marked improvement of livedo reticularis. Only 1 of the 7 patients reported significant loss of motor benefit when amantadine was replaced with rimantadine. Our results demonstrate that rimantadine may be considered as an alternative to amantadine in patients experiencing amantadine‐induced peripheral side effects.