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

156

168

Glucose is the primary energy substrate for the adult mammalian brain. However, lactate produced within the brain might be able to serve this purpose in neurons. In the present study, the relative significance of glucose and lactate as substrates to maintain neurotransmitter homeostasis was investigated. Cultured cerebellar (primarily glutamatergic) neurons were superfused in medium containing [U-13 C]glucose (2.5 mmol/L) and lactate (1 or 5 mmol/L) or glucose (2.5 mmol/L) and [U-13 C]lactate (1 mmol/L), and exposed to pulses of N-methyl-D-aspartate (300 lmol/L), leading to synaptic activity including vesicular release. The incorporation of 13 C label into intracellular lactate, alanine, succinate, glutamate, and aspartate was determined by mass spectrometry. The metabolism of [U-13 C]lactate under non-depolarizing conditions was high compared with that of [U-13 C]glucose; however, it decreased significantly during induced depolarization. In contrast, at both concentrations of extracellular lactate, the metabolism of [U-13 C]glucose was increased during neuronal depolarization. The role of glucose and lactate as energy substrates during vesicular release as well as transporter-mediated influx and efflux of glutamate was examined using preloaded D-[ 3 H]aspartate as a glutamate tracer and DL-threo-b-benzyloxyaspartate to inhibit glutamate transporters. The results suggest that glucose is essential to prevent depolarization-induced reversal of the transporter (efflux), whereas vesicular release was unaffected by the choice of substrate. In conclusion, the present study shows that glucose is a necessary substrate to maintain neurotransmitter homeostasis during synaptic activity and that synaptic activity does not induce an upregulation of lactate metabolism in glutamatergic neurons.

Section: Metabolism Of Glucose and Lactatesupporting

confidence: 93%

Section: Metabolism Of Glucose and Lactatesupporting

confidence: 83%

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

Bak¹,

Schousboe²,

Sonnewald

et al. 2006

156

168

“…30 However, lactate and pyruvate can readily cross the blood-brain barrier and enter the tricarboxylic acid cycle, 31,32 being preferential oxidative energy substrates over glucose for neurons. 33,34 The beneficial effect of exogenous glucose, lactate, and pyruvate has been shown in some TBI models, [35][36][37] but these substrates only modestly reduce the lesion size, with no apparent functional protection in our model. However, when lactate or pyruvate is combined with LLL illumination, mitochondrial functions are improved either additively or synergistically, giving rise to a faster recovery and less brain tissue loss compared with LLL, pyruvate, or lactate alone.…”

Section: Discussionmentioning

confidence: 67%

Low-Level Light in Combination with Metabolic Modulators for Effective Therapy of Injured Brain

Dong

Zhang

Hamblin

et al. 2015

Vascular damage occurs frequently at the injured brain causing hypoxia and is associated with poor outcomes in the clinics. We found high levels of glycolysis, reduced adenosine triphosphate generation, and increased formation of reactive oxygen species and apoptosis in neurons under hypoxia. Strikingly, these adverse events were reversed significantly by noninvasive exposure of injured brain to low-level light (LLL). Low-level light illumination sustained the mitochondrial membrane potential, constrained cytochrome c leakage in hypoxic cells, and protected them from apoptosis, underscoring a unique property of LLL. The effect of LLL was further bolstered by combination with metabolic substrates such as pyruvate or lactate both in vivo and in vitro. The combinational treatment retained memory and learning activities of injured mice to a normal level, whereas other treatment displayed partial or severe deficiency in these cognitive functions. In accordance with well-protected learning and memory function, the hippocampal region primarily responsible for learning and memory was completely protected by combination treatment, in marked contrast to the severe loss of hippocampal tissue because of secondary damage in control mice. These data clearly suggest that energy metabolic modulators can additively or synergistically enhance the therapeutic effect of LLL in energyproducing insufficient tissue-like injured brain.

“…For instance, Itoh et al (2003) found that unlabeled glucose did not inhibit 14 CO 2 production from labeled lactate in cortical neurons. In contrast, both Itoh et al (2003) and Bouzier-Sore et al (2003) have shown that unlabeled lactate strongly reduced the production of 14 CO 2 from labeled glucose. Itoh et al (2003) explained their results by postulating that lactate conversion to pyruvate also reduces NAD þ to NADH, minimizing the availability of the former for the oxidation of glyceraldehyde-3-phosphate during glycolysis.…”

Section: Testing the Hypothesismentioning

confidence: 88%

Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Schurr

2006

268

236

Research over the past two decades has renewed the interest in lactate, no longer as a useless end product of anaerobic glycolysis in brain (and other tissues), but as an oxidative substrate for energy metabolism. While this topic would be considered blasphemy only three decades ago, much recent evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle, and possibly in any other tissue and organ. Nevertheless, this concept has challenged the old dogma and ignited a fierce debate, especially among neuroscientists, pitting the supporters of glucose as the major oxidative energy substrate against those who support lactate as a possible alternative to glucose under certain conditions. Meanwhile, researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, while avoiding the high decibels of an emotional debate. Employing their findings along with the existing old and new data on cerebral energy metabolism, it is postulated here that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Consequently, this postulate entails that lactate is a major, if not the only, substrate for the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis could provide better understanding of the biochemistry and physiology of (cerebral) energy metabolism, while holding important implications in the field of neuroimaging. Concomitantly, it could satisfy both 'glucoseniks' and 'lactatians' in the ongoing debate.