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Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: An in vitro study
Abstract
Lactate has been considered for many years to be a useless, and frequently, harmful end-product of anaerobic glycolysis. In the present in vitro study, lactate-supplied rat hippocampal slices showed a significantly higher degree of recovery of synaptic function after a short hypoxic period than slices supplied with an equicaloric amount of glucose. More importantly, all slices in which anaerobic lactate production was enhanced by pre-hypoxia glucose overload exhibited functional recovery after a prolonged hypoxia. An 80% recovery of synaptic function was observed even when glucose utilization was blocked with 2-deoxy-D-glucose during the later part of the hypoxic period and during reoxygenation. In contrast, slices in which anaerobic lactate production was blocked during the initial stages of hypoxia did not recover their synaptic function upon reoxygenation despite the abundance of glucose and the removal of 2-deoxy-D-glucose. Thus, for brain tissue to show functional recovery after prolonged period of hypoxia, the aerobic utilization of lactate as an energy substrate is mandatory.
... Recent evidence also suggests that lactate might be a neuroprotective agent in certain pathological contexts. Studies in animal models of ischemic stroke showed that lactate, either endogenously produced during hypoxia or applied exogenously at reoxygenation, supports energy metabolism and functional recovery in neurons [23][24][25][26] , and that direct intracerebroventricular injection of lactate led to a decrease in infarct volume and an improvement in neurological outcome 26,27 . Moreover, it has been demonstrated that lactate mediates neuroprotection through different mechanisms of action which are relevant in ischemic stroke (i.e., support to energy metabolism [23][24][25] , counteraction of glutamate excitotoxicity [27][28][29] , oxidative stress [28][29][30] and cellular death 31,32 , expression of plasticity-related and pro-survival genes 31,32 , and protection of astrocytes 33 ). ...
... Studies in animal models of ischemic stroke showed that lactate, either endogenously produced during hypoxia or applied exogenously at reoxygenation, supports energy metabolism and functional recovery in neurons [23][24][25][26] , and that direct intracerebroventricular injection of lactate led to a decrease in infarct volume and an improvement in neurological outcome 26,27 . Moreover, it has been demonstrated that lactate mediates neuroprotection through different mechanisms of action which are relevant in ischemic stroke (i.e., support to energy metabolism [23][24][25] , counteraction of glutamate excitotoxicity [27][28][29] , oxidative stress [28][29][30] and cellular death 31,32 , expression of plasticity-related and pro-survival genes 31,32 , and protection of astrocytes 33 ). According to the ANLS hypothesis, lactate production and release by astrocytes is dependent on neuronal activity 21,22 . ...
... Studies on in vitro rodent models, showed that lactate, either endogenously produced during hypoxia or applied exogenously at the end of it, can be metabolically used by neurons, and it is preferential to glucose for functional recovery during the reoxygenation period [23][24][25][26] According to literature, lactate contributes to neuroprotection through different mechanisms of action. Firstly, lactate represents a convenient metabolic substrate for energydeprived neurons, since, as compared to glucose, its use reduces the strain on the depleted energy levels. ...
In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. However, the biological mechanisms underlying the benefit from neuronal activation are unknown. We hypothesized that neuronal activation might trigger the astrocyte-to-neuron lactate shuttle, whereby lactate is released from astrocytes to support the energy requirements of hypoxic neurons, and this leads to the observed neuroprotection. We tested this by establishing a human cell based in vitro model of the ischemic penumbra. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation, that lactate exogenously administered before hypoxia correlated with neuroprotection, and that stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. We presented evidence that lactate contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.
... Evidence from in vitro and in vivo studies has shown that the healthy brain uses lactate as an efficient energy substrate that may even be preferred to glucose to maintain synaptic transmission. [10][11][12] Interestingly, lactate may also be the preferred energy substrate for recovery of neuronal function after insults like prolonged oxygen deprivation 13,14 such as in stroke, which likely plays a role in the brain's attempt at self-healing. We and others have shown that L-lactate administration is neuroprotective in several preclinical models of acute brain injury, including hypoxia/ischemia, [14][15][16][17] intracerebral hemorrhage, 18 or traumatic brain injury. ...
... [10][11][12] Interestingly, lactate may also be the preferred energy substrate for recovery of neuronal function after insults like prolonged oxygen deprivation 13,14 such as in stroke, which likely plays a role in the brain's attempt at self-healing. We and others have shown that L-lactate administration is neuroprotective in several preclinical models of acute brain injury, including hypoxia/ischemia, [14][15][16][17] intracerebral hemorrhage, 18 or traumatic brain injury. 19 Importantly, administration of hypertonic lactate solution to human acute brain injury patients has beneficial effects. ...
... In the severe pMCAO model, protective effects of lactate are observed when administered shortly after ischemia onset. Lactate effects may relate to its contribution as energy supply, 14 possibly preventing the immediate demise of suffering neurons, its induction of plasticity genes, 32 and/or the functional modulation via lactate receptor interaction, which results in decreased neuronal activity 33 that could alleviate the effects of excess excitotoxic stimulation. It is interesting to note that in the lactate-treated groups, fewer animals had to be euthanized due to repeated seizures than controls. ...
Lactate has been shown to have beneficial effect both in experimental ischemia–reperfusion models and in human acute brain injury patients. To further investigate lactate’s neuroprotective action in experimental in vivo ischemic stroke models prior to its use in clinics, we tested (1) the outcome of lactate administration on permanent ischemia and (2) its compatibility with the only currently approved drug for the treatment of acute ischemic stroke, recombinant tissue plasminogen activator (rtPA), after ischemia–reperfusion. We intravenously injected mice with 1 µmol/g sodium l-lactate 1 h or 3 h after permanent middle cerebral artery occlusion (MCAO) and looked at its effect 24 h later. We show a beneficial effect of lactate when administered 1 h after ischemia onset, reducing the lesion size and improving neurological outcome. The weaker effect observed at 3 h could be due to differences in the metabolic profiles related to damage progression. Next, we administered 0.9 mg/kg of intravenous (iv) rtPA, followed by intracerebroventricular injection of 2 µL of 100 mmol/L sodium l-lactate to treat mice subjected to 35-min transient MCAO and compared the outcome (lesion size and behavior) of the combined treatment with that of single treatments. The administration of lactate after rtPA has positive influence on the functional outcome and attenuates the deleterious effects of rtPA, although not as strongly as lactate administered alone. The present work gives a lead for patient selection in future clinical studies of treatment with inexpensive and commonly available lactate in acute ischemic stroke, namely patients not treated with rtPA but mechanical thrombectomy alone or patients without recanalization therapy.
... Neurons are also sensitive to oxidation, and tight regulation of oxidative stress is imperative for neuronal health [69,70]. To support their ATP needs while minimizing oxidative stress, neurons use oxidative metabolism with lactate as a substrate [71][72][73][74], utilizing lactate over glucose [75,76]. The use of lactate over glucose allows for the production of nicotinamide adenine dinucleotide phosphate (NADPH) by the pentose phosphate pathways which provides a substrate for glutathione (GSH) reductase to reduce oxidized glutathione [77]; GSH being one of the primary antioxidative molecules in the brain [78]. ...
... Much of the lactate formed is released into the extracellular space via MCT1, MCT2, high-capacity cation channel and pannexins [75,76,82,[99][100][101][102]. Lactate is then taken up by neurons via MCT2 where it is broken down and used to generate ATP [71][72][73]75,76]. As discussed earlier, use of lactate reduces the need for glycolysis that promotes cell death by oxidative stress due to decreased formation of NADPH to recycle oxidized GSH and decrease oxidative stress [77]. ...
... Conceivably, an increase in the delivery of metabolic intermediates such as lactate and promotion of mitochondrial health through redox and ion homeostasis may help survival of neurons and prevent progression and neuropathic pain in MS. While lactate can promote proinflammatory phenotypes in immune cells [190], increase in the uptake of lactate by neurons can be promoted specifically by an increase in MCT2 expression [71]. MCT2 expression is promoted by IGF-1 and insulin [191]. ...
While the etiology of multiple sclerosis (MS) remains unclear, research from the clinic and preclinical models identified the essential role of inflammation and demyelination in the pathogenesis of MS. Current treatments focused on anti-inflammatory processes are effective against acute episodes and relapsing-remitting MS, but patients still move on to develop secondary progressive MS. MS progression is associated with activation of microglia and astrocytes, and importantly, metabolic dysfunction leading to neuronal death. Neuronal death also contributes to chronic neuropathic pain. Metabolic support of neurons by glia may play central roles in preventing progression of MS and chronic neuropathic pain. Here, we review mechanisms of metabolic cooperation between glia and neurons and outline future perspectives exploring metabolic support of neurons by glia.
... Most vertebrate species devote 2%-8% of basal metabolic rate to the brain, but primates typically devote 20%-25% of basal metabolic rate to brain maintenance (Mink et al., 1981). Although oxidative processes are preferred when it comes to brain metabolism, research finds the brain depends on lactate, the end-product of anaerobic glycolysis, as well (Schurr et al., 1997). Lactate has been linked to quicker neuron recovery rate and more efficient recovery rates after hypoxic conditions (Schurr et al., 1997). ...
... Although oxidative processes are preferred when it comes to brain metabolism, research finds the brain depends on lactate, the end-product of anaerobic glycolysis, as well (Schurr et al., 1997). Lactate has been linked to quicker neuron recovery rate and more efficient recovery rates after hypoxic conditions (Schurr et al., 1997). ...
... Yet, when additional factors are considered that supposition may not hold up. Physiological research has found that Type II fibers assist in explosive, and most importantly, short-lived activities (Schurr et al., 1997). Therefore, although Type II muscle fibers are expensive to contract, their contractions are short lived, only sustaining the first few seconds to minutes of movement. ...
Skeletal muscle fibers are often used to evaluate functional differences in locomotion. However, because there are energetic differences among muscle fiber cells, muscle fiber composition could be used to address evolutionary questions about energetics. Skeletal muscle is composed of two main types of fibers: Type I and II. The difference between the two can be reduced to how these muscle cells use oxygen and glucose. Type I fibers convert glucose to ATP using oxygen, while Type II fibers rely primarily on anaerobic metabolic processes. The expensive tissue hypothesis (ETH) proposes that the energetic demands imposed on the body by the brain result in a reduction in other expensive tissues (e.g., gastrointestinal tract). The original ETH dismisses the energetic demands of skeletal muscle, despite skeletal muscle being (1) an expensive tissue when active and (2) in direct competition for glucose with the brain. Based on these observations we hypothesize that larger brained primates will have relatively less muscle mass and a decrease in Type I fibers. As part of a larger study to test this hypothesis, we present data from 10 species of primates. We collected body mass, muscle mass, and biopsied four muscles from each specimen for histological procedures. We collected endocranial volumes from the literature. Using immunohistochemistry, a muscle fiber composition profile was created for each species sampled. Results show that larger brained primates have less muscle and fewer Type I fibers than primates with smaller brains. Results clarify the relationship between muscle mass and brain mass and illustrate how muscle mass could be used to address energetic questions. Anat Rec, 301:528–537, 2018.
... a neuroprotective agent in certain pathological contexts. Studies in animal models of ischemic stroke showed that lactate, either endogenously produced during hypoxia or applied exogenously at reoxygenation, supports energy metabolism and functional recovery in neurons [23][24][25][26] , and that direct intracerebroventricular or intravenous injection of lactate led to a decrease in infarct volume and an improvement in neurological outcome 26,27 . ...
... In addition, it has been shown that lactate has a neuroprotective effect in pathological conditions in which the availability of energy substrates is limited, such as cerebral ischemic stroke. Studies on in vitro rodent models, showed that lactate, either endogenously produced during hypoxia or applied exogenously at the end of it, can be metabolically used by neurons, and it is preferential to glucose for functional recovery during the reoxygenation period [23][24][25][26] . In in vivo models, Berthet et al. showed that either intracerebroventricular and intravenous injection of lactate after reperfusion led to a significant decrease in lesion size and an improvement in neurologic outcome in a rat model of cerebral ischemia 26,27 . ...
In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect stressed yet viable brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. Here, we hypothesized that neuronal activation might maintain or trigger the astrocyte-to-neuron lactate shuttle (ANLS), whereby lactate is released from astrocytes to support the energy requirements of ATP-starved hypoxic neurons, and this leads to the observed neuroprotection. We tested this by using a human cell based in vitro model of the ischemic penumbra and investigating whether lactate might be neuroprotective in this setting. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation. Furthermore, we showed that lactate exogenously administered before hypoxia correlated with neuroprotection in our cellular model. In addition, stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. To conclude, here we presented evidence that lactate transport into neurons contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.
... This is due, most likely, to a 'habit of mind' [13,14], a mental-habitual barrier that many find very difficult to cross. This would best explain the reactions to the research by George A. Brooks on skeletal muscle lactate shuttle and utilization [15][16][17][18] and by Avital Schurr and his colleagues who demonstrated that aerobic utilization of lactate as the sole energy substrate supports neuronal function [19,20]. First, the lactate shuttle offered by Brooks, which implies that lactate enters into mitochondria to be converted to pyruvate, the substrate of the TCA cycle, requires the presence of lactate dehydrogenase (LDH) intramitochondrially, the enzyme that converts lactate to pyruvate and NAD + (nicotinamide adenine dinucleotide) to NADH. ...
... Clearly, the skeptics perceived the ability of neurons to aerobically utilize lactate for ATP production as a threat to the dominion of glucose as the ultimate energy substrate in the brain and elsewhere. Although such a "threatening" claim was never made, it is clear that under specific conditions, lactate could replace glucose, such as during recovery from neuronal insults [20,21], where lactate is absolutely the obligatory aerobic energy substrate, not glucose, and the preferable energy substrate during neuronal activation [39]. Nevertheless, upon the publication of the astrocytic neuronal lactate shuttle (ANLS) hypothesis by Magistretti and Pellerin in 1994 [40], a great debate and much criticism ensued that which is still continuing today. ...
The division of glycolysis into two separate pathways, aerobic and anaerobic, depending on the presence or absence of oxygen, respectively, was formulated over eight decades ago. The former ends with pyruvate, while the latter ends with lactate. Today, this division is confusing and misleading as research over the past 35 years clearly has demonstrated that glycolysis ends with lactate not only in cancerous cells but also in healthy tissues and cells. The present essay offers a review of the history of said division and the more recent knowledge that has been gained about glycolysis and its end-product, lactate. Then, it presents arguments in an attempt to explain why separating glycolysis into aerobic and anaerobic pathways persists among scientists, clinicians and teachers alike, despite convincing evidence that such division is not only wrong scientifically but also hinders progress in the field of energy metabolism.
... Usually considered a waste product of glycolysis, lactate has now been pondered as an efficient energy substrate for the central nervous system (CNS) (Berthet et al., 2012;Castillo et al., 2015;Carrard et al., 2016;Morland et al., 2017;Lev-Vachnish et al., 2019;Buscemi et al., 2020). Moreover, although glucose is considered the main brain energy substrate in adults, lactate appears to be a preferential substrate for neonatal neurons (Schurr et al., 1997). According to the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis Magistretti, 1994, 2012;Allaman et al., 2011;Be´langer et al., 2011;Magistretti and Allaman, 2018), astrocytes are the main ''producers" of lactate which is shuttled to neurons through monocarboxylate transporters (MCTs). ...
... Lactate is an energy substrate for neurons (Schurr et al., 1997;Ma¨chler et al., 2016) and astrocytes play an important role in fulfilling metabolic requirements to ensure neurons survival after a brain injury, as evidenced by the ANLS (Astrocyte-Neuron Lactate Shuttle) (Bergersen, 2007;Pellerin and Magistretti, 2012;Ma¨chler et al., 2016;Magistretti and Allaman, 2018). ...
Neonatal hypoxic-ischemic encephalopathy is a major cause of mortality and disability in newborns and the only standard approach for treating this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models. The present study evaluated the administration of lactate, a potential energy substrate of the central nervous system (CNS) in an animal model of hypoxia-ischemia (HI), that mimics in neonatal rats the brain damage observed in human newborns. Seven-day-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 minutes. Animals were assigned to four experimental groups: HI, HI+LAC, SHAM, SHAM+LAC. Lactate was administered intraperitoneally 30 minutes and 2 h after hypoxia in HI+LAC and SHAM+LAC groups. HI and SHAM groups received vehicle at the same time points. The volume of brain lesion was evaluated in P9. Animals underwent behavioral assessments: negative geotaxis, righting reflex (P8 and P14), and cylinder test (P20). Lactate administration reduced the volume of brain lesion and improved behavioral parameters after HI in both sexes. Thus, lactate administration could be a neuroprotective strategy for the treatment of neonatal HI, a disorder still affecting a significant percentage of human newborns.
... For example, during physical exercise, more than half of the energy turnover rate in the heart muscle is recruited from lactate oxidation [68]. In the brain, besides its capacity to support adequate energy levels and the optimal synaptic function [69], lactate per se (and not glucose) was revealed as a key player in alleviating the hypoxia-induced damages of neurons [70]. In rapidly proliferating cancer cells, including lung and pancreatic tumors, lactate could feed the tricarboxylic acid (TCA) cycle; lactate's contribution as a respiratory fuel exceeded that of glucose, especially in rapidly growing tumors [71,72]. ...
... For example, during physical exercise, more than half of the energy turnover rate in the heart muscle is recruited from lactate oxidation [68]. In the brain, besides its capacity to support adequate energy levels and the optimal synaptic function [69], lactate per se (and not glucose) was revealed as a key player in alleviating the hypoxia-induced damages of neurons [70]. In rapidly proliferating cancer cells, including lung and pancreatic tumors, lactate could feed the tricarboxylic acid (TCA) cycle; lactateʹs contribution as a respiratory fuel exceeded that of glucose, especially in rapidly growing tumors [71,72]. ...
A defining hallmark of tumor phenotypes is uncontrolled cell proliferation, while fermentative glycolysis has long been considered as one of the major metabolic pathways that allows energy production and provides intermediates for the anabolic growth of cancer cells. Although such a vision has been crucial for the development of clinical imaging modalities, it has become now evident that in contrast to prior beliefs, mitochondria play a key role in tumorigenesis. Recent findings demonstrated that a full genetic disruption of the Warburg effect of aggressive cancers does not suppress but instead reduces tumor growth. Tumor growth then relies exclusively on functional mitochondria. Besides having fundamental bioenergetic functions, mitochondrial metabolism indeed provides appropriate building blocks for tumor anabolism, controls redox balance, and coordinates cell death. Hence, mitochondria represent promising targets for the development of novel anti-cancer agents. Here, after revisiting the long-standing Warburg effect from a historic and dynamic perspective, we review the role of mitochondria in cancer with particular attention to the cancer cell-intrinsic/extrinsic mechanisms through which mitochondria influence all steps of tumorigenesis, and briefly discuss the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.
... Alternately, lactate was more favored by neurons than glucose to meet its energy needs; even lactate, not glucose, is the fuel used in the repair function of synapses after the occurrence of hypoxia in time re-oxygenation. (12,13) In addition to the necessary process energy metabolism, ATP also plays an important role in maintaining the function of neurons and glia. The ATP levels determine the severity of brain ischemia injury; without a sufficient supply of ATP the cascade of ischemia will continue, leading to cell necrosis. ...
... (19)(20)(21) In studying ischemic mice models, MCT-1 expression increases in the injured cerebral cortex. (12) Lactate endogenous and exogenous form ATP through glycolysis. Some literatures suggest that the study of glucose metabolism in the brain via the glycolytic pathway begins with the phosphorylation of glucose and lactate, finishing with the formation of astrocyte-neuron lactate shuttle hypothesis (ANLSH). ...
Objective: To discover the role of hypertonic sodium lactate (HSL) as the energy source, which in turn will act as a neuroprotector, by measuring adenosine triphosphate (ATP) level, monocarboxylate transporter 1 (MCT-1) and the extent of the necrotic areas. Design: This was an experimental study that used randomized post-test only control group design. Setting: Experimental Animal Care Unit Universitas Gadjah Mada. Patient and participant: 32 white mice of Rattus norvegicus. Intervention: After the protocol of this study was approved by the research ethic committee, _ 32 rats were randomly divided into two groups: HSL group (n=16) and NaCl 3% group (n=16) as the control group. Both groups were anesthetized using conversion-dose pentothal. Results: ATP level in HSL group was higher compared to the control group (p=0.031). MCT-1 in HSL group was also higher than the control group (p=0.010). Necrotic areas were less extensive in the HSL group than the control group (p=0.000). Lactate levels at minute 30 (T30) and minute 360 (T360) increased in the HSL group, while increasing in the control group up to T30, then decreased gradually until T360. Conclusion: Exogenous lactate in solution has effect as a neuroprotective of brain in the in-tracerebral hemorrhage (ICH).
... Blood and brain lactate concentration also reliably oscillates according to the wake and sleep cycles of mice including a rise during rapid eye movement (REM) sleep [10]. Astrocytes and neurons can produce lactate as a product of glycolysis [11]. Lactate can also be transported across the blood-brain barrier based on concentration gradients [12] through bidirectional diffusion using the MCT1 monocarboxylate transporter [13,14]. ...
... As isolation is linked with increased anxiety and higher locomotive behaviour, it is likely that blood lactate and general running wheel activity increased due to housing protocol. Day 1 baseline blood lactate concentrations are greater than average [4,11,47], a possible response to isolation. Comparisons to control groups and analysis of data as a percentage relative to individual baselines in both experiments allow for direct analysis of the effect of lactate/MCT oil and sodium lactate on blood metabolite concentration and late day activity, respectively. ...
While investigating the effect of alternative energy substrates on extracellular brain glucose or lactate, Béland-Millar (2017) noted a reduction of physical activity after intraperitoneal administration of lactate and ketone bodies. These observations were similar to an older study that examined the impact of drinking a sodium lactate/lactic acid solution before sleep in hospitalized patients with major depression. Patients and control participants self-reported drowsiness, early sleep onset and better overall sleep after consumption. Some patients showed improved mood after several days of treatment. We re-evaluated the effects of the solution used (0.59 g/kg) as well as several smaller doses (0.47, 0.35, 0.24 and 0.12 g/kg) on blood lactate and glucose in CD-1 mice and on sleep onset associated activity reduction. Because of adverse effects with the lactate/lactic acid solution, we also examined the effects of a medium chain triglyceride (MCT) solution (10, 5, 2.5, and 1 ml/kg) on blood lactate and glucose. Oral gavage administration of lactic acid/lactate produced adverse effects particularly for the largest doses. However consumption of 10 and 5 ml/kg volumes of MCT oils significantly increased blood lactate concentration to levels comparable to Lowenbach's solution without piloerection indicative of adverse effects. To evaluate pre-sleep activity reduction produced by lactate, mice were intraperitoneally administered diluted sodium lactate (2.0 g/kg, 1.0 g/kg, 0.5 g/kg, 0.25 g/kg, or saline) for 6 days, 120 min before their sleep period and their running activity was measured. Larger lactate doses reduced pre-sleep running each day up to 60 min post injection. Smaller doses reduced running after a single treatment only. These results suggest that the modulation of blood lactate levels may be useful in treating sleep onset problems associated with depression.
... AJDL is calculated by subtracting jugular lactate from arterial lactate and provides an outline of net uptake of export of lactate from the brain. Lactate, generally conceived as an anaerobic waste product, is an important energy source for the brain, especially after brain injury resulting in lactate uptake (Schurr et al., 1997;Bartnik et al., 2005;Bouzat and Oddo, 2014). However, during extensive brain damage with mitochondrial dysfunction or anaerobic metabolism, the brain may have lactate production exceeding consumption leading to lactate export (Cruz et al., 1993). ...
... Negative AJDL has been suggested to imply severe brain damage in other etiologies of brain injury (Cruz et al., 1993;Perez et al., 2003;Chieregato et al., 2007;Tholance et al., 2015). The calculated measurements were evaluated during patient treatment, and under instances of derangements outside of the normal ranges or drastic changes (Schurr et al., 1997;Chieregato et al., 2007), hemodynamic parameters and oxygenation were reviewed to see if there were any reversible causes of suspected secondary brain injury. ...
For better care of postcardiac arrest patients, objective serial assessments of brain injury severity are needed. We hypothesized that monitoring of cerebral energy metabolism based on arterio-jugular (AJ) differences of metabolites will provide serial details of brain injury and information about neurologic outcomes in patients. Measurements of lactate and glucose in addition to blood gas analyses were done every 6 hours from the radial artery and jugular bulb in postcardiac arrest patients throughout targeted temperature management (TTM). Jugular bulb saturation, AJ difference of O2, and AJ difference of lactate (AJDL) were calculated and compared between the different neurologic outcome groups. Linear mixed-model analysis was done to assess AJDL based on the different phases of TTM and neurologic outcome. A total of 13 patients were included in the study (n = 4 good outcome, n = 9 poor outcome). AJDL as an indicator of cerebral metabolism was significantly different between the outcome groups and demonstrated negative values in the poor neurologic outcome group (0.06 [0.05-0.09] vs. -0.14 [-0.06 to -0.27], p < 0.01). However, there was no significant difference in AJDL between the outcome groups in the mixed effects model (p = 0.05). In addition, there were no differences between the phases of TTM in both groups (p = 0.46). AJDL was observed to be informative but was not significantly different between neurologic outcome groups throughout the different phases of TTM in our pilot study. Future studies are needed for further investigation of AJDL as an indicator of brain injury severity.
... After 120 min of reperfusion; T6. endpoint, after a 180-min reperfusion. (b) The skull sketch map for placing probes (A for coronal suture; B for sagittal suture; C for ICP; D for temperature; E for microdalysis; F for bregma) 30 clamping and stopped CPB. Passive venous drainage into the blood reservoir was allowed after undergoing DHCA. ...
... When glucose is anaerobically metabolized, astrocytes can produce lactate for the aerobic metabolism of neurons at hypoxia/anoxia (29). Another study claimed that the aerobic utilization of lactate instead of glucose fuels the recovery of synaptic function during reoxygenation (30). Lactate and pyruvate are the end products of anaerobic glycolysis and aerobic glycolysis, respectively. ...
Objective:
The aim of this study was to elucidate the mechanism of cerebral injury and to evaluate selective antegrade cerebral perfusion (SACP) as a superior neuroprotective strategy for prolonged deep hypothermic circulatory arrest (DHCA).
Methods:
Twelve pigs (6-8-week old) were randomly assigned to DHCA alone (n=6) and DHCA with SACP (n=6) at 18°C for 80 min groups. Serum S100 was determined using an immunoassay analyzer. The concentrations of cerebral dialysate glucose, lactate, pyruvate, glycerol, and glutamate were measured using a microdialysis analyzer.
Results:
Compared with a peak at T4 (after 60 min of rewarming) in the DHCA group, the serum S100 in the SACP group was significantly lower throughout the study. The DHCA group was susceptible to significant increases in the levels of lactate, glycerol, and glutamate and the ratio of lactate/pyruvate as well as decreases in the level of glucose. These microdialysis variables showed only minor changes in the SACP group. There was a positive correlation between cerebral lactate and intracranial pressure during reperfusion in the DHCA group. However, the apoptosis index and C-FOS protein levels were lower in the SACP group.
Conclusion:
Metabolic dysfunction is involved in the mechanism of cerebral injury. SACP is a superior neuroprotective strategy for both mild and prolonged DHCA.
... After 120 min of reperfusion; T6. endpoint, after a 180-min reperfusion. (b) The skull sketch map for placing probes (A for coronal suture; B for sagittal suture; C for ICP; D for temperature; E for microdalysis; F for bregma) 30 clamping and stopped CPB. Passive venous drainage into the blood reservoir was allowed after undergoing DHCA. ...
... When glucose is anaerobically metabolized, astrocytes can produce lactate for the aerobic metabolism of neurons at hypoxia/anoxia (29). Another study claimed that the aerobic utilization of lactate instead of glucose fuels the recovery of synaptic function during reoxygenation (30). Lactate and pyruvate are the end products of anaerobic glycolysis and aerobic glycolysis, respectively. ...
Objective
The aim of this study was to elucidate the mechanism of cerebral injury and to evaluate selective antegrade cerebral perfusion (SACP) as a superior neuroprotective strategy for prolonged deep hypothermic circulatory arrest (DHCA).
Methods
Twelve pigs (6–8-week old) were randomly assigned to DHCA alone (n=6) and DHCA with SACP (n=6) at 18°C for 80 min groups. Serum S100 was determined using an immunoassay analyzer. The concentrations of cerebral dialysate glucose, lactate, pyruvate, glycerol, and glutamate were measured using a microdialysis analyzer.
Results
Compared with a peak at T4 (after 60 min of rewarming) in the DHCA group, the serum S100 in the SACP group was significantly lower throughout the study. The DHCA group was susceptible to significant increases in the levels of lactate, glycerol, and glutamate and the ratio of lactate/pyruvate as well as decreases in the level of glucose. These microdialysis variables showed only minor changes in the SACP group. There was a positive correlation between cerebral lactate and intracranial pressure during reperfusion in the DHCA group. However, the apoptosis index and C-FOS protein levels were lower in the SACP group.
Conclusion
Metabolic dysfunction is involved in the mechanism of cerebral injury. SACP is a superior neuroprotective strategy for both mild and prolonged DHCA.
... Our data indicate that lactate availability during OGD increases cell viability and promotes long-term protective effects observed later, after reoxygenation, in both, microglial and neuronal cell lines. It has already been argued that lactate accumulation during hypoxia in vitro allows the recovery of synaptic function upon reoxygenation [52]. Interestingly, a recent study showed that lactate treatment during reoxygenation also increased BV-2 cells viability, which decreased neuronal apoptosis when co-cultured with primary cultured neurons [28]. ...
Lactate has received attention as a potential therapeutic intervention for brain diseases, particularly those including energy deficit, exacerbated inflammation, and disrupted redox status, such as cerebral ischemia. However, lactate roles in metabolic or signaling pathways in neural cells remain elusive in the hypoxic and ischemic contexts. Here, we tested the effects of lactate on the survival of a microglial (BV-2) and a neuronal (SH-SY5Y) cell lines during oxygen and glucose deprivation (OGD) or OGD followed by reoxygenation (OGD/R). Lactate signaling was studied by using 3,5-DHBA, an exogenous agonist of lactate receptor GPR81. Inhibition of lactate dehydrogenase (LDH) or monocarboxylate transporters (MCT), using oxamate or 4-CIN, respectively, was performed to evaluate the impact of lactate metabolization and transport on cell viability. The OGD lasted 6 h and the reoxygenation lasted 24 h following OGD (OGD/R). Cell viability, extracellular lactate concentrations, microglial intracellular pH and TNF-ɑ release, and neurite elongation were evaluated. Lactate or 3,5-DHBA treatment during OGD increased microglial survival during reoxygenation. Inhibition of lactate metabolism and transport impaired microglial and neuronal viability. OGD led to intracellular acidification in BV-2 cells, and reoxygenation increased the release of TNF-ɑ, which was reverted by lactate and 3,5-DHBA treatment. Our results suggest that lactate plays a dual role in OGD, acting as a metabolic and a signaling molecule in BV-2 and SH-SY5Y cells. Lactate metabolism and transport are vital for cell survival during OGD. Moreover, lactate treatment and GPR81 activation during OGD promote long-term adaptations that potentially protect cells against secondary cell death during reoxygenation.
Graphical Abstract
... A substantial amount of the generated lactate is then transported to neurons to fuel and facilitate the maintenance of synaptic connections. During prolonged cerebral ischemia, excessive accumulation of lactate leads to lactic acidosis, which alters the intracerebral milieu and damages neurons via various pathophysiological pathways [190][191][192]. Additionally, acidosis inhibits glycolysis in astrocytes, which may be one of the possible causes of energy deficiency after the onset of cerebral ischemia. ...
Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes tobe reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.
... Further supporting studies reveal the importance of a lactate gradient in the efficient transport of lactate from astrocytes to neurons (Machler et al., 2016). Lactate itself serves as a pivotal energy source, maintaining normal synaptic activity in hippocampal slice cultures and aiding energy recovery during hypoxia (Schurr et al., 1997;Schurr et al., 1988). Both glycogenolysis and lactate derived from aerobic glycolysis are required for long-term potentiation (LTP) and memory formation, as disruptions in glycogen mobilization or lactate transport between astrocytes and neurons impair memory processes (Alberini et al., 2018;Boury-Jamot et al., 2016;Gibbs et al., 2008;Hertz and Gibbs, 2009;Newman et al., 2011;Suzuki et al., 2011;Zhang et al., 2016). ...
Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders
... Finally, a number of experiments have shown that lactate could be neuroprotective against excitotoxicity induced by high glutamate concentrations in the rat cerebral cortex [24]. More translationally relevant studies showed a neuroprotective effect of lactate in the transient middle cerebral artery occlusion model of stroke [16]. ...
Lactate is now considered an additional fuel or signaling molecule in the brain. In this study, using an oxygen–glucose deprivation (OGD) model, we found that treatment with lactate inhibited the global increase in intracellular calcium ion concentration ([Ca²⁺]) in neurons and astrocytes, decreased the percentage of dying cells, and caused a metabolic shift in astrocytes and neurons toward aerobic oxidation of substrates. OGD resulted in proinflammatory changes and increased expression of cytokines and chemokines, whereas incubation with lactate reduced these changes. Pure astrocyte cultures were less sensitive than neuroglia cultures during OGD. Astrocytes exposed to lipopolysaccharide (LPS) also showed pro‐inflammatory changes that were reduced by incubation with lactate. Our study suggests that lactate may have neuroprotective effects under ischemic and inflammatory conditions.
... It is important to highlight that lactate administered peripherally post-ischemia rapidly reaches the CNS and is metabolized (Hyacinthe et al., 2020;Roumes et al., 2021;Tassinari et al., 2020). Decades ago, it was already demonstrated in vitro that, after the reoxygenation phase, it is lactate, not glucose, that helps the recovery of synaptic function (Schurr et al., 1997); this adds up to the role of lactate as a metabolic substrate for the brain with low perfusion, which is reinforced by the observation that an increase in MCTs expression leads to a significant reduction in the volume of brain lesion in a rat model of stroke (Wang et al., 2011). ...
GPR81 is a G-protein coupled receptor (GPCR) discovered in 2001, but deorphanized only 7 years later, when its affinity for lactate as an endogenous ligand was demonstrated. More recently, GPR81 expression and distribution in the brain were also confirmed and the function of lactate as a volume transmitter has been suggested since then. These findings shed light on a new function of lactate acting as a signaling molecule in the central nervous system, in addition to its well-known role as a metabolic fuel for neurons. GPR81 seems to act as a metabolic sensor, coupling energy metabolism, synaptic activity, and blood flow. Activation of this receptor leads to Gi-mediated downregulation of adenylyl cyclase and subsequent reduction in cAMP levels, regulating several downstream pathways. Recent studies have also suggested the potential role of lactate as a neuroprotective agent, mainly under brain ischemic conditions. This effect is usually attributed to the metabolic role of lactate, but the underlying mechanisms need further investigation and could be related to lactate signaling via GPR81. The activation of GPR81 showed promising results for neuroprotection; it modulates many processes involved in the pathophysiology of ischemia. In this review, we summarize the history of GPR81, starting with its deorphanization; then, we discuss GPR81 expression and distribution, signaling transduction cascades, and neuroprotective roles. Lastly, we propose GPR81 as a potential target for the treatment of cerebral ischemia.
... Obviously, this concept has taken roots despite the fact that drawing glycolysis as a 10-reaction pathway, ending with pyruvate, rather than an 11-reaction one, ending with lactate, is contradictory to the basic thermodynamic rule of free energy change. Accordingly, lactate has been proposed as the oxidative substrate of mitochondrial oxphos (Schurr, 2006) based on cumulative indirect experimental data (Schurr et al., 1997a(Schurr et al., ,b, 1999) that later were supported by direct biochemical and electrophysiological data (Schurr and Payne, 2007;Gozal, 2011, 2015;Schurr, 2014Schurr, , 2018. Additional studies showing that cerebellum mitochondria metabolize lactate have strengthened this concept (Atlante et al., 2007;Passarella et al., 2008). ...
... Prácticamente todos los órganos tienen la capacidad de metabolizar la glucosa a lactato, pero el hígado es el principal en cuanto a la capacidad de hacer el proceso "inverso" de gluconeogénesis a partir del lactato, y se han descrito otros órganos que pueden usar el lactato como sustrato metabólico sobre todo en estados de estrés. 24,29 Este proceso de compartir sustratos para la formación de ATP se ha denominado "transbordador" de lactato (lactate shuttle); en él, el lactato sirve como transporte y el hígado como "regenerador" de glucosa. 24,28 ...
La sepsis como causante de alta mortalidad en instituciones hospitalarias es un evento reconocido mundialmente. Existe un interés creciente en identificar el grupo de pacientes que más se pueda beneficiar de una terapia temprana e intensiva. El lactato es un marcador importante de los procesos metabólicos celulares, y en sepsis se lo ha interpretado como un biomarcador que indica la deficiencia de aporte de oxígeno a los tejidos. Si se tienen en cuenta investigaciones recientes sobre la fisiología de la producción de lactato, y se entiende la sepsis como una respuesta sistémica, la interpretación del nivel elevado de lactato puede incluir diversos procesos, no todos ellos perjudiciales para el organismo. En esta revisión se describen los diferentes fenómenos celulares que pueden explicar el nivel elevado de lactato en la sepsis y se analizan su utilidad actual y las propuestas de interpretación futura en el proceso de reanimación de pacientes con sepsis.
... Research interest has recently grown in the role of alternative energy substrates that facilitate the preservation of cell viability in response to limited glucose availability (Berthet et al., 2009;Rabinowitz and Enerbäck, 2020). Accumulating evidence shows that lactate is more than a metabolic waste product (Dong et al., 2021;Xue et al., 2022) that can be preferred over glucose as a fuel and constitutes an important metabolic reserve molecule (Pellerin and Magistretti, 1994;Schurr et al., 1997b;Bouzier-Sore et al., 2003;Karagiannis et al., 2021). Lactate levels Abbreviations: 0 G, medium without glucose; ATP, adenosine triphosphate; ECAR, extracellular acidification rate; GLUT4, solute carrier family 2, facilitated glucose transporter member 4; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; SG, standard glucose (11.1 mM glucose); SMCT, sodium-coupled monocarboxylate transporter; TCA, tricarboxylic acid. ...
Lactate has long been acknowledged to be a metabolic waste product, but it has more recently been found as a fuel energy source in mammalian cells. Podocytes are an important component of the glomerular filter, and their role in maintaining the structural integrity of this structure was established. These cells rely on a constant energy supply and reservoir. The utilization of alternative energy substrates to preserve energetic homeostasis is a subject of extensive research, and lactate appears to be one such candidate. Therefore, we investigated the role of lactate as an energy substrate and characterize the lactate transport system in cultured rat podocytes during sufficient and insufficient glucose supplies. The present study, for the first time, demonstrated the presence of lactate transporters in podocytes. Moreover, we observed modified the amount of these transporters in response to limited glucose availability and after l-lactate supplementation. Simultaneously, exposure to l-lactate preserved cell survival during insufficient glucose supply. Interestingly, during glucose deprivation, lactate exposure allowed the steady flow of glycolysis and prevented glycogen reserves depletion. Summarizing, podocytes utilize lactate as an energy substrate and possess a developed system that controls lactate homeostasis, suggesting that it plays an essential role in podocyte metabolism, especially during fluctuations of energy availability.
... Under anaerobic conditions, glycolysis continues to function unabated, resulting in lactate accumulation, as the TCA cycle is nonfunctional (Figure 2). When lactate is accumulating, under anaerobic conditions, it becomes upon return to aerobic conditions the principal energy substrate until its levels are falling back to their minimal, normal levels [57,[61][62][63]. ...
... Some research groups have found that taking L-lactate has a neuroprotective effect in hypoxia/ischemia, cerebral hemorrhage, and traumatic brain injury animal models, respectively (Schurr et al. 1997;Rice et al. 2002;Horn and Klein 2013;Berthet et al. 2009Berthet et al. , 2012. Furthermore, taking a hypertonic lactate solution is beneficial to patients with AIS (Bouzat et al. 2014;Laurent et al. 2018;Buscemi et al. 2020). ...
Acute ischemic stroke (AIS) is a serious threat to human health. Following AIS, cerebral ischemia–reperfusion injury (CIRI) must be treated to improve prognosis. By combining 4D label-free quantitative proteomics with lactylation modification-specific proteomics analysis, we assessed lysine lactylation (Kla) in cortical proteins of a CIRI rat model. We identified a total of 1003 lactylation sites on 469 proteins in this study, gathering quantitative information (PXD034232) on 660 of 310 proteins, which were further classified by cell composition, molecular function, and biological processes. In addition, we analyzed the metabolic pathways, domains, and protein–protein interaction networks. Lastly, we evaluated differentially expressed lysine lactylation sites, determining 49 upregulated proteins and 99 downregulated proteins with 54 upregulated sites and 54 downregulated sites in the experimental group in comparison with the healthy control group. Moreover, we identified the Kla of Scl25a4 and Slc25a5 in the Ca²⁺ signaling pathway, but the Kla of Vdac1 was eliminated, as confirmed in vivo. Overall, these results provide new insights into lactylation involved in the underlying mechanism of CIRI because this post-translational modification affects the mitochondrial apoptosis pathway and mediates neuronal death. Therefore, this study may enable us to develop new molecules with therapeutic properties, which have both theoretical significance and broad clinical application prospects.
Graphical Abstract
A new model of cerebral ischemia–reperfusion injury (CIRI) induced by lactylation through the regulation of key proteins of the Ca²⁺ signaling pathway.
... Since the discovery that lactate can act as an agonist of the hydroxycarboxylic acid receptor 1 (HCAR1) [11,12], expressed in rodent and human brain tissue [13][14][15][16][17], a dual mechanism of action for neuroprotection has been proposed [4]. On the one hand, lactate could be used as a preferential metabolic substrate providing energy to suffering neurons [18][19][20]. On the other, lactate could trigger a signaling response after binding to its receptor, a Gi-coupled protein receptor that modulates neuronal firing rates [13,15,21]. ...
Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 (HCAR1) was proposed to account for lactate’s beneficial effects. However, the administration of HCAR1 agonists to mice subjected to middle cerebral artery occlusion (MCAO) at reperfusion did not appear to exert any relevant protective effect. To further evaluate the involvement of HCAR1 in the protection against ischemic damage, we looked at the effect of HCAR1 absence. We subjected wild-type and HCAR1 KO mice to transient MCAO followed by treatment with either vehicle or lactate. In the absence of HCAR1, the ischemic damage inflicted by MCAO was less pronounced, with smaller lesions and a better behavioral outcome than in wild-type mice. The lower susceptibility of HCAR1 KO mice to ischemic injury suggests that lactate-mediated protection is not achieved or enhanced by HCAR1 activation, but rather attributable to its metabolic effects or related to other signaling pathways. Additionally, in light of these results, we would disregard HCAR1 activation as an interesting therapeutic strategy for stroke patients.
... Besides, high intracellular lactate level can impede the coupled oxidation of NADH to nicotinamide adenine dinucleotide (NAD + ) in MCT1 inhibitor-treated cells (92). As a result, GSH reduction facilitates the production of hypoxia-enhanced superoxide radicals and hydrogen peroxide (92,93). Then, more cytochrome C is released from mitochondria, which further contributes to the cell death through an apoptotic pathway (87). ...
Monocarboxylate transporter 1 (MCT1) is expressed in glial cells and some populations of neurons. MCT1 facilitates astrocytes or oligodendrocytes (OLs) in the energy supplement of neurons, which is crucial for maintaining the neuronal activity and axonal function. It is suggested that MCT1 upregulation in cerebral ischemia is protective to ischemia/reperfusion (I/R) injury. Otherwise, its underlying mechanism has not been clearly discussed. In this review, it provides a novel insight that MCT1 may protect brain from I/R injury via facilitating lactate transport from glial cells (such as, astrocytes and OLs) to neurons. It extensively discusses (1) the structure and localization of MCT1; (2) the regulation of MCT1 in lactate transport among astrocytes, OLs, and neurons; and (3) the regulation of MCT1 in the cellular response of lactate accumulation under ischemic attack. At last, this review concludes that MCT1, in cerebral ischemia, may improve lactate transport from glial cells to neurons, which subsequently alleviates cellular damage induced by lactate accumulation (mostly in glial cells), and meets the energy metabolism of neurons.
... Similarly, Larrabee [72,73] provided further support for neuronal oxidative utilization of L-LAC. L-LAC was shown to be the obligatory energy substrate for the recovery of neuronal function from hypoxic/ischemic insult [74,75]. Using in vivo recording in the rat brain, Hu and Wilson [76] demonstrated that fluctuations in the levels of extracellular L-LAC and oxygen levels are coupled to neuronal activity. ...
Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment.
... In agreement with these findings, it has been previously shown in patients with traumatic brain injury that administration of hypertonic sodium lactate prevented raise in intracranial pressure, and improved cerebral perfusion and neurologic outcomes, independently of any hyperosmolar effect (15,25). These neuroprotective effects may be related to the fact that lactate is a better substrate than glucose in vitro and in vivo for ischemic neurons (18,26). Indeed, unlike glucose, lactate diffuses freely through cell membranes and does not require ATP-dependent activation via phosphorylation to enter the glycolysis pathway (27). ...
Objectives:
To determine whether continuous IV infusion of molar sodium lactate would limit cardiac arrest-induced neurologic injury and cardiovascular failure.
Design:
Randomized blinded study (animal model).
Setting:
University animal research facility.
Subjects:
Twenty-four adult male "New Zealand White" rabbits.
Interventions:
Anesthetized rabbits underwent 12.5 minutes of asphyxial cardiac arrest and were randomized to receive either normal saline (control group, n = 12) or molar sodium lactate (molar sodium lactate group, n = 12) at a rate of 5 mL/kg/hr during the whole 120-minute reperfusion period.
Measurements and main results:
Pupillary reactivity (primary outcome), levels of S100β protein, in vitro brain mitochondria functions, cardiovascular function, and fluid balance were assessed. Molar sodium lactate reduced brain injury, with a higher proportion of animals exhibiting pupillary reactivity to light (83% vs 25% in the CTRL group, p = 0.01) and lower S100β protein levels (189 ± 42 vs 412 ± 63 pg/mL, p < 0.01) at the end of the protocol. Molar sodium lactate significantly prevented cardiac arrest-induced decrease in oxidative phosphorylation and mitochondrial calcium-retention capacity compared with controls. At 120 minutes of reperfusion, survival did not significantly differ between the groups (10/12, 83% in the molar sodium lactate group vs nine of 12, 75% in the control group; p > 0.99), but hemodynamics were significantly improved in the molar sodium lactate group compared with the control group (higher mean arterial pressure [49 ± 2 vs 29 ± 3 mm Hg; p < 0.05], higher cardiac output [108 ± 4 vs 58 ± 9 mL/min; p < 0.05], higher left ventricle surface shortening fraction [38% ± 3% vs 19% ± 3%; p < 0.05], and lower left ventricular end-diastolic pressure [3 ± 1 vs 8 ± 2 mm Hg; p < 0.01]). While fluid intake was similar in both groups, fluid balance was higher in control animals (11 ± 1 mL/kg) than that in molar sodium lactate-treated rabbits (1 ± 3 mL/kg; p < 0.01) due to lower diuresis.
Conclusions:
Molar sodium lactate was effective in limiting the severity of the postcardiac arrest syndrome. This preclinical study opens up new perspectives for the treatment of cardiac arrest.
... Also, infarction is not correlated with the acidity of the cytosol in brain cells (276). More to the point, mild acidity of interstitial fluid, as well as high glucose-induced tissue acidosis, actually improve functional recovery from hypoxia in neuron cultures and brain tissue slices (324,345,347,349,401,402). The emphasis here is on the word "mild," for severe acidity undoubtedly kills cells (106,274). ...
Spreading depression (SD) and the related hypoxic SD-like depolarization (HSD) are characterized by rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments, that evolves as a regenerative, “all-or-none” type process, and propagates slowly as a wave in brain tissue. This article reviews the characteristics of SD and HSD and the main hypotheses that have been proposed to explain them. Both SD and HSD are composites of concurrent processes. Antagonists of N-methyl-d-aspartate (NMDA) channels or voltage-gated Na ⁺ or certain types of Ca ²⁺ channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD. Recent computer simulation confirmed that SD can be produced by positive feedback achieved by increase of extracellular K ⁺ concentration that activates persistent inward currents which then activate K ⁺ channels and release more K ⁺ . Any slowly inactivating voltage and/or K ⁺ -dependent inward current could generate SD-like depolarization, but ordinarily, it is brought about by the cooperative action of the persistent Na ⁺ current I Na,P plus NMDA receptor-controlled current. SD is ignited when the sum of persistent inward currents exceeds persistent outward currents so that total membrane current turns inward. The degree of depolarization is not determined by the number of channels available, but by the feedback that governs the SD process. Short bouts of SD and HSD are well tolerated, but prolonged depolarization results in lasting loss of neuron function. Irreversible damage can, however, be avoided if Ca ²⁺ influx into neurons is prevented.
... Lactate dehydrogenase (LDH), which is widespread in nearly every cell in the cytoplasm, converts lactate to pyruvate [138]. LDH levels differ with each tissue's metabolic needs, such as growth, biological conditions, and pathological aspects [139][140][141]. The human genome includes the following four LDH genes: LDHA, LDHB, LDBC, and LDHD [142]. ...
Abstract: Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.
... Lactate dehydrogenase (LDH), which is widespread in nearly every cell in the cytoplasm, converts lactate to pyruvate [138]. LDH levels differ with each tissue's metabolic needs, such as growth, biological conditions, and pathological aspects [139][140][141]. The human genome includes the following four LDH genes: LDHA, LDHB, LDBC, and LDHD [142]. ...
Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.
... Lactate production and accumulation happens in the adult brain during conditions when there is lack of oxygen (anoxia, hypoxia, or ischemia) [70]. Due to excess lactate production, the intracellular pH becomes low leading to an increase in the activity of hTREK-1 channel [28]. ...
TREK-1, a two-pore domain potassium channel, responds to ischemic levels of intracellular lactate and acidic pH to provide neuroprotection. There are two splice variants of hTREK1: the shorter splice variant having a shorter N-terminus compared with the full-length hTREK1 with similar C-terminus sequence that is widely expressed in the brain. The shorter variant was reported to be irresponsive to hypoxia—a condition attributed to ischemia, which has put the neuroprotective role of hTREK-1 channel into question. Since interaction between N- and C-terminus of different ion channels shapes their gating, we re-examined the sensitivity of the full-length as well as the shorter hTREK-1 channel to intracellular hypoxia along with lactate. Single-channel data obtained from the excised inside-out patches of the full-length channel expressed in HEK293 cells indicated an increase in activity as opposed to a decrease in activity in the shorter isoform. However, both the isoforms showed an increase in activity under combined hypoxia, 20mM lactate, and low pH 6 condition, albeit with subtle differences in their individual actions, confirming the neuroprotective role played by hTREK-1 irrespective of the differences in the N-terminus among the splice variants. Furthermore, E321A mutant that disrupts the interaction of the C-terminus with the membrane showed a decrease in activity with hypoxia indicating the importance of the C-terminus in the hypoxic response of the full-length hTREK-1. We propose an increase in activity of both the splice variants of hTREK-1 in combined hypoxia, high lactate, and low pH conditions typically associated with ischemia provides neuroprotection.
... 15 Moreover, in hippocampal slices, after a period of oxygen deprivation, accumulated brain lactate allows the recovery of neuronal functions upon reoxygenation. 59,60 In vivo, in rats undergoing a transient global cerebral ischemia, the inhibition of monocarboxylate transporter, reducing lactate transport, increased neuronal damages leading the authors to conclude that lactate is a critical oxidative energy substrate in the post-ischemic rat brain. 15 Considering the aforementioned data together with the fact that the immature brain readily metabolizes ketones as well as lactate, 30 and that MCTs are overexpressed during the entire breastfeeding period, 61,62 led us to investigate whether lactate administration after a neonatal HI insult could be neuroprotective. ...
Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1–6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.
... Beyond an energy source, a recent work proposed that lactate exerts a neuromodulatory role on excitatory synapses of the brain via GPR81 receptors (Lauritzen et al., 2014). This is particularly important, because generalized seizures trigger a transient hypoxia and increases non-oxidative glycolysis (Bromfield et al., 2006;Schurr et al., 1997aSchurr et al., , 1997b. Therefore, along with the availability of cerebral glycogen, glucose and lactate, the engagement of these substrates on complementary metabolic pathways should be performed in synchronized manner to avoid unnecessary waste of energy and substrates mobilization (Bouzier-Sore et al., 2006;Darbin et al., 2005;Fornai et al., 2000;Walling et al., 2007). ...
Generalized seizures trigger excessive neuronal firing that imposes large demands on the brain glucose/lactate availability and utilization, which synchronization requires an integral mitochondrial oxidative capability. We investigated whether a single convulsive crisis affects brain glucose/lactate availability and mitochondrial energy production. Adult male Wistar rats received a single injection of pentylentetrazol (PTZ, 60 mg/kg, i.p.) or saline. The cerebrospinal fluid (CSF) levels of glucose and lactate, mitochondrial respirometry, [ ¹⁴ C]-2-deoxy-D-glucose uptake, glycogen content and cell viability in hippocampus were measured. CSF levels of glucose and lactate (mean ± SD) in control animals were 68.08 ± 11.62 mg/dL and 1.17 ± 0.32 mmol/L, respectively. Tonic-clonic seizures increased glucose levels at 10 min (96.25 ± 13.19) peaking at 60 min (113.03 ± 16.34) returning to control levels at 24 h (50.12 ± 12.81), while lactate increased at 10 min (3.23 ± 1.57) but returned to control levels at 360 min after seizures (1.58 ± 0.21). The hippocampal [ ¹⁴ C]-2-deoxy-D-glucose uptake, glycogen content, and cell viability decreased up to 60 min after the seizures onset. Also, an uncoupling between mitochondrial oxygen consumption and ATP synthesis via FoF1-ATP synthase was observed at 10 min, 60 min and 24 h after seizures. In summary, after a convulsive seizure glucose and lactate levels immediately rise within the brain, however, considering the acute impact of this metabolic crisis, mitochondria are not able to increase energy production thereby affecting cell viability.
... Glycerol levels and uptake are not as strictly regulated as is glucose by insulin, thus WAT breaking up of glucose to 3C units has the advantage to eliminate excess glucose (and thus lower glycemia) 51 without creating a problem of energy supply to the brain, which can be sustained by both lactate and glycerol. 52,53 In sum, we found that NSC can match the glycolytic activity of adipocytes, being responsible for a significant portion (which may be a major part) of glycolytic conversion of blood glucose to lactate, a main substrate used to sustain a sizeable part of the energy needs of most body cells. 39 However, the efflux and gene expression data suggest that NSC do not participate in WAT active glycerol metabolism. ...
White adipose tissue (WAT) nucleated stromal cells (NSC) play important roles in regulation, defense, regeneration and metabolic control. In WAT sites, the proportions and functions of NSC change under diverse physiological or pathologic conditions. We had previously observed the massive anaerobic wasting of glucose to lactate and glycerol in rat epididymal adipocytes. To test site variability, and whether the adipocyte extensive anaerobic metabolism of glucose was found in NSC, we analyzed, in parallel, subcutaneous, mesenteric and epididymal WAT of male adult Wistar rats. Adipocytes and NSC fractions, were isolated, counted and incubated (as well as red blood cells: RBC) with glucose, and their ability to use glucose and produce lactate, glycerol, and free fatty acids was measured. Results were computed taking into account the number of cells present in WAT samples. Cell numbers were found in proportions close to 1:13:100 (respectively, for adipocytes, NSC and RBC) but their volumes followed a reversed pattern: 7,500:10:1. When counting only non-fat cell volumes, the ratios changed dramatically to 100:10:1. RBC contribution to lactate production was practically insignificant. In most samples, NSC produced more lactate than adipocytes did, but only adipocytes secreted glycerol (and fatty acids in smaller amounts). Glucose consumption was also highest in NSC, especially in mesenteric WAT. The heterogeneous NSC showed a practically anaerobic metabolism (like that already observed in adipocytes). Thus, NSC quantitative production of lactate markedly contributed (i.e. more than adipocytes) to WAT global use (wasting) of glucose. We also confirmed that glucose-derived glycerol is exclusively produced by adipocytes.
... The ability of lactate to replace glucose has been debated since the 1988 report by Schurr and colleagues (578) that 20 mmol/l lactate supported synaptic transmission in brain slices in the absence of glucose. This finding has been replicated by some studies [e.g., (202,320,576)], but not by others, and technical aspects of brain slice experiments contribute to discrepant findings (92,634,699). For example, the Okada group found that removal of glucose from the slice medium led to failure of evoked population spikes well before ATP and PCr were depleted and that lactate could not substitute for glucose [reviewed by Okada and Lipton (463)]. ...
Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components. Neuronal glucose oxidation exceeds that in astrocytes, but both rates increase in direct proportion to excitatory neurotransmission; signaling and metabolism are closely coupled at the local level. Exact details of neuron-astrocyte glutamate-glutamine cycling remain to be established, and the specific roles of glucose and lactate in the cellular energetics of these processes are debated. Glycolysis is preferentially upregulated during brain activation even though oxygen availability is sufficient (aerobic glycolysis). Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in excess of oxygen, and adrenergic regulation of aerobic glycolysis draws attention to astrocytic metabolism, particularly glycogen turnover, which has a high impact on the oxygen-carbohydrate mismatch. Aerobic glycolysis is proposed to be predominant in young children and specific brain regions, but re-evaluation of data is necessary. Shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation, neurotransmission, and memory consolidation are controversial topics for which alternative mechanisms are proposed. Nutritional therapy and vagus nerve stimulation are translational bridges from metabolism to clinical treatment of diverse brain disorders.
... Shortly thereafter, Schurr et al. (1988) observed the ability of lactate to maintain normal neuronal function in vitro in the absence of glucose or any other energy substrate. As the number of studies and reviews that support lactate role in oxidative energy metabolism in muscle (Brooks, 1998(Brooks, , 2000(Brooks, , 2002aBrooks et al., 1999a,b) and brain (Izumi et al., 1994;Pellerin and Magistretti, 1994;Larrabee, 1995Larrabee, , 1996Tsacopoulos and Magistretti, 1996;Hu and Wilson, 1997;Schurr et al., 1997Schurr et al., , 1999aSchurr and Rigor, 1998;Magistretti, 2000;Qu et al., 2000;Van Hall, 2000;Bliss and Sapolsky, 2001;Bouzier-Sore et al., 2003;Mangia et al., 2003;Smith et al., 2003;Dalsgaard et al., 2004;de Bari et al., 2004de Bari et al., , 2010Kasischke et al., 2004;Aubert et al., 2005;Schurr, 2006;Atlante et al., 2007;Schurr and Payne, 2007;Passarella et al., 2008;Herrero-Mendez et al., 2009;Zielke et al., 2009;Schurr and Gozal, 2011;Sotelo-Hitschfeld et al., 2012;Barros, 2013;Barros et al., 2013;Schurr, 2014;Rogatzki et al., 2015;Mächler et al., 2016;Barros and Weber, 2018; increased, the resistance to this concept escalated. As to muscle oxidative lactate utilization and the role of m-LDH in it, the pushback was based on the argument that mitochondria do not contain LDH (Rasmussen et al., 2002;Sahlin et al., 2002). ...
In 1988 two seminal studies were published, both instigating controversy. One concluded that “the energy needs of activated neural tissue are minimal, being fulfilled via the glycolytic pathway alone,” a conclusion based on the observation that neural activation increased glucose consumption, which was not accompanied by a corresponding increase in oxygen consumption (Fox et al., 1988). The second demonstrated that neural tissue function can be supported exclusively by lactate as the energy substrate (Schurr et al., 1988). While both studies continue to have their supporters and detractors, the present review attempts to clarify the issues responsible for the persistence of the controversies they have provoked and offer a possible rationalization. The concept that lactate rather than pyruvate, is the glycolytic end-product, both aerobically and anaerobically, and thus the real mitochondrial oxidative substrate, has gained a greater acceptance over the years. The idea of glycolysis as the sole ATP supplier for neural activation (glucose → lactate + 2ATP) continues to be controversial. Lactate oxidative utilization by activated neural tissue could explain the mismatch between glucose and oxygen consumption and resolve the existing disagreements among users of imaging methods to measure the metabolic rates of the two energy metabolic substrates. The postulate that the energy necessary for active neural tissue is supplied by glycolysis alone stems from the original aerobic glycolysis paradigm. Accordingly, glucose consumption is accompanied by oxygen consumption at 1–6 ratio. Since Fox et al. (1988) observed only a minimal if non-existent oxygen consumption compared to glucose consumption, their conclusion make sense. Nevertheless, considering (a) the shift in the paradigm of glycolysis (glucose → lactate; lactate + O2 + mitochondria → pyruvate → TCA cycle → CO2 + H2O + 17ATP); (b) that one mole of lactate oxidation requires only 50% of the amount of oxygen necessary for the oxidation of one mole of glucose; and (c) that lactate, as a mitochondrial substrate, is over eight times more efficient at ATP production than glucose as a glycolytic substrate, suggest that future studies of cerebral metabolic rates of activated neural tissue should include along with the measurements of CMRO2 and CMRglucose the measurement of CMRlactate.
... Use of pH as a surrogate marker of blood lactate in sick infants is rather inaccurate and it is conversely true for using lactate as indictor for acidosis [112]. After hypoxic episode the brain uses lactate and not glucose as energy source for the recovering synaptic function and may be the host's natural mechanism to protect against hypoglycaemia [113][114][115][116]. Hyperlactaemia in malaria may illustrate the metabolic derangement in the patient than a risk factor for nRA [58]. ...
Malaria is a composite condition of the Plasmodium parasite infection and accompanying pathologies. Parasite induced red blood cell perturbations and immunological response to infection drive various organ-specifc syndromes accounting for a huge percentage of deaths
amongst children <5 years and pregnant women. Te multi-factorial pathophysiology includes acute renal failure, hypoglycaemia, severe malaria anaemia, acute respiratory distress syndrome/ acute lung injury and cerebral malaria as some of the prominent presentations of the disease. Current malaria treatment has largely remained “anti-parasite” or “anti-infection” necessitating discovery of “anti-disease” drugs that will ameliorate immunological aberrations, infammation and metabolic disturbances which are ultimately the cause of high morbidity and mortality. Asiatic acid, a phytochemical, has well known curative properties on other conditions which share disease manifestations with malaria. However, the infuence of Asiatic acid on malaria has not yet been reported. Tis review unravels the diferent facets of Asiatic acid and their possible remedial efects on molecular and biological changes introduced by the disease with emphasis on how this relates to glucose metabolism, acute renal failure, severe malaria anaemia, acute respiratory distress syndrome/ acute lung injury and cerebral malaria.
... The present results confirm the association of sustained neuronal stimulation with a simultaneous increase in extracellular lactate and a decrease in extracellular glucose [17,[54][55][56][57][58][59][60][61]. Certain similarities can even be observed within the current and previous findings, such that the relative rise in brain extracellular lactate is higher than the relative decrease in glucose. ...
... Following the introduction of La − shuttling by the Brooks group, early evidence suggested that La − could support both normal synaptic function, and reactivate glucose-depleted synaptic quiescence in hippocampal slices (Schurr et al. 1988). This was furthered to conclude that La − , rather than glucose (Schurr et al. 1997b), is shuttled to post-hypoxic neurons to recover function (Schurr et al. 1997c) and that the La − is produced in glial cells (Schurr et al. 1997a). At approximately the same time that the supportive role of La − was being elucidated in the brain, the ANLS framework for the contemporary view of neuroenergetics was posited . ...
Lactate (La⁻) has long been at the center of controversy in research, clinical, and athletic settings. Since its discovery in 1780, La⁻ has often been erroneously viewed as simply a hypoxic waste product with multiple deleterious effects. Not until the 1980s, with the introduction of the cell-to-cell lactate shuttle did a paradigm shift in our understanding of the role of La⁻ in metabolism begin. The evidence for La⁻ as a major player in the coordination of whole-body metabolism has since grown rapidly. La⁻ is a readily combusted fuel that is shuttled throughout the body, and it is a potent signal for angiogenesis irrespective of oxygen tension. Despite this, many fundamental discoveries about La⁻ are still working their way into mainstream research, clinical care, and practice. The purpose of this review is to synthesize current understanding of La⁻ metabolism via an appraisal of its robust experimental history, particularly in exercise physiology. That La⁻ production increases during dysoxia is beyond debate, but this condition is the exception rather than the rule. Fluctuations in blood [La⁻] in health and disease are not typically due to low oxygen tension, a principle first demonstrated with exercise and now understood to varying degrees across disciplines. From its role in coordinating whole-body metabolism as a fuel to its role as a signaling molecule in tumors, the study of La⁻ metabolism continues to expand and holds potential for multiple clinical applications. This review highlights La⁻’s central role in metabolism and amplifies our understanding of past research.
... Other sources of lactate can be glycogen [97], the astrocyte-neuron lactate shuttle pathway [98], and the inter-astrocytic gap junction pathway [99]. The increased lactate is most likely utilized by neurons as an alternative energy supply [100][101][102], and in the hypoxic state observed during seizures, lactate harvested from different sources is then converted into pyruvate which is directed into glycolysis. The reduction of oxygen induces the expression of Hypoxia-Inducible Factors (HIF), whose major effects are the inhibition of the mitochondrial TCA cycle (aerobic) and the activation of glycolysis (anaerobic). ...
Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse.
... These genes are glucose transporter (GLUT1), hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase (PFKL), fructose-bisphosphate aldolase (ALDO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGM), enolase 1 (ENOA), pyruvate kinase (PK), pyruvate dehydrogenase kinase (PDK1) and lactate dehydrogenase A (LDH-A) [125,126]. Under stressful and pathological conditions, lactate and ketone bodies can be used as a substitute for glucose [127]. High concentration of lactate was known to induce glioma cell migration through its strong association with TGF-beta2-dependent regulation of MMP-2 and integrin α v β 3 ...
Cell migration is identified as a highly orchestrated process. It is a fundamental and essential phenomenon underlying tissue morphogenesis, wound healing, and immune response. Under dysregulation, it contributes to cancer metastasis. Brain is considered to be the most complex organ in human body containing many types of neural cells with astrocytes playing crucial roles in monitoring both physiological and pathological functions. Astrocytoma originates from astrocytes and its most malignant type is glioblastoma multiforme (WHO Grade IV astrocytoma), which is capable to infiltrate widely into the neighboring brain tissues making a complete resection of tumors impossible. Very recently, we have reviewed the mechanisms for astrocytes in migration. Given the fact that astrocytoma shares many histological features with astrocytes, we therefore attempt to review the mechanisms for glioma cells in migration and compare them to normal astrocytes, hoping to obtain a better insight into the dysregulation of migratory mechanisms contributing to their metastasis in the brain.
Isotope tracer infusion studies employing lactate, glucose, glycerol, and fatty acid isotope tracers were central to the deduction and demonstration of the Lactate Shuttle at the whole-body level. In concert with the ability to perform tissue metabolite concentration measurements, as well as determinations of unidirectional and net metabolite exchanges by means of arterial–venous difference (a-v) and blood flow measurements across tissue beds including skeletal muscle, the heart and the brain, lactate shuttling within organs and tissues was made evident. From an extensive body of work on men and women, resting or exercising, before or after endurance training, at sea level or high altitude, we now know that Organ–Organ, Cell–Cell, and Intracellular Lactate Shuttles operate continuously. By means of lactate shuttling, fuel-energy substrates can be exchanged between producer (driver) cells, such as those in skeletal muscle, and consumer (recipient) cells, such as those in the brain, heart, muscle, liver and kidneys. Within tissues, lactate can be exchanged between white and red fibers within a muscle bed and between astrocytes and neurons in the brain. Within cells, lactate can be exchanged between the cytosol and mitochondria and between the cytosol and peroxisomes. Lactate shuttling between driver and recipient cells depends on concentration gradients created by the mitochondrial respiratory apparatus in recipient cells for oxidative disposal of lactate.
The extracellular matrix (ECM) is a complex network of biomolecules that mechanically and biochemically directs cell behavior and is crucial for maintaining tissue function and health. The heterogeneous organization and composition of the ECM varies within and between tissue types, directing mechanics, aiding in cell-cell communication, and facilitating tissue assembly and reassembly during development, injury and disease. As technologies like 3D printing rapidly advance, researchers are better able to recapitulate in vivo tissue properties in vitro; however, tissue-specific variations in ECM composition and organization are not given enough consideration. This is in part due to a lack of information regarding how the ECM of many tissues varies in both homeostatic and diseased states. To address this gap, we describe the components and organization of the ECM, and provide examples for different tissues at various states of disease. While many aspects of ECM biology remain unknown, our goal is to highlight the complexity of various tissues and inspire engineers to incorporate unique components of the native ECM into in vitro platform design and fabrication. Ultimately, we anticipate that the use of biomaterials that incorporate key tissue-specific ECM will lead to in vitro models that better emulate human pathologies.
Statement of Significance
Biomaterial development primarily emphasizes the engineering of new materials and therapies at the expense of identifying key parameters of the tissue that is being emulated. This can be partially attributed to the difficulty in defining the 3D composition, organization, and mechanics of the ECM within different tissues and how these material properties vary as a function of homeostasis and disease. In this review, we highlight a range of tissues throughout the body and describe how ECM content, cell diversity, and mechanical properties change in diseased tissues and influence cellular behavior. Accurately mimicking the tissue of interest in vitro by using ECM specific to the appropriate state of homeostasis or pathology in vivo will yield results more translatable to humans.
Purpose:
Besides being actively metabolized, lactate may also function as a signaling molecule by activation of the G-protein-coupled receptor 81 (GPR81). Thus, we aimed to characterize the metabolic effects of GPR81 activation in Müller cells.
Method:
Primary Müller cells from mice were treated with and without 10 mM L-lactate in the presence or absence of 6 mM glucose. The effects of lactate receptor GPR81 activation were evaluated by the addition of 5 mM 3,5-DHBA (3,5-dihydroxybenzoic acid), a GPR81 agonist. Western blot analyses were used to determine protein expression of GPR81. Cell survival was assessed through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assays. Lactate release was quantified by commercially available lactate kits. 13C-labeling studies via mass spectroscopy and Seahorse analyses were performed to evaluate metabolism of lactate and glucose, and mitochondrial function. Finally, Müller cell function was evaluated by measuring glutamate uptake.
Results:
The lactate receptor, GPR81, was upregulated during glucose deprivation. Treatment with a GPR81 agonist did not affect Müller cell survival. However, GPR81 activation diminished lactate release allowing lactate to be metabolized intracellularly. Furthermore, GPR81 activation increased metabolism of glucose and mitochondrial function. Finally, maximal glutamate uptake decreased in response to GPR81 activation during glucose deprivation.
Conclusions:
The present study revealed dual properties of lactate via functioning as an active metabolic energy substrate and a regulatory molecule by activation of the GPR81 receptor in primary Müller cells. Thus, combinational therapy of lactate and GPR81 agonists may be of future interest in maintaining Müller cell survival, ultimately leading to increased resistance toward retinal neurodegeneration.
Loss of retinal ganglion cells (RGCs) is a leading cause of blinding conditions. The purpose of this study was to evaluate the effect of extracellular L-lactate on RGC survival facilitated through lactate metabolism and ATP production. We identified lactate as a preferred energy substrate over glucose in murine RGCs and showed that lactate metabolism and consequently increased ATP production are crucial components in promoting RGC survival during energetic crisis. Lactate was released to the extracellular environment in the presence of glucose and detained intracellularly during glucose deprivation. Lactate uptake and metabolism was unaltered in the presence and absence of glucose. However, the ATP production declined significantly for 24 h of glucose deprivation and increased significantly in the presence of lactate. Finally, lactate exposure for 2 and 24 h resulted in increased RGC survival during glucose deprivation. In conclusion, the metabolic pathway of lactate in RGCs may be of great future interest to unravel potential pharmaceutical targets, ultimately leading to novel therapies in the prevention of blinding neurodegenerative diseases, for example, glaucoma.
Astrocytes clear glutamate and potassium, both of which are released into the extracellular space during neuronal activity. These processes are intimately linked with energy metabolism. Whereas astrocyte glutamate uptake causes cytosolic and mitochondrial acidification, extracellular potassium induces bicarbonate-dependent cellular alkalinization. This study aimed at quantifying the combined impact of glutamate and extracellular potassium on mitochondrial parameters of primary cultured astrocytes. Glutamate in 3mM potassium caused a stronger acidification of mitochondria compared to cytosol. 15mM potassium caused alkalinization that was stronger in the cytosol than in mitochondria. While the combined application of 15mM potassium and glutamate led to a marked cytosolic alkalinization, pH only marginally increased in mitochondria. Thus, potassium and glutamate effects cannot be arithmetically summed, which also applies to their effects on mitochondrial potential and respiration. The data implies that, because of the non-linear interaction between the effects of potassium and glutamate, astrocytic energy metabolism will be differentially regulated.
Objectives:
Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats.
Methods:
Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effects of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effects of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury.
Findings:
Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats.
Conclusions:
Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage.
Until recently, astrocyte processes were thought to be too small to contain mitochondria. However, it is now clear that mitochondria are found throughout fine astrocyte processes and are mobile with neuronal activity resulting in positioning near synapses. In this review, we discuss evidence that astrocytic mitochondria confer selective resiliency to astrocytes during ischemic insults and the functional significance of these mitochondria for normal brain function.
Mitochondria are key cellular organelles that play crucial roles in the energy production and regulation of cellular metabolism. Accumulating evidence suggests that mitochondrial activity can be modulated by nitric oxide (NO). As a key neurotransmitter in biologic systems, NO mediates the majority of its function through activation of the cyclic guanylyl cyclase (cGC) signaling pathway and S-nitrosylation of a variety of proteins involved in cellular functioning including those involved in mitochondrial biology. Moreover, excess NO or the formation of reactive NO species (RNS), e.g. peroxynitrite (ONOO-), impairs mitochondrial functioning and this, in conjunction with nuclear events, eventually affects neuronal cell metabolism and survival, contributing to the pathogenesis of several neurodegenerative diseases. In this review we highlight the possible mechanisms underlying the noxious effects of excess NO and RNS on mitochondrial function including (i) negative effects on electron transport chain (ETC); (ii) ONOO--mediated alteration in mitochondrial permeability transition; (iii) enhanced mitochondrial fragmentation and autophagy through S-nitrosylation of key proteins involved in this process such as dynamin-related protein 1 (DRP-1) and Parkin/PINK1 (protein phosphatase and tensin homolog-induced kinase 1) complex; (iv) alterations in the mitochondrial metabolic pathways including Krebs cycle, glycolysis, fatty acid metabolism, and urea cycle; and finally (v) mitochondrial ONOO--induced nuclear toxicity and subsequent release of apoptosis-inducing factor (AIF) from mitochondria, causing neuronal cell death. These proposed mechanisms highlight the multidimensional nature of NO and its signaling in the mitochondrial function. Understanding the mechanisms by which NO mediates mitochondrial (dys)function can provide new insights into the treatment of neurodegenerative diseases.
Anesthetics, particularly barbiturates, have depressive effects on cerebral blood flow and metabolism and likely have similar effects on blood-brain barrier (BBB) transport. In previous studies utilizing the carotid injection technique, it was necessary to anesthetize the animals prior to performing the experiment. The carotid injection technique was modified by catheter implantation in the external carotid artery at the bifurcation of the common carotid artery. The technique was used to determine cerebral blood flow, the Km, Vmax, and KD of glucose transport in hippocampus, caudate, cortex, and thalamus-hypothalamus in conscious rats. Blood flow increased two to three times from that seen in the anesthetized rat. The Km in the four regions ranged between 6.5 and 9.2 mM, the Vmax ranged between 1.15 and 2.07 μmol/min/g, and the KD ranged between 0.015 and 0.035 ml/min/g. The Km and KD in the conscious rat did not differ from the values seen in the barbiturate anesthetized rat. The Vmax, on the other hand, increased two- to three-fold from that seen in the anesthetized rat and was nearly proportional to the increase in blood flow seen in the conscious rat. The development of the external carotid catheter technique now allows for determination of BBB substrate transport in conscious animals.
Previous animal and human studies showed that photic stimulation (PS) increased cerebral blood flow and glucose uptake much more than oxygen consumption, suggesting selective activation of anaerobic glycolysis. In the present studies, image-guided 1H and 31P magnetic resonance spectroscopy (MRS) was used to monitor the changes in lactate and high-energy phosphate concentrations produced by PS of visual cortex in six normal volunteers. PS initially produced a significant rise (to 250% of control, p less than 0.01) in visual cortex lactate during the first 6.4 min of PS, followed by a significant decline (p = 0.01) as PS continued. The PCr/Pi ratios decreased significantly from control values during the first 12.8 min of PS (p less than 0.05), and the pH was slightly increased. The positive P100 deflection of the visual evoked potential recorded between 100 and 172 ms after the strobe was significantly decreased from control at 12.8 min of PS (p less than 0.05). The finding that PS caused decreased PCr/Pi is consistent with the view that increased brain activity stimulated ATPase, causing a rise in ADP that shifted the creatine kinase reaction in the direction of ATP synthesis. The rise in lactate together with an increase in pH suggest that intracellular alkalosis, caused by the shift of creatine kinase, selectively stimulated glycolysis.
Brain lactate concentration is usually assumed to be stable except when pathologic conditions cause a mismatch between glycolysis and respiration. Using newly developed 1H NMR spectroscopic techniques that allow measurement of lactate in vivo, we detected lactate elevations of 0.3-0.9 mM in human visual cortex during physiologic photic stimulation. The maximum rise appeared in the first few minutes; thereafter lactate concentration declined while stimulation continued. The results are consistent with a transient excess of glycolysis over respiration in the visual cortex, occurring as a normal response to stimulation in the physiologic range.
Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state
molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose
uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar
ratio for the increases of 0.4:1. Transient increases in neural activity cause a tissue uptake of glucose in excess of that
consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow
for purposes other than oxidative metabolism.
Levels of energy metabolites were measured in forebrain regions in fasted rats subjected to 4-h recirculation after 1 h of either incomplete or complete ischemia. Both models of ischemia were produced by a procedure combining bilateral common carotid artery occlusion, systemic hypotension, and CSF pressure elevation; the degree of intracranial hypertension was varied to produce incomplete and complete ischemia. Levels of brain lactate at the end of ischemia ranged from 16 to 19 mmol/kg in incomplete ischemia and from 11 to 13 mmol/kg in complete ischemia. Energy metabolism recovered evenly in the neocortical and subcortical regions with recirculation after incomplete ischemia. The metabolic recovery in the cerebral cortex after complete ischemia was similar to that observed after incomplete ischemia; however, recovery in the subcortical regions after complete ischemia was less extensive, NADH fluorescence remained high, and there was a fall in total creatine. Intracellular pH in the dorsal thalamus was more alkalotic after complete than incomplete ischemia. Thus, in the absence of profound tissue lactic acidosis, residual CBF during prolonged ischemia helps postischemic restitution of brain energy metabolism in subcortical regions. The pattern of poor recovery in these regions after complete ischemia suggests inadequate reperfusion. The decreased total creatine and the severe tissue alkalosis may be biochemical markers of advanced tissue injury during reflow.
Entry into CSF and consumption by brain of blood borne lactate (La) was quantified in pentobarbital anesthetized, normocapnic dogs loaded and infused with NaLa and HLa to hold constant, in arterial blood, both the La concentration at about 8 mM (normal = 1 mM) and the pH at 7.4. In 4 dogs studied hourly over 6 hr, the arteriosagittal sinus blood concentration difference (ΔA-V La) was 0.41 ± 0.14 (SE) mM (P <0.05) and was time independent. CSF La rose slowly over 4 hours to about 0.6 of blood La while cisternal CSF pH remained nearly constant. Four acetate loaded controls showed no changes of ΔA-V La, CSF La, CSF, or arterial pH. Brain uptake of La was quantified in 8 dogs during insulin induced hypoglycemia, to mimimize possible competition by glucose. Cerebral blood flow (CBF) and ΔA-V for La, glucose, and O 2 were determined at 30 min intervals. CBF and cerebral metabolic rate of O 2 (CMRO 2) both fell about 17% during 2 hr of hypoglycemia and returned to control with La loading although blood glucose continued to fall to 1.5 mM. In the 2 hr La loaded period ΔA-V La was 0.27 ± 0.10 mM (n = 32) and CSF La rose to 0.7 of arterial La without altering CSF pH. CMRO 2 averaged 1.61 ± 0.14 μ mol/(min.gm brain), of which CMR glucose (x6 to give O 2 equivalents) provided 75% or 1.18 ± 0.13 μ 0 2 eq/(min/gm). CMR La x 3 was 28% of CMRO 2 or 0.45 ± 0.15 μ 0 2 eg(min/gm). The results suggest that blood borne La can stoichiometrically replace about one fourth of the glucose used as brain substrate during hypoglycemia, and probably during normoglycemia. Uptake may be limited by saturation of carriers facilitating passage of La across the blood brain barrier and into brain cells.
This study explores the influence of severe lactic acidosis in the ischemic rat brain on postischemic recovery of the tissue energy state and neurophysiological parameters. Severe incomplete brain ischemia (cerebral blood flow below 5% of normal) was induced by bilateral carotid artery clamping combined with hypovolemic hypotension. We varied the production of lactate in the tissue by manipulating the blood glucose concentrations. A 30-min period of incomplete ischemia induced in food-deprived animals caused lactate to accumulate to 15-16 mumol g-1 in cortical tissue. Upon recirculation these animals showed: (1) a considerable recovery of the cortical energy state as evaluated from the tissue concentrations of phosphocreatine, ATP, ADP, and AMP; and (2) return of spontaneous electrocortical activity as well as of somatosensory evoked response (SER). In contrast, administration of glucose to food-deprived animals prior to ischemia caused an increase in tissue lactate concentration to about 35 mumol g-1. These animals did not recover energy balance in the tissue and neurophysiological functions did not return. In other experiments the production of lactate during 30 min of complete compression ischemia was increased from about 12 mumol g-1 (normoglycemic animals) to 20-30 mumol g-1 by preischemic hyperglycemia and, in separate animals, combined hypercapnia. The recovery of the cortical energy state upon recirculation was significantly poorer in hyperglycemic animals. It is concluded that a high degree of tissue lactic acidosis during brain ischemia impairs postischemic recovery and that different degrees of tissue lactic acidosis may explain why severe incomplete ischemia, in certain experimental models, is more deleterious than complete brain ischemia.
Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
• Thirteen juvenile monkeys were taught two visual discrimination tasks. After 12 to 24 hours of food deprivation, ten underwent 14-minute episodes of cardiac arrest. Three served as controls. Five of the ten arrested animals survived and were tested in the discrimination box. All continued to perform color and pattern discrimination tasks with one to eight days' delay. All appeared neurologically intact, while brain pathologic examination after 11 to 64 days' survival showed either intact brains or injury restricted to nuclear structures in the brain stem, cerebellar Purkinje cells, and hippocampus. Five animals died 4 to 36 hours after they were resuscitated. Two required prolonged cardiac massage and, despite return of adequate cardiovascular function, died early. A third animal dislodged its arterial catheter and exsanguinated. The remaining two animals, who received infusions of glucose just prior to arrest, developed widespread fasciculations and myoclonic seizures. They became decerebrate and opisthotonic and were killed after 10 and 36 hours. Their brains showed mild edema and widespread necrosis of cortex and basal ganglia. Thus, food-deprived monkeys tolerate 14 minutes of circulatory arrest well and show minimal neurologic and pathologic changes, while administration of glucose just before arrest markedly augments the severity of brain injury and alters its distribution.
The rat hippocampal slice preparation was used to evaluate the effect of increasing glucose levels in the perfusion medium on the recovery of synaptic function after a standardized hypoxic insult. Slices exposed to low glucose (5 mM) did not recover from a standard hypoxic insult (10 min of 95% N2/5% CO2 atmosphere). Following the same insult, 39% of the control (10 mM glucose) slices recovered their synaptic function, while 93% of the slices provided with high glucose level (20 mM) exhibited recovery of synaptic function. Thus, a dose-dependent effect of glucose on recovery of neuronal function following an intermediate period (10 min) of oxygen deprivation was found. The high-glucose-treated slices could tolerate a severe hypoxic insult of 15 min or even 20 min from which 94% and 81% of them recovered, respectively. Only 21% of the control (10 mM glucose) slices recovered their synaptic activity following 15 min of hypoxia, and none survived 20 min of that insult.The adverse effects of hyperglycemia reported in vivo were not seen in our study. This may be due to the sustained perfusion of the brain slice preparation, which could limit accumulation of lactic acid during hypoxia. However, treatment of slices with lactic acid prior to and during the hypoxic insult did not worsen the outcome. Alternatively, glucose may protect against the damaging effects of oxygen free radicals formed during reoxygenation. Nevertheless, the antihypoxic effect of glucose appears to be a metabolic one, since l-glucose (the non-metabolic analog of d-glucose) was innocuous in this respect.
Rats with different levels of blood glucose concentration were exposed to 10 min of complete brain ischemia achieved by compression of neck vessels by a pneumatic cuff.
All normoglycemic rats survived the ischemic period and made the best clinical recovery. Hyperglycemic rats died within 12 h. Seizure activity was observed in all animals in this group. Three of eight hypo-glycemic rats died between 3 and 16 days. The clinical recovery was less complete than in the control group.
Thus, recovery from cerebral ischemia depends upon preischemic blood glucose concentration. Hyper- and hypoglycemia hamper the clinical recovery after transient cerebral ischemia.
Brain uptake of radiolabeled D and L-lactate, D-glucose and nicotine, as measured by the intra-carotid bolus method, was examined over a range of pH of the injected solution. The uptake of L-lactate was highest at pH 6.1, and lowered significantly at pH 7.2, 7.5 and 8.4. In contrast, the uptake of the D-enantiomer was not as dramatically affected. Glucose uptake was not affected by alterations in pH. Nicotine uptake decreased with pH reduction through a range of 8.3-4.2. These data suggest that it is the uncharged molecule which penetrates the blood-brain barrier by both carrier and lipid mediation. A mechanism relating to these observations is postulated and possible relevance to lactate washout from ischemic brain discussed.
—Cerebral blood flow (CBF) and the cerebral metabolic rates for oxygen, glucose, acetoacetate, β-hydroxybutyrate and lactate were measured in 1- to 5-day old Beagle dogs under nitrous oxide anesthesia. CBF was determined by 133Xe washout with mechanically integrated blood samples withdrawn simultaneously from a femoral artery and from the posterior one-third of the superior sagittal sinus. CBF and CMRO2 in normocapnia (PaCO2 40 × 1 mm Hg) were 48 × 5 ml/100 g/min and 2.15 ml/100 g/min, respectively. There was a positive, linear relationship between CBF and PaCO2, calculated for PaCO2 values ranging from 26 to 70 mm Hg. Induced hypocapnia (PaCO2 31 × 1 mm Hg) or hypercapnia (PaCO2 58 × 2 mm Hg) did not alter the CMRO2. Glucose and acetoacetate were taken up by the brain at all PaCO2 levels examined; however, the cerebral uptake of glucose always exceeded the combined uptake of ketone bodies by more than a factor of ten. The cerebral metabolic rate for glucose (94.6 × 3.6 μmol/100 g/min) more than accounted for overall cerebral oxygen consumption, and yielded an oxygen:glucose ratio (mol:mol) of 5.1. Thus, as in adult animals, PaCO2 is an important regulator of cerebral blood flow in puppies, and glucose is the major substrate for oxidative energy production in the immature brain. The oxidation of ketone bodies by the newborn dog brain accounts for not more than 6% of the in vivo cerebral oxygen consumption.
It has been reported that incomplete cerebral ischemia with cerebral blood flow less than 10% of control may be more damaging than an equal period of complete ischemia. In this study, the effects of severe, incomplete cerebral ischemia on neurological outcome and cerebral metabolism were studied in dogs anesthetized with nitrous oxide. The results were compared with those of a previous study concerned with the effects of complete ischemia. Dogs could sustain only 8 to 9 minutes of complete ischemia with return of normal neurological function, whereas maintenance of a cerebral blood flow rate less than 10% of control extended this limit to 10 6o 12 minutes. Following a 10-minute exposure, only dogs undergoing incomplete ischemia regained a normal cerebral oxygen consumption within 90 minutes; similarly, animals subjected to incomplete ischemia enjoyed a faster return of EEG activity than dogs exposed to complete ischemia of the same duration. Cerebral metabolite levels did not prove to be a good index of return of neurological function. Within periods of cerebral ischemia in which meaningful neurological recovery might be expected, we conclude that some blood flow is better than no flow.
— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.
Fed and starved rats were studied on successive days during a 5-day starvation period. The ability of ketone bodies to pass the blood-brain barrier was estimated by single common carotid injections of labeled ketone bodies and water, and results were expressed as the ratio between the normalized activities of tracers in tissue and blood, the brain uptake index (BUI). BUI of D-3-hydroxybutyrate and acetoacetate decreased as their total concentrations increased in the injectate bolus: BUI of D-3-hydroxybutyrate decreased significantly from 8% at 0.2 mM to 3--4% at 20.2 mM in fed rats and from 11.5% at 0.2 mM to 6% at 20.2 mM in starved rats, indicating saturation of the uptake mechanism. The BUI of both ketone bodies increased significantly with increasing duration of starvation, indicating adaptation to ketonemia. Enzymatic kinetics explained the uptake behavior of D-3-hydroxybutyrate in both fed and starved rats and involved a rise of Km and Vmax during starvation consistent with a doubling of the transport rate at the degree of ketonemia found in starved rats. The uptake of glucose was not influenced by starvation or ketonemia.
A dual linear-flow chamber for comparative studies using brain slices is described. Electrophysiological and ultrastructural analysis of rat hippocampal slices incubated in the chamber showed that its two compartments allows performance of reliable paired comparison studies in a highly efficient manner.
The present study was undertaken to examine the possibility that cerebral energy metabolism can be fueled by lactate. As a sole energy substrate, lactate supported normal synaptic function in rat hippocampal slices for hours without any sign of deterioration. Slices that were synaptically silent as a result of glucose depletion could be reactivated with lactate to show normal synaptic function. When slices were exposed to the glycolytic inhibitor iodoacetic acid, lactate-supported synaptic function was unaffected, whereas that supported by glucose was completely abolished. This indicated that lactate was metabolized directly via pyruvate to enter the tricarboxylic acid cycle. Thus, under conditions that lead to lactate accumulation (cerebral ischemia) this "end product" may be a useful alternative as a substrate for energy metabolism.
Coupling between cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) was studied using multiple sequential administrations of 15O-labeled radiotracers (half-life, 123 sec) and positron emission tomography. In the resting state an excellent correlation (mean r, 0.87) between CBF and CMRO2 was found when paired measurements of CBF and CMRO2 from multiple (30-48) brain regions were tested in each of 33 normal subjects. Regional uncoupling of CBF and CMRO2 was found, however, during neuronal activation induced by somatosensory stimulation. Stimulus-induced focal augmentation of cerebral blood flow (29% mean) far exceeded the concomitant local increase in tissue metabolic rate (mean, 5%), when resting-state and stimulated-state measurements were obtained in each of 9 subjects. Stimulus duration had no significant effect on response magnitude or on the degree of CBF-CMRO2 uncoupling observed. Dynamic, physiological regulation of CBF by a mechanism (neuronal or biochemical) dependent on neuronal firing per se, but independent of the cerebral metabolic rate of oxygen, is hypothesized.
The present investigation examined the effects of two glucose analogues, 3-0-methyl-D-glucose (30MG) and 2-deoxy-D-glucose (2DOG) on basal levels of rat brain glucose and lactate. The results showed that pretreatment (iv) with 30MG up to 2 g/kg caused a transient drop in brain glucose levels to 42% of control value within 2.5 min and a drop in lactate levels to 75% of control value by 5 min. 2DOG administration (2 g/kg) affected glucose in a biphasic response with an initial drop to 46% of control value seen by 2.5 min, followed by a progressive increase to 290% of the control value by 40 min. This elevated level of glucose was sustained for approximately 40 min. Lactate levels responded to 2DOG administration by a decrease to 37% of control value within 10 min post-injection and returned to near basal levels by 160 min. A dose response was also examined for both compounds. Behaviorally 30MG had no apparent effects. However, the response to 2DOG was a reduction in voluntary movements, piloerection, irregular clonic jerks, splayed limbs and fits of wild running. These experiments were designed to evaluate the potential of 30MG or 2DOG for attenuating the well documented rise in brain lactate levels following an ischemic insult. Our results suggest that under certain experimental conditions either 30MG or 2DOG could prevent brain lactate rise and might have beneficial effects in minimizing the neuropathological consequences of ischemic damage that could be related to increases in brain lactate.
The susceptibility of the brain to anoxia is considered to be the limiting factor for resuscitation after transient circulatory arrest, both in clinical and experimental conditions.1,2 In the classic experiments of Weinberger et al,3 Kabat et al,4 Grenell,5 Hirsch et al,6 and others, the upper limit for full recovery was found to be three to four minutes of cardiocirculatory arrest, and eight to ten minutes of isolated cerebrovascular arrest.
The high sensitivity of the central nervous tissue to ischemia has been attributed to low reserves in substrates suitable for anaerobic energy metabolism, because a close correlation was found between the depletion of energy-rich phosphates and the irreversibility of brain damage.7 This concept, however, is difficult to reconcile with more recent demonstrations of the recovery of various neuronal functions after time intervals which by far exceed the limit of energy depletion. Examples are the return
—The time course of effects of 2-deoxy-d-glucose on cerebral glucose metabolism has been studied in vivo and the inhibitory actions of 2-deoxy-d-glucose and 2-deoxy-d-glucose-6-phosphate on cerebral glycolytic enzymes in vitro. Mice were given 2-deoxy-d-glucose 3 g/kg intraperitoneally. Blood 2-deoxy-d-glucose/glucose ratio was 2–3 from 5 to 30 min after injection, the hyperglycaemic response to 2-deoxy-d-glucose having been suppressed with propranolol. Maximal cerebral 2-deoxy-d-glucose uptake observed was 1μ11 μmol/g/min between 5 and 10 min after injection. At 10 min brain concentrations of 2-deoxy-d-glucose and 2-deoxy-d-glucose-6-phosphate were 5·82 and 3·12 μmol/g. Analysis of the fate of d-[U-¹⁴C] glucose given subcutaneously 5 min before death showed that glucose uptake was reduced to 40–60 per cent of control from 5 to 30 min after 2-deoxy-d-glucose. However brain glucose concentration rose three to five-fold 20–30 min after 2-deoxy-d-glucose. The majority of glucose entering the brain after 10 min of 2-deoxy-d-glucose treatment was recovered as glucose. Conversion of brain glucose to other acid soluble components was reduced to 1/3 at 10 min and 1/5 at 20–30 min. Glucose-6-phosphate concentration rose from 5 min onwards and was maintained at twice control concentration from 10–30 min. However, because of the rapid entry of 2-deoxy-d-glucose and its conversion to 2-deoxy-d-glucose-6-phosphate, the 2-deoxy-d-glucose 6-P/glucose 6-P ratio was between 19 and 32. Brain adenosine triphosphate concentration did not change, creatine phosphate concentration fell after 25 min.
Although the brain may rephosphorylate phosphocreatine, recharge the adenine nucleotide pool to values within 1% of normal, and metabolize accumulated lactate even after ischemic periods lasting 15 min, the results do not exclude the possibility of a permanent biochemical lesion. There is no indication that a failure of reperfusion after the ischemia is responsible for the metabolic alterations observed. Since any biochemical lesion may affect only a small number of neurons, further studies of biochemical recovery must utilize very sensitive methods and include more metabolites than those studied so far.
Until a few years ago, it was generally thought that irreversible brain damage would result from any condition that produced a profound cerebral anoxia of greater than eight to ten minutes' duration. This conclusion was based on observations made by physicians during clinical emergencies and by investigators using experimental models in which the onset, degree, and duration of anoxia could be controlled.1-6 Most techniques for producing anoxia in the intact animal also produce ischemia and there is some evidence to suggest that cerebral anoxia is exacerbated by ischemia.7 However, the results of recent studies with totally ischemic brain tissue suggest that many of the variables measured approach normal after reoxygenation. This has led some workers to question whether cerebral anoxia actually causes irreversible brain damage within so short a period as ten minutes.8-11
If proper protocols are to be established for the treatment of cardiac arrests and
Blood and whole brain 14C and 32P activities were determined in hepatectomized rats one, two, five and ten minutes after intravenous (I.V.) injection of 14C-labeled L-lactate or D-lactate and 32P-labeled rat red blood cells. Whole brain homogenate 14C was corrected for blood 14C and chemically partitioned into 14C-lactate, 14CO2and other 14C compounds. In controls, lactate was replaced with 14C-D-glucose and 125l-antipyrine. At one minute postinjection, whole brain 14C expressed as percent of total injected 14C activity and as percent of the antipyrine value were: antipyrine 1.78% (100%); D-glucose 1.45% (81%); L-lactate 0.36% (20%); and D-lactate 0.13% (7%). One minute after L-lactate injection, brain 14C was 74% lactate, 5% CO2and 21% other compounds. Preloading rats with cold racemic Na-lactate reduced L-lactate uptake to 0.14% of the injectate (8% of antipyrine), and reduced D-Iactate uptake to 0.09% (=5% of antipyrine). At two, five and ten minutes, brain contained more 14C with larger fractions metabolized to CO2and other compounds from both L-lactate and D-lactate. The blood-brain barrier appears to contain a saturable lactate carrier exhibiting threefold L-stereospecificity to D-stereospecificity, but resulting in far less net transport than the comparable glucose carrier. Lactate transport may be limited by the scarcity of neutral lactic acid at normal blood pH.
In order to evaluate the influence of cellular acidosis upon the restitution of brain energy metabolism after ischemia the amount of lactate accumulated during a 5 min period of total compression ischemia was varied by means of induced hypoglycemia (administration of insulin) or hyperglycemia (administration of glucose). In this way the lactate content of the tissue varied between 4.8 (hypoglycemia) and 20.7 (hyperglycemia) μmoles/g. Calculations indicate that the corresponding intracellular pH values differed by 0.8 units, and that the hyperglycemic animals had an intracellular pH of close to 6. In spite of these pH differences the energy state of the tissue, as evaluated from the concentrations of phosphocreatine, creatine, ATP, ADP and AMP, and from the adenylate energy charge, did not differ between the groups. Furthermore, when the tissue was recirculated for 15 min following a 5 min ischemic period there was an identical degree of restitution of the energy state in the hypo-, normo- and hyperglycemic animals. Thus, the results lend no support to the view that even a marked lactic acidosis adversely affects the ability of brain cells to survive total ischemia of limited duration.
BSA, Bovine serum albumin; EDTA, Ethylenediaminetetraacetate; FFA, Free fatty acids; GABA, γ-Aminobutyric acid; GSH and GSSG, Reduced and oxidized glutathione, respectively; P/O and ADP/O ratios, Ratios between Pi or ADP consumed, respectively, and of oxygen (atoms) utilized; RCR, Respiratory control ratios
Glucose was infused intravenously into cats prior to cerebral ischemia. Brain concentrations of glucose, measured in 7 regions, were elevated 2.5-fold compared to those of non-infused animals. Ischemia of 15 or 30 minutes duration caused a greater accumulation of lactic acid in the brain of glucose-infused animals. Post-ischemic restitution of cerebral ATP, phosphocreatine, and lactate during 90 minutes of recirculation was severely impaired in the brain of animals pretreated with glucose compared to untreated animals. Thus, excess lactic acidosis may be a major factor interfering with metabolic restitution following cerebral ischemia.
Severe hypoglycaemia with brain dysfunction limits intensified therapy in patients with insulin-dependent diabetes mellitus, despite evidence that such therapy reduces the risk of chronic complications of the disease. We have investigated the effect of infusing lactate (a potential non-glucose fuel for brain metabolism) on protective, symptomatic neurohumoral responses and on brain function during hypoglycaemia in seven healthy men. Elevation of lactate (within a physiological range) substantially diminished catecholamines, growth hormone, cortisol, and symptomatic responses to hypoglycaemia and lowered the glucose level at which these responses began. Glucagon responses were unaffected. Lactate was also associated with a significant lowering of the glucose level at which brain function deteriorated, suggesting that brain function was protected during the hypoglycaemia. The defect in counter-regulation is similar to that seen in hypoglycaemia-prone diabetic patients. Initiation of the protective responses to hypoglycaemia (except glucagon) can be delayed by supporting metabolism with an alternative metabolic fuel. Cerebral cortical dysfunction of severe hypoglycaemia is also delayed. Our demonstration that higher brain function can be protected during hypoglycaemia may have therapeutic potential.
Rat hippocampal slices were used to evaluate the effects of glucose deprivation and the ability of lactate or pyruvate to preserve histological integrity and synaptic function. Dark cell changes were observed during 180 min incubations in glucose-free solutions. These changes were blocked by substituting 10 mM lactate or pyruvate for glucose during the incubation. Excitatory postsynaptic potentials disappeared during 60 min of glucose deprivation but were restored by subsequent introduction of glucose, lactate or pyruvate. Incubation of slices with iodoacetate revealed a distinct pattern of damage that was blocked completely by pyruvate and partially by lactate. These results indicate that exogenous pyruvate and lactate can serve as energy substrates in the hippocampus when glucose is unavailable or glycolytic metabolism is impaired.
Lactate supports normal synaptic function and may be neuroprotective following an anoxic insult. The present study investigated the effects of lactate on epileptic depolarization and long-term synaptic failure during a zero-magnesium-induced epileptic insult using the hippocampal slice preparation. In artificial cerebrospinal fluid (aCSF) containing 10 mM D-glucose, no epileptic depolarization was observed. At lower concentrations of D-glucose, epileptic depolarization occurred and often was followed by long-term synaptic failure. Low concentrations of lactate, in place of D-glucose, supported normal synaptic transmission. However, no concentration of lactate tested (up to 30 mM) blocked the occurrence of epileptic depolarization. High concentrations of lactate allowed for partial recovery of synaptic responses following epileptic depolarization. Reinstatement of D-glucose was necessary to observe this recovery. The results confirm that lactate can replace D-glucose in maintaining synaptic responses, but demonstrate that lactate cannot replace D-glucose in blocking an insult-induced depolarization. The inability of lactate to mimic all the effects of D-glucose is consistent with the notion of compartmentation of energy utilization within neurons.
The effects of mild stress on nonoxidative glucose metabolism were studied in the brain of the freely moving rat. Extracellular lactate levels in the hippocampus and striatum were monitored at 2.5-min intervals with microdialysis coupled with an enzyme-based flow injection analysis system. Ten minutes of restraint stress led to a 235% increase in extracellular lactate levels in the striatum. A 5-min tail pinch caused an increase of 193% in the striatum and 170% in the hippocampus. Local application of tetrodotoxin in the striatum blocked the rise in lactate following tail pinch and inhibited the subsequent clearance of lactate from the extracellular fluid. Local application of the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 had no effect on the tail pinch-stimulated increase in lactate in the striatum. These results show that mild physiological stimulation can lead to a rapid increase in nonoxidative glucose metabolism in the brain.
Brain metabolism: A perspective from the blood-brain barrier
- W M Partridge