Cerebral Lactate Research Articles

Lactate supplementation in severe traumatic brain injured adults by primed constant infusion of sodium L-lactate.

Carbohydrate fuel augmentation following traumatic brain injury may be a viable treatment to improve recovery when cerebral oxidative metabolism of glucose is depressed. We performed a primed constant sodium L-lactate infusion in 11 moderate to severely brain injured adults. Blood was collected before and periodically during the infusion study. We quantified global cerebral uptake of glucose and lactate and other systemic metabolites associated with energy metabolism. Our hypothesis was that cerebral lactate uptake, as measured by the arteriovenous difference of lactate (AVDlac), would increase in severely injured TBI patients in the neurocritical care unit. Infusion of sodium L-lactate changed net cerebral lactate release, where the arteriovenous difference of lactate is negative, to net cerebral lactate uptake. Results from a mixed effects model of AVDlac with the fixed effects of infusion time, arterial lactate concentration, arterial glucose concentration and arteriovenous difference of glucose shows that doubling arterial lactate concentration (from .92 to 1.84 mM) results in an increase in AVDlac from -.078 mM to .090 mM. We did not detect changes in systemic glucose during the course of the infusion study and observed significant changes in alanine (30% [20 39]), glutamine (34% [24 43]), acetate (87% [60 113]), valine (40% [28 51]), and leucine (24% [16 32]) from baseline levels. Further studies are required to establish the impact of lactate supplementation on cerebral and systemic flux of lactate, on gluconeogenesis, and on the impact on cerebral energetics following injury. © 2017 Wiley Periodicals, Inc.

Analysis of extracellular brain chemistry during percutaneous dilational tracheostomy: A retrospective study of 19 patients

ObjectiveThe purpose of this study was to analyze changes in brain tissue chemistry around percutaneous dilational tracheostomy (PDT) in patients with acute brain injury (ABI) in a retrospective single-center analysis. Patients and methodsWe included 19 patients who had continuous monitoring of brain tissue chemistry and intracranial pressure (ICP) during a 20h period before and after PDT. Different microdialysis parameters (lactate, pyruvate, lactate pyruvate ratio (LPR), glycerol and glutamate) and values of ICP, cerebral perfusion pressure (CPP) and brain tissue oxygenation (PBrO2) were recorded per hour. Mean values were compared between a 10h period before PDT (prePDT) and after PDT (postPDT). ResultsMean values of cerebral lactate, pyruvate, LPR, glycerol and glutamate did not differ significantly between prePDT and postPDT. In addition, the rate of patients, which exceeded the known threshold was similar between prePDT and postPDT. Only one patient showed a strong increase of cerebral glycerol during the postPDT period, but analysis of subcutaneous glycerol could exclude an intracerebral event. ICP, CPP and PBrO2 did not exhibit significant changes. ConclusionsWe could exclude the occurrence of cerebral metabolic crisis and the excess release of cerebral glutamate and glycerol in a series of 19 patients. Our results support the safety of PDT in patients with ABI.

Brain metabolism in health, aging, andneurodegeneration.

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.

Accumulation of lactate in the rat brain during hyperammonaemia is not associated with impaired mitochondrial respiratory capacity

In acute liver failure (ALF) cerebral oedema and high intracranial pressure (ICP) are potentially deadly complications. Astrocytes cultured in ammonia have shown mitochondrial dysfunction and in rat models of liver failure, de novo lactate production in the brain has been observed and has led to a hypothesis of compromised brain metabolism during ALF. In contrast, normal lactate levels are found in cerebral microdialysate of ALF patients and the oxygen: glucose ratio of cerebral metabolic rates remains normal. To investigate this inconsistency we studied the mitochondrial function in brain tissue with respirometry in animal models of hyperammonaemia. Wistar rats with systemic inflammation induced by lipopolysaccharide or liver insufficiency induced by 90% hepatectomy were given ammonium or sodium acetate for 120min. A cerebral cortex homogenate was studied with respirometry and substrates of the citric acid cycle, uncouplers and inhibitors of the mitochondrial complexes were successively added to investigate the mitochondrial function in detail. In a separate dose-response experiment cortex from healthy rats was incubated for 120min in ammonium acetate in concentrations up to 80mM prior to respirometry. Hyperammonaemia was associated with elevated ICP and increased tissue lactate concentration. No difference between groups was found in total respiratory capacity or the function of individual mitochondrial complexes. Ammonium in concentrations of 40 and 80mM reduced the respiratory capacity in vitro. In conclusion, acute hyperammonaemia leads to elevated ICP and cerebral lactate accumulation. We found no indications of impaired oxidative metabolism in vivo but only in vitro at extreme concentrations of ammonium.

Abstract 12025: Higher Lactate Oxygen Index Rather than Artery Lactate Indicate Poor 24h-survival After Resuscitation in a Porcine Model of Prolonged Cardiac Arrest

Introduction: Increases in arterial lactate concentration (ALac) and cerebral lactate oxygen index (LOI) are documented indicators of poor prognosis in critically ill patients. In the present study, we investigated the changes of ALac and LOI after successful cardiopulmonary resuscitation (CPR) in a porcine model of prolonged cardiac arrest (CA). Hypothesis: Lactate oxygen index serves as a more sensitive indicator of post resuscitation survival than arterial lactate. Methods: Twelve male domestic pigs weighing 40 ± 3kg were studied. Ventricular fibrillation was electrically induced and untreated for 10 min. All animals were successfully resuscitated. Blood gas samples were obtained from the internal jugular vein and abdominal descending aorta at baseline (BL), 30 min and 120 min after resuscitation (PR). LOI was calculated based on the arterial (CaO 2 ) and jugular venous oxygen (CjO 2 ) content: CaO 2 = (1.34 х Hb х SaO 2 ) + (0.003 х paO 2 ), CjO 2 = (1.34 х Hb х SjO 2 ) + (0.003 х pjO 2 ), LOI = -(arterial lactate-jugular vein lactate)/(CaO 2 -CjO 2 ). Results: Five animals died in <24 h after initial resuscitation and the other seven survived > 24 h. The level of ALac in all animals increased significantly at PR30 and returned to BL at PR120. No significant differences in ALac were observed between survivors and non-survivors. LOI was increased in all animals after resuscitation when compared with BL. We observed significantly higher LOI levels at PR30 and PR120 in non-survivors vs. survivors. Conclusions: Higher LOI levels after resuscitation indicate poor 24 h survival in a pig model of prolonged CA.

Cerebral tissue oxygenation index and lactate at 24 hours postoperative predict survival and neurodevelopmental outcome after neonatal cardiac surgery.

There are no well-established noninvasive biomarkers for identifying patients at risk for poor outcome after surgery for congenital heart disease. Few studies have assessed prognostic accuracy of cerebral tissue oxygenation index (cTOI) measured by near infrared spectroscopy (NIRS). To assess the utility of noninvasive NIRS monitoring as a predictor of outcomes after neonatal cardiac surgery through measurement of cTOI. To examine the utility of noninvasive NIRS monitoring in combination with lactate concentration and inotropic score in prediction of outcomes after neonatal cardiac surgery. Prospective longitudinal cohort study. Operating room and cardiac intensive care unit, Children's National Heart Institute. Seventy-five patients with complex congenital heart disease undergoing surgical repair within first month of life. Cerebral TOI, blood lactate, and inotropic scores were measured preoperative, intraoperative and up to 24 hours postoperative. Postoperative mortality and neurodevelopmental outcome assessed by the Bayley Scales of Infant Development (BSID II). Mental and motor scores were obtained at 6, 15, and 21 months. Good outcome was defined as survival and BSID mental and motor scores ≥70 points. Poor outcome was defined as death or BSID scores <70 at most recent follow-up. Cohort of 75 patients prospectively followed including 40 patients with single ventricle and 35 with two ventricles. Four patients died before discharge and ten died within 21 months. Seven patients were lost to follow-up. Among survivors with follow-up (n = 54), BSID was abnormal in 25 (46%). Patients with poor outcome (n = 39) had lower mean cTOI 60 minutes off-CPB (48% vs. 58%, P = .003) and 24 hours postoperative (49% vs. 59%, P < .001), higher lactate (8.2 vs. 5.0 mmol/L, P = .005) and higher inotropic scores (10 vs. 6, P = .02) at 24 hours postoperative. ROC analysis indicated that cTOI had moderate predictive accuracy of outcome (AUC = 0.751, P < .001). Multivariable regression analysis confirmed that predictive accuracy was improved using both cTOI and lactate at 24 hours postoperative (AUC = 0.813, 95% CI: 0.705-0.921, P < .001) with optimal cutoff values <58% and >7.4 mmol/L, respectively (sensitivity = 95%). Cerebral TOI combined with lactate at 24 hours postoperative are accurate non-invasive predictive biomarkers of patient survival and neurodevelopmental outcome in neonates with CHD undergoing cardiac surgery.

Cerebral Ketone Body Oxidation Is Facilitated by a High Fat Diet Enriched with Advanced Glycation End Products in Normal and Diabetic Rats

Diabetes mellitus (DM) causes important modifications in the availability and use of different energy substrates in various organs and tissues. Similarly, dietary manipulations such as high fat diets also affect systemic energy metabolism. However, how the brain adapts to these situations remains unclear. To investigate these issues, control and alloxan-induced type I diabetic rats were fed either a standard or a high fat diet enriched with advanced glycation end products (AGEs) (HAGE diet). The HAGE diet increased their levels of blood ketone bodies, and this effect was exacerbated by DM induction. To determine the effects of diet and/or DM induction on key cerebral bioenergetic parameters, both ketone bodies (β-hydroxybutyric acid) and lactate oxidation were measured. In parallel, the expression of Monocarboxylate Transporter 1 (MCT1) and 2 (MCT2) isoforms in hippocampal and cortical slices from rats submitted to these diets was assessed. Ketone body oxidation increased while lactate oxidation decreased in hippocampal and cortical slices in both control and diabetic rats fed a HAGE diet. In parallel, the expression of both MCT1 and MCT2 increased only in the cerebral cortex in diabetic rats fed a HAGE diet. These results suggest a shift in the preferential cerebral energy substrate utilization in favor of ketone bodies in animals fed a HAGE diet, an effect that, in DM animals, is accompanied by the enhanced expression of the related transporters.

Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study.

Various lines of evidence suggest that brain bioenergetics and mitochondrial function may be altered in schizophrenia. On the basis of prior phosphorus-31 (31P)-magnetic resonance spectroscopy (MRS), post-mortem and preclinical studies, this study was designed to test the hypothesis that abnormal glycolysis leads to elevated lactate concentrations in subjects with schizophrenia. The high sensitivity of 7 Tesla proton (1H)-MRS was used to measure brain lactate levels in vivo. Twenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips ‘Achieva' 7T scanner, and spectra were acquired from a voxel in the anterior cingulate cortex. Patients were assessed for psychiatric symptom severity, and all participants completed the MATRICS Consensus Cognitive Battery (MCCB) and University of California, San Diego Performance-Based Skills Assessment (UPSA). The relationship between lactate, psychiatric symptom severity, MCCB and UPSA was examined. Lactate was significantly higher in patients compared with controls (P=0.013). Higher lactate was associated with lower MCCB (r=−0.36, P=0.01) and UPSA total scores (r=−0.43, P=0.001). We believe this is the first study to report elevated in vivo cerebral lactate levels in schizophrenia. Elevated lactate levels in schizophrenia may reflect increased anaerobic glycolysis possibly because of mitochondrial dysfunction. This study also suggests that altered cerebral bioenergetics contribute to cognitive and functional impairments in schizophrenia.

Cerebral Lactate Metabolism After Traumatic Brain Injury.

Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome.

Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis.

Lactate has recently emerged as a key metabolite necessary for memory consolidation. Lactate is the end product of aerobic glycolysis, a unique form of metabolism that occurs within certain regions of the brain. Here we detected an age-dependent decline in the expression of aerobic glycolysis enzymes and a concomitant decrease in lactate levels within the frontal cortex of wild-type mice. Improved memory performance in wild-type mice correlated with elevated expression of aerobic glycolysis enzymes. Surprisingly, lactate levels remained elevated with age and increased aerobic glycolysis enzyme expression correlated with poorer memory performance in APP/PS1 mice. These findings suggest that while lactate production is beneficial for memory in the healthy aging brain, it might be detrimental in an Alzheimer's disease context.

Beta EEG reflects sensory processing in active wakefulness and homeostatic sleep drive in quiet wakefulness.

Markers of sleep drive (<10Hz; slow-wave activity and theta) have been identified in the course of slow-wave sleep and wakefulness. So far, higher frequencies in the waking electroencephalogram have not been examined thoroughly as a function of sleep drive. Here, electroencephalogram dynamics were measured in epochs of active wake (wake characterized by high muscle tone) or quiet wake (wake characterized by low muscle tone). It was hypothesized that the higher beta oscillations (15-35Hz, measured by local field potential and electroencephalography) represent fundamentally different processes in active wake and quiet wake. In active wake, sensory stimulation elevated beta activity in parallel with gamma (80-90Hz) activity, indicative of cognitive processing. In quiet wake, beta activity paralleled slow-wave activity (1-4Hz) and theta (5-8Hz) in tracking sleep need. Cerebral lactate concentration, a measure of cerebral glucose utilization, increased during active wake whereas it declined during quiet wake. Mathematical modelling of state-dependent dynamics of cortical lactate concentration was more precisely predictive when quiet wake and active wake were included as two distinct substates rather than a uniform state of wakefulness. The extent to which lactate concentration declined in quiet wake and increased in active wake was proportionate to the amount of beta activity. These data distinguish quiet wake from active wake. Quiet wake, particularly when characterized by beta activity, is permissive to metabolic and electrophysiological changes that occur in slow-wave sleep. These data urge further studies on state-dependent beta oscillations across species.

Adjuvant therapies using normobaric oxygen with hypothermia or ethanol for reducing hyperglycolysis in thromboembolic cerebral ischemia

Background and purpose: Normobaric oxygen (NBO), ethanol (EtOH), and therapeutic hypothermia (TH) delivered alone or in combination have neuroprotective properties after acute stroke. We used an autologous thromboembolic rat stroke model to assess the additive effects of these treatments for reducing the deleterious effects of hyperglycolysis post-stroke in which reperfusion is induced with recombinant tissue plasminogen activator (rt-PA).Methods: Sprague–Dawley rats were subjected to middle cerebral artery (MCA) occlusion with an autologous embolus. One hour after occlusion, rt-PA was administered alone or with NBO (60%), EtOH (1.0g/kg), TH (33°C), either singly or in combination. Infarct volume and neurological deficit were assessed at 24h after rt-PA-induced reperfusion with or without other treatments. The extent of hyperglycolysis, as determined by cerebral glucose and lactate levels was evaluated at 3 and 24h after rt-PA administration. At the same time points, expressions of glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), phosphofructokinase1 (PFK-1), and lactate dehydrogenase were (LDH) measured by Western blotting.Results: Following rt-PA in rats with thromboembolic stroke, NBO combined with TH or EtOH most effectively decreased infarct volume and neurological deficit. As compared to rt-PA alone, EtOH or TH but not NBO monotherapies significantly reduced post-stroke hyperglycolysis. The increased utilization of glucose and production of lactate post-stroke was prevented most effectively when NBO was combined with either EtOH or TH after reperfusion with rt-PA, as shown by the significantly decreased Glut1, Glut3, PFK-1, and LDH levels.Conclusions: In a rat thromboembolic stroke model, both EtOH and TH used individually offer neuroprotection after the administration of rt-PA. While NBO monotherapy does not appear to be effective, it significantly potentiates the efficacy of EtOH and TH. The similar neuroprotection and underlying mechanisms pertaining to the attenuation of hyperglycolysis provided by EtOH or TH in combination with NBO suggest a possibility of substituting EtOH for TH. Thus a combination of NBO and EtOH, which are widely available and easily used, could become a novel and effective neuroprotective strategy in the clinical setting.

Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% (), glutamate increased by 4.7% () and creatine and phosphocreatine decreased by 15.2% (p). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia.

Dynamic correlations between hemodynamic, metabolic, and neuronal responses to acute whole-brain ischemia.

Cerebral ischemia sets off a cascade of neuronal and metabolic responses to preserve brain viability. An understanding of the temporal evolution of these changes during and after ischemia, and their correlation with hemodynamic changes, is essential. In this study, a 12-min whole-brain ischemia based on the four-blood-vessel occlusion model was employed in rats. Using a high-temporal-resolution simultaneous (1)H-(31)P MRS acquisition sequence at 9.4 T, we investigated dynamic occlusion and reperfusion responses in cerebral lactate (Lac), phosphocreatine (PCr), adenosine triphosphate (ATP), pH, and blood oxygenation level dependence (BOLD), together with changes in neuronal field potential activity. We reveal tightly coupled dynamics between hemodynamic, metabolic, and neuronal responses to ischemia. Neuronal activity, BOLD, PCr, Lac, and pH changed immediately following occlusion, indicating reduced energy substrates and consumption, and increased glycolysis to maintain cellular ATP levels, which started to decrease 2.2 min after the onset of occlusion. ATP stores were then gradually consumed to maintain a minimum housekeeping neuronal activity level. By correlating dynamic changes of brain activity, BOLD, and energy metabolism, new insights into the brain's survival ability and mechanisms during an acute ischemic attack from the perspectives of cerebral metabolism, neuroenergetics, and neuronal activity were gained.

An automated sleep-state classification algorithm for quantifying sleep timing and sleep-dependent dynamics of electroencephalographic and cerebral metabolic parameters.

IntroductionRodent sleep research uses electroencephalography (EEG) and electromyography (EMG) to determine the sleep state of an animal at any given time. EEG and EMG signals, typically sampled at >100 Hz, are segmented arbitrarily into epochs of equal duration (usually 2–10 seconds), and each epoch is scored as wake, slow-wave sleep (SWS), or rapid-eye-movement sleep (REMS), on the basis of visual inspection. Automated state scoring can minimize the burden associated with state and thereby facilitate the use of shorter epoch durations.MethodsWe developed a semiautomated state-scoring procedure that uses a combination of principal component analysis and naïve Bayes classification, with the EEG and EMG as inputs. We validated this algorithm against human-scored sleep-state scoring of data from C57BL/6J and BALB/CJ mice. We then applied a general homeostatic model to characterize the state-dependent dynamics of sleep slow-wave activity and cerebral glycolytic flux, measured as lactate concentration.ResultsMore than 89% of epochs scored as wake or SWS by the human were scored as the same state by the machine, whether scoring in 2-second or 10-second epochs. The majority of epochs scored as REMS by the human were also scored as REMS by the machine. However, of epochs scored as REMS by the human, more than 10% were scored as SWS by the machine and 18 (10-second epochs) to 28% (2-second epochs) were scored as wake. These biases were not strain-specific, as strain differences in sleep-state timing relative to the light/dark cycle, EEG power spectral profiles, and the homeostatic dynamics of both slow waves and lactate were detected equally effectively with the automated method or the manual scoring method. Error associated with mathematical modeling of temporal dynamics of both EEG slow-wave activity and cerebral lactate either did not differ significantly when state scoring was done with automated versus visual scoring, or was reduced with automated state scoring relative to manual classification.ConclusionsMachine scoring is as effective as human scoring in detecting experimental effects in rodent sleep studies. Automated scoring is an efficient alternative to visual inspection in studies of strain differences in sleep and the temporal dynamics of sleep-related physiological parameters.

Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate.

Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4 ± 2.3 to 5.4 ± 2.9 mmol/L), pyruvate (126.9 ± 65.1 to 172.3 ± 74.1 μmol/L), and lactate/pyruvate ratio (LPR; 27 ± 6 to 35 ± 9; all, p < 0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r = 0.56; p < 0.0001), while an inverse correlation (r = -0.11; p = 0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r = 0.62 to r = 0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel.

Abstract T P76: Cerebral Lactate and Monocarboxylate Transporters Are Reduced by Ethanol and Normobaric Oxygen Therapy after Severe Transient and Permanent Ischemic Stroke

Objectives: Recent studies conducted by this lab have shown the neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO), which is partially due to amelioration of aberrant glucose metabolism and a reduction in reactive oxygen species (ROS). In the current study, we sought to identify whether the neuroprotective benefits of EtOH, with or without NBO, attenuates lactic acidosis by reducing expression of monocarboxylate transporters (MCTs), resulting in ROS reduction after transient and permanent ischemic stroke. Methods: Sprague-Dawley rats (n=64) were subjected to right middle cerebral artery occlusion (MCAO) for 2 h or 4 h (transient ischemia), or 28h (permanent ischemia) followed by 3h, 24h, or no reperfusion. Rats in each group were randomly assigned to receive either an injection of saline (sham treatment), an intraperitoneal injection of EtOH (1.5g/kg), two doses of EtOH (1.5g/kg at onset of reperfusion followed by 1.0 g/kg 2 h after 1 st dose), or EtOH + 95% NBO for 6 h (permanent ischemia). Lactate and ROS levels were detected at 3h and 24h following reperfusion. Gene and protein expressions of MCT-1, MCT-2, and MCT-4 were assessed by RT-PCR and Western Blotting, respectively. Results: A dose dependent neuroprotection of EtOH administration was found in transient ischemia. Single dose in 2 h MCAO and double dose in 4 h MCAO significantly attenuated lactate levels and ROS generation, MCT-1, MCT-2, and MCT-4 mRNA and protein expression after severe transient ischemia. However, EtOH treatment alone, even with 2 doses, was insufficient for permanent stroke, while combination therapy (EtOH + 95% NBO) resulted in a more potent decrease of all levels and expressions. Conclusions: Our study suggests that acute EtOH administration can attenuate lactic acidosis-induced oxidative stress following a transient ischemic stroke. This EtOH-induced attenuation of brain injury was enhanced by NBO in permanent ischemic stroke. Both EtOH and NBO are widely available, inexpensive, easy to administer, and have few side effects. Ultimately, this combination therapy could be an effective approach to future stroke treatments.

Abstract 99: A Magnetic Resonance Spectroscopy [1H-MRS] Study of Peri-infarct Neuro-glial Interactions in Recovering Stroke Patients

Background: The adult brain has the capacity to reorganize after acute stroke and the ability to follow neuroplastic processes can be useful in predicting and monitoring recovery after stroke. This study investigates the ability of 1H-MRS to measure metabolic events in the structurally intact peri-infarct region between 2-12 weeks after stroke and their relationship to motor recovery. Method: The study included 15 first-ever stroke patients aged 18-75 years and age/sex matched controls. Structural, perfusion and 1H-MRS imaging was undertaken to measure regional cerebral blood flow (rCBF), N-acetylaspartate (NAA), choline (Cho), myoinositol (mI), creatine (cr) and lactate in the ipsilesional and contralesional hemisphere of stroke patients at 2 weeks, 6±1 and 12±3 weeks after stroke onset. Simultaneous clinical assessments were undertaken to measure motor impairments using the Fugl-Meyer [F-M]) scale. Patients were compared with controls at all time-points and the relationships between metabolites and with motor outcome were assessed. Results: Stroke patients were aged 51.4 (SD 13.3) years and all improved significantly between 2 and 12 weeks. Ipsilesional rCBF was decreased (22.7 v 36.8 mL/100 g/min, p=0.0036) at 2 weeks but increased to normal values by 12 weeks. Cr concentration (energy balance) were decreased in parallel and increased to normal concentration by 12 weeks. Ipsilesional NAA (neuronal integrity) was similar to healthy controls at 2 weeks it decreased significantly by 6 weeks. Cho (membrane turnover) significantly higher compared with controls at all time points; mI (glial cells) did not differ at 2 weeks but increased significantly between 2 and 12 weeks and there was a significant rise in lactate (inflammation) concentration at 12 weeks. There were strong positive correlations of rCBF with NAA at 12 weeks (r=0.42, p &lt;0.002), NAA at 2 and 12 weeks with FM scores at 12 weeks (r = 0.79, p= 0.004, r = 0.799, p = 0.006) and rCBF with change in F-M score between 2-12 weeks (r = 0.44, p=0.01). Conclusions: Ipsilesional CBF and metabolite estimation may be a sensitive tool to quantify vascular and neuro-glial interactions in the spared cortex after stroke that can be used to predict and monitor recovery.

Reduced cerebral monocarboxylate transporters and lactate levels by ethanol and normobaric oxygen therapy in severe transient and permanent ischemic stroke

ObjectivesNeuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO) were previously demonstrated in transient and permanent ischemic stroke. Here we sought to identify whether the enhanced lactic acidosis and increased expression of monocarboxylate transporters (MCTs) observed after stroke might be attenuated by single and/or combined EtOH and NBO therapies. MethodsSprague-Dawley rats (n=96) were subjected to right middle cerebral artery occlusion (MCAO) for 2 or 4h (transient ischemia), or 28h (permanent ischemia) followed by 3, 24h, or no reperfusion. Rats received: (1) either an intraperitoneal injection of saline (sham treatment), one dose of EtOH (1.5g/kg), two doses of EtOH (1.5g/kg at 2h of MCAO, followed by 1.0g/kg 2h after 1st dose), or (2) EtOH+95% NBO (at 2h of MCAO for 6h in permanent ischemia). Lactate levels were detected at 3 and 24h of reperfusion. Gene and protein expressions of MCT-1, -2, -4 were assessed by real-time PCR and western blotting. ResultsA dose-dependent EtOH neuroprotection was found in transient ischemia. Following transient ischemia, a single dose of EtOH (in 2h-MCAO) or a double dose (in 4h-MCAO), significantly attenuated lactate levels, as well as the mRNAs and protein expressions of MCT-1, MCT-2, and MCT-4. However, while two doses of EtOH alone was ineffective in permanent stroke, the combined therapy (EtOH+95% NBO) resulted in a more significant attenuation in all the above levels and expressions. ConclusionsOur study demonstrates that acute EtOH administration attenuated lactic acidosis in transient or permanent ischemic stroke. This EtOH-induced beneficial effect was potentiated by NBO therapy in permanent ischemia. Because both EtOH and NBO are readily available, inexpensive and easy to administer, their combination could be implemented in the clinics shortly after stroke.

Cerebral lactate dynamics across sleep/wake cycles.

Cerebral metabolism varies dramatically as a function of sleep state. Brain concentration of lactate, the end product of glucose utilization via glycolysis, varies as a function of sleep state, and like slow wave activity (SWA) in the electroencephalogram (EEG), increases as a function of time spent awake or in rapid eye movement sleep and declines as a function of time spent in slow wave sleep (SWS). We sought to determine whether lactate concentration exhibits homeostatic dynamics akin to those of SWA in SWS. Lactate concentration in the cerebral cortex was measured by indwelling enzymatic biosensors. A set of equations based conceptually on Process S (previously used to quantify the homeostatic dynamics of SWA) was used to predict the sleep/wake state-dependent dynamics of lactate concentration in the cerebral cortex. Additionally, we applied an iterative parameter space-restricting algorithm (the Nelder-Mead method) to reduce computational time to find the optimal values of the free parameters. Compared to an exhaustive search, this algorithm reduced the computation time required by orders of magnitude. We show that state-dependent lactate concentration dynamics can be described by a homeostatic model, but that the optimal time constants for describing lactate dynamics are much smaller than those of SWA. This disconnect between lactate dynamics and SWA dynamics does not support the concept that lactate concentration is a biochemical mediator of sleep homeostasis. However, lactate synthesis in the cerebral cortex may nonetheless be informative with regard to sleep function, since the impact of glycolysis on sleep slow wave regulation is only just now being investigated.