Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids

During the first few minutes following traumatic brain injury, cells are exposed to an indiscriminate release of glutamate from nerve terminals resulting in a massive ionic flux (e.g., K⁺ efflux) via stimulation of excitatory amino acid (EAA)-coupled ion channels. The present study was undertaken to elucidate the causal relationship between these ionic shifts and lactate accumulation in the injured brain, by examining the effects of ouabain (an inhibitor of Na⁺/K⁺-ATPase), Ba²⁺ (an inhibitor of non-energy-dependent glial K⁺ uptake) and kynurenic acid (KYN; a broad-spectrum EAA antagonist) on lactate accumulation. Two microdialysis probes were placed bilaterally in the rat parietal cortex. One was perfused with a test drug (1.0 mM ouabain, 2.0 mM Ba²⁺ or 10 mM KYN) and the other with Ringer's solution (control) for 30 min prior to injury. Following a 2.2–2.7 atm fluid-percussion injury, lactate levels in the dialysate increased (up to 116.6% above baseline) for the first 16 min and returned to baseline levels within 20 min after injury. This lactate accumulation was attenuated by preinjury administration of ouabain and KYN and was prolonged by Ba²⁺ administration. These findings indicate that lactate accumulation following concussive brain injury is a result of increased glycolysis which supports ion-pumping mechanisms, thereby, restoring the ionic balance which was disrupted by stimulation of EAA-coupled ion channels.     

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30–100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q₁₀ (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases. Received: 15 October 1997 Received in revised form: 6 February 1998 Accepted: 20 March 1998     

Increase in plasma lactate at the menopause and its relation to the "anion gap"

The mean plasma anion gap (Na + K + Ca + Mg)--(Cl + HCO3(-) + HPO4(2-) + protein), was significantly higher in post-menopausal women compared with pre-menopausal women (8.04 mEq/l compared with 7.03 mEq/l). This change was due, in part, to an increase in the plasma lactate concentration and to smaller increases in citrate and pyruvate concentrations. There were also changes in bicarbonate and chloride concentrations which suggested an increase pH of approximately 0.02 U. Together, these changes accounted for 46% of the increase in the "anion gap", leaving 54% unexplained. It is suggested that the rise in plasma lactate concentration may be due to mild alkalosis and that this change may account for the rise in plasma urate concentration which also occurs at the menopause.     

Relationship between the size of the capillary bed and oxidative capacity in various cat skeletal muscles

The size of the capillary bed, assessed by capillary density (CD), capillary per muscle fibre ratio (C/F), total capillary length, surface area and volume was related to the oxidative capacity, assessed by the volume density of mitochondria and O₂max in cat muscles with a different composition of glycolytic and oxidative fibres: predominantly glycolytic gracilis, purely oxidative soleus and gracilis transformed towards oxidative by chronic low frequency (10 Hz) electrical stimulation. Maximal blood flow and lactate output were measured in the muscles during isometric contractions.When capillary supply was estimated by C/F ratio, there was a close correlation between various parameters only in stimulated gracilis. The combined data of all muscles showed a significant correlation between the total volume of mitochondria, O₂max and total capillary surface area. Capillary volume showed a tight correlation with maximal blood flow in both control and stimulated gracilis, but not in soleus. Maximal blood flow was correlated withVO₂max in oxidative muscles (stimulated gracilis and soleus) but not in control glycolytic gracilis. Moreover normal gracilis did not show any relationship between the volume density of mitochondria and the size of the capillary bed. The latter was inversely correlated with the output of lactate which was greater in muscles with a lower C/P ratio.The data on gracilis indicates that the capillary bed can adapt to the increased demand for oxygen and a greater oxidative capacity induced by long-term activity imposed on a glycolytic muscle, while it may be more important for the removal of lactate in the glycolytic muscles under their normal activity. The factors involved in the regulation of blood flow in control soleus — when the morphological size of the vascular bed is not related to blood flow — are discussed.     

Mitochondrial associated metabolic proteins are selectively oxidized in A30P alpha-synuclein transgenic mice--a model of familial Parkinson's disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra compacta. alpha-Synuclein is strongly implicated in the pathophysiology of PD because aggregated alpha-synuclein accumulates in the brains of subjects with PD, mutations in alpha-synuclein cause familial PD, and overexpressing mutant human alpha-synuclein (A30P or A53T) causes degenerative disease in mice or drosophila. The pathophysiology of PD is poorly understood, but increasing evidence implicates mitochondrial dysfunction and oxidative stress. To understand how mutations in alpha-synuclein contribute to the pathophysiology of PD, we undertook a proteomic analysis of transgenic mice overexpressing A30P alpha-synuclein to investigate which proteins are oxidized. We observed more than twofold selective increases in specific carbonyl levels of three metabolic proteins in brains of symptomatic A30P alpha-synuclein mice: carbonic anhydrase 2 (Car2), alpha-enolase (Eno1), and lactate dehydrogenase 2 (Ldh2). Analysis of the activities of these proteins demonstrates decreased functions of these oxidatively modified proteins in brains from the A30P compared to control mice. Our findings suggest that proteins associated with impaired energy metabolism and mitochondria are particularly prone to oxidative stress associated with A30P-mutant alpha-synuclein.     

Admission lactate level and the APACHE II score are the most useful predictors of prognosis following torso trauma

BACKGROUND: Markers of dysoxic metabolism and scoring systems for triage have been widely used in critically injured patients. However, so far, no model is sufficiently reliable to predict the outcome in trauma victims. The purposes of the present study, therefore, were to determine whether a correlation exits between the main trauma scoring systems and the markers of dysoxic metabolism. Moreover, to assess if any of the admission parameters can be used to indicate outcome. METHODS: Sixty-four patients were included in this study. Admission data, including arterial lactate level, base deficit (BD), pH, revised trauma score (RTS), injury severity score (ISS), shock index (SI), and Acute Physiology and Chronic Health Evaluation (APACHE II), were collected and analysed by logistic regression analysis. Degree of association between continuous variables were calculated by either Pearson's or Spearman's correlation coefficient, where applicable. The dependence of lactate on two or more other variables was evaluated by multiple linear regression analysis. RESULTS: Logistic regression analysis showed that the fatal outcome following major torso trauma was principally associated with the APACHE II score and lactate. The specificity and the sensitivity of this logistic regression model was 94.6 and 79.2%, respectively. According to standardised linear regression coefficients, BD was the best single predictor of lactate, and APACHE II added a small amount of predictive power. The proportion of total variation in lactate level explained by base deficit, APACHE II and age is R2=85.2%. CONCLUSION: APACHE II score and the arterial lactate level are the most important determinants of clinical outcome in critically injured patients. A correlation exits between lactate and APACHE II and between lactate and base deficit.     

Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington's disease

In this study, we have examined the mechanisms involved in pyruvate-mediated neuroprotection against quinolinic acid (QA)-induced striatal damage. QA injection into the striatum caused widespread neuronal damage and extensive areas of lesions in core and penumbra. The involvement of oxidative-mediated striatal damage was suggested by increased expressions of peroxynitrite, marked lipid peroxidation, and formation of DNA oxidative damage products. Administration of pyruvate, a glycolysis end product with antioxidant activity, significantly reduced QA-mediated striatal lesions, neuronal degeneration, and oxidative damage, whereas another energy substrate, lactate, was ineffective against oxidative damage and only partially effective in reducing lesions and neuronal degeneration. Treatment with the iNOS inhibitor aminoguanidine attenuated QA-mediated striatal lesions and reduced oxidative damage, indicating that iNOS activation may be involved in the striatal oxidative damage induced by QA. A role for glial cells in mediating oxidative damage was suggested because pyruvate blocked the expression of iNOS and nitrotyrosine in activated microglia and astrocytes in QA-injected striatum. These data suggest that pyruvate reduces oxidative free radical damage in QA-injected striatum and could have clinical utility in the treatment of Huntington's disease (HD).     

Limiting factors to oxygen transport on Mount Everest 30 years after: a critique of Paolo Cerretelli’s contribution to the study of altitude physiology

In 1976, Paolo Cerretelli published an article entitled Limiting factors to oxygen transport on Mount Everest in the Journal of Applied Physiology . The paper demonstrated the role of cardiovascular oxygen transport in limiting maximal oxygen consumption (O_2max). In agreement with the predominant view of O_2max limitation at that time, however, its results were taken to mean that cardiovascular oxygen transport does not limit O_2max at altitude. So it was argued that the limiting factor could be in the periphery, and muscle blood flow was proposed as a possible candidate. Despite this suggestion, the conclusion generated a series of papers on muscle structural characteristics. These experiments demonstrated a loss of muscle oxidative capacity in chronic hypoxia, and thus provided an unambiguous refutation of the then widespread hypothesis that an increased muscle oxidative capacity is needed at altitude to compensate for the lack of oxygen. This analysis is followed by a short account of Cerretellis more recent work, with a special attention to the subject of the so-called lactate paradox.     

Influence of caffeine, cold and exercise on multiple choice reaction time

RATIONALE: The effects of caffeine on psychomotor performance have been evaluated under resting conditions and in a thermoneutral environment. Our hypothesis was that these effects could be modified by factors enhancing the level of alertness, such as exercise and cold exposure. OBJECTIVE: The purpose of this study was to follow up changes in the multiple choice reaction time (RT) during exercise at room and low ambient temperatures after caffeine or placebo administered in a double blind manner. METHODS: Nine soccer players performed multistage, incremental exercise until volitional exhaustion on a bicycle ergometer at 22 degrees C or 4 degrees C, 1 h after ingestion of coffee with caffeine (CAF) or without it (PL). Immediately before exercise and at the end of each workload, RT and blood lactate (LA) were measured. Oxygen uptake (VO2) and heart rate (HR) were recorded continuously. Blood LA threshold and the workload associated with the shortest RT were determined. RESULTS: During exercise at 22 degrees C, RT was significantly shorter in CAF than in the PL test, while at 4 degrees C there were no differences in RT between CAF and PL trials. Cold exposure did not affect RT either at rest or during exercise. Neither caffeine nor cold exposure influenced the maximal VO2, the maximal HR and LA threshold. CONCLUSION: In the thermoneutral environment, caffeine ingestion improved psychomotor performance during exercise, whilst at low ambient temperature this effect was blunted. These findings suggest that the stimulating action of caffeine depends on the level and source of arousal.