Lactate Storm Marks Cerebral Metabolism following Brain Trauma

Abstract

Background: In brain metabolism, neurons are fueled by lactate passed to them by glia in a metabolic coupling. Results: Following brain trauma, lactate uptake into neurons from glia was impaired, producing a metabolic lactate storm. Conclusion: Brain trauma results in neuronal-glial metabolic uncoupling, releasing free lactate. Significance: Inhibition of lactate production or its removal may be an important therapeutic strategy for brain trauma.

Elevated glutamate and lactate predict brain death after severe head trauma

“…In contrast, our study, suggests that lactate production may significantly increase even in the presence of a satisfactory glucose supply (Table 1) to attend brain metabolic needs. However, as proposed by Lama et al, 201428, the acute increase in the brain tissue lactate concentrations after severe TBI is associated to decreased neuronal uptake, probably leading to irreversible injury and pan‐necrosis. Therefore, although the high extracellular availability of lactate suggests that the metabolic machinery in astrocytes was responsive to the increased energy demands after TBI, neurons were apparently not capable of using lactate as substrate, ultimately contributing to the patient's death.…”

“…As previously stated, astrocytes take up glutamate in the synaptic space thereby triggering glycolysis and lactate production, which is shuttled to neurons 15. The flux of these substrates in the body fluids has been explored in the clinical setting as biomarkers of neuroenergetic support, neuron‐to‐astrocyte interactions, and clinical outcomes 28. Recently, Thelin et al, 2014 showed that an increased brain extracellular levels of lactate and pyruvate after TBI were correlated with unfavorable neurological outcome based on Glasgow Outcome Scale29.…”

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

“…Similarly, while TNF signaling is detrimental to CNS homeostasis, transforming growth factor-β (TGF-β) is strongly neuroprotective as signaling acts to reduce inflammation, excitotoxicity and apoptosis, and to enhance neuronal regeneration [for review, see (31)]. The trend toward increased lactate release in females is also intriguing, as lactate levels are increased during several types of brain injury and are thought to both indicate and enhance tissue damage (63,102). Thus, alcohol-induced astrocyte dysfunction in females is predicted to accelerate alcohol-induced neurotoxicity in a sexually dimorphic fashion.…”

The Monocarboxylate Transporter 4 Is Required for Glycolytic Reprogramming and Inflammatory Response in Macrophages

“…Augmented glycolysis, such as that occurring in the activated inflammatory cells, leads to increased lactate production that results in intracellular and extracellular acidification. Extracellular lactate is known to have many biological activities (22)(23)(24)(25). However, it is less clear how the export of the intracellular lactate is regulated or what the functional implication of lactate export is during inflammation.…”

“…For example, augmented aerobic glycolysis was found in LPS-treated dendritic cells and macrophages and has an important role in reg-ulating the activation of these cells (13)(14)(15)(16). Although the biological activities of extracellular lactate are well studied (22)(23)(24)(25), it is less understood how the lactate export is regulated or whether lactate export affects glycolysis during inflammatory activation. In this study, we found that MCT4 is up-regulated in activated macrophages.…”