Neuroprotective effects of lactate and ketone bodies in acute brain injury

Abstract

The goal of neurocritical care is to prevent and reverse the pathologic cascades of secondary brain injury by optimizing cerebral blood flow, oxygen supply and substrate delivery. While glucose is an essential energetic substrate for the brain, we frequently observe a strong decrease in glucose delivery and/or a glucose metabolic dysregulation following acute brain injury. In parallel, during the last decades, lactate and ketone bodies have been identified as potential alternative fuels to provide energy to the brain, both under physiological conditions and in case of glucose shortage. They are now viewed as integral parts of brain metabolism. In addition to their energetic role, experimental evidence also supports their neuroprotective properties after acute brain injury, regulating in particular intracranial pressure control, decreasing ischemic volume, and leading to an improvement in cognitive functions as well as survival. In this review, we present preclinical and clinical evidence exploring the mechanisms underlying their neuroprotective effects and identify research priorities for promoting lactate and ketone bodies use in brain injury.

Keywords: Alternative brain fuels; TBI; brain metabolism; hypoxia; ketone bodies; lactate; neuroprotection; stroke.

Figure 1.

Glucose metabolism pathway. In the cytoplasm, glucose is metabolized to pyruvate through glycolysis. This pyruvate can either provide lactate or be redirected to the mitochondria to provide ATP through (i) the Krebs cycle (TCA cycle) coupled to and (ii) oxidative phosphorylation (OXPHOS).

Figure 2.

Compartmentalization of cerebral glucose metabolism and consequence in brain injury as well as for neuroprotective strategies. (a) In the brain, glucose from the bloodstream enters both astrocytes and neurons. It is metabolized to pyruvate in the cytoplasm (glycolysis) then supplies ATP via pyruvate oxidation into mitochondria (TCA cycle + OXPHOS). However, astrocytes have a greater glycolytic capacity compared to neurons, which are highly oxidative cells. Astrocytes are known to produce high levels of lactate, which can be further transferred to neurons where it can be used as an energy substrate through the TCA and OXPHOS. Glucose can also enter directly into neurons. Low glycolysis in neurons allows glucose conversion into the pentose phosphate pathway PPP to sustain antioxidant protection. (b) In acute brain injury condition, the low level of circulating glucose can not meet cerebral energy needs and the metabolic cooperation between astrocytes and neurons can not be maintained. Glucose is mainly used for oxidative metabolism in both cell types to maintain ATP levels. (c) In order to overcome the energy deficit induced by acute brain injury, energy substitution strategies could be adopted. Lactate or exogenous KB enter directly into brain cells but predominantly in neurons.^,, Lactate is then converted into pyruvate, while KB are precursors of acetyl-CoA. Pyruvate and Acetyl-CoA are then oxidized through TCA cycle and OXPHOS to provide energy. Saved glucose can be redirected to the PPP pathway to reestablish antioxidant defenses. GLUT: glucose transporter; KB: ketone bodies; MCT: monocarboxylate transporter; OXPHOS: oxidative phosphorylation: PPP: pentose phosphate pathway; TCA: tricarboxylic acid cycles.

Figure 3.

Neuroprotection by exogenous lactate and ketone bodies, as alternative energy substrates, in a context of brain injury. (a) Lactate conteracts glutamate excitotoxicity through the PI3K pathway leading to neuronal hyperpolarization. KB also decrease excitotoxicity through a competition with Cl⁻, responsible of a decrease in vGLU exocytosis. (b) Both exogenous lactate and KB limit brain damages by decreasing intracranial pressure, brain edema as well as brain lesion volume. (c) Lactate and KB increase brain energy metabolism by providing respectively pyruvate and acetyl-CoA to feed the TCA cycle and OXPHOS while preserving glucose for the PPP pathway, helping to fight ROS. (d) Both alternative substrates also switch microglia from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype, through a stimulation of the Akt pathway. (e) Lactate and KB increase cerebral blood flow. (f) Both lactate and KB regulate the oxidative stress by increasing the NAD⁺/NADH ratio. (g) Altogether, beneficial effects of exogenous lactate and KB lead to increase recovery and survival, as well as improvement of cognitive functions. ANLS: astrocyte-neurone lactate shuttle; KB: ketone bodies; OXPHOS: oxidative phosphorylation; PPP: pentose phosphate pathway; ROS: reactive oxygen species; TCA: tricarboxylic acid; vGLU: vesicular glutamate transporters. Related reference numbers are shown in brackets [].