The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

Abstract

Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre‐registration of a review protocol, we systematically searched the PubMed, EMBASE , and Cochrane databases for literature covering themes of ‘lactate’, ‘the brain’, and ‘microcirculation’. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty‐eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose‐dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD + / NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose‐dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. Open Science Badges This article has received a badge for * Pre‐registration * because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer_lactate_protocol.aspx . The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/ .

Activation of GPR81 by lactate inhibits oscillatory shear stress‐induced endothelial inflammation by activating the expression of KLF2

“…As the product of glucose and glycogen glycolysis, lactate is the conjugate base of lactic acid and the main endogenous ligand of GPR81 . A contemporary review on the involvement of lactate in cerebral microcirculation reports that GPR81 is expressed on endothelial cells, pericytes, astrocytes, and synaptic spines and serves as a signaling molecule that may play a role in regulating blood flow in brain microvasculature . However, there is still considerable debate regarding the potential benefit of lactate.…”

Longitudinal, Multiparametric MRI Assessment of repetitive mild TBI in rats

“…Increase in lactate concentrations over 5 mmol/kg were found to induce cerebral hyperemia and this may also contribute to increased CTH after repetitive mTBI [71],. Therefore, diffusion, perfusion, and 1 H MRS parameters are complementary and interdependent and support the usefulness of multiparametric MRI.…”

Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine

“…In humans, the CBF response to physiological activation induced by visual stimulation was increased with lactate injection and plasma lactate/pyruvate ratio and subsequently augmented the NADH/NAD + ratio [89]. This increase in lactate/pyruvate and NADH/NAD + ratios may be related to the increase in CBF, probably through nitric oxide (NO) production [90]. In a clinical setting, hypertonic lactate injection increased cerebral perfusion and brain glucose availability and decreased the pulsatility index after acute brain injury [91].…”