A novel, multi-faceted perception of lactate in neurology

Abstract

Lactate has become one of the most re-evaluated metabolites in energy metabolism, particularly as a shuttle in neuroenergetics (Mason, 2017; Ferguson et al., 2018). In a comprehensive review in 2018, Brooks, one of the originators of the “lactate shuttle” concept, discusses the roles that lactate plays in the delivery of oxidative, and gluconeogenic substrates, as well as in cell signaling (Brooks, 2018). Brooks also appraises clinical studies that feature lactate to treat pro-inflammatory conditions, as well as reports on historic and recent studies of lactate metabolism and shuttling. A pioneering astrocyte–neuron lactate shuttle (ANLS) hypothesis was first proposed in 1994 by Pellerin and Magistretti for homeostatic conditions within the brain (Pellerin and Magistretti, 1994). The ANLS hypothesis has withstood challenges for 25 years but remains controversial as scientists continue to debate its validity (Bak and Walls, 2018; Barros and Weber, 2018). I believe, however, that the ANLS hypothesis can be extended beyond homeostatic conditions into neuropathophysiological states. The focus of this short opinion paper is to highlight studies over the past 2 years that support the notion that the route of lactate, as it acts as a shuttle in the brain, in neuropathophysiological states is emerging as crucial in neuroenergetics. This behavior is reviewed in more detail by Mason (2017). Further, this paper presents recent experimental evidence that has emerged supporting an extension of the ANLS—the newly postulated astrocyte–microglia lactate shuttle (AMLS) hypothesis (Mason et al., 2015), as described for the infectious, chronic neuroinflammatory disease tuberculous meningitis (TBM)