The Warburg Effect in Human Brain: It does benefit energetically by lactate Gerd Krüger consultation-liaison psychiatry, psychosomatics, psychooncology Anaerobic vs. Aerobic glycolysis In the 70s we started with lack of O2 studies on the transport of glucose into the brain in rats. There remains the question: Might the reduced energy support by glucose be compensated by increasing the glycolysis? But technical processes, i.e. brain imaging and scientific knowledge of psychiatric thinking and clinical acting, have not been jointly developed. Apparently separate ways of research about glycolysis and lactate (see below*) ended in a final common pathway , i.e. that one of the so- called “aerobic glycolysis“. Despite intensive and extensive studies to establish the causes and functions of the Warburg effect as aerobic glycolysis in cancer cells the result remains unclear. Liberti M and Locasale J Trends Biochemical Sciences 2016, 41 (3):211-216). But the role of aerobic glycolysis has been explored for actively proliferating cancer cells in great detail by Vander Heiden MG, Cantley LC, Th in 2009 doi:10.1126/science.1160809. The breakthrough for recognizing the importance of lactate/aerobic glycolysis, and Warburg effect in the brain was illustrated by Marcus Raichle in Philosophical Transactions B(2015) Nobel prize for their work * Archibald V. Hill (left) and Otto Meyerhof (right) 1922 Otto Warburg 1931 Aerobic glycolysis, i.e. glycolysis in the presence of oxygen that exceeds that needed for oxidative phosphorylation. (a) A map of aerobic glycolysis here illustrated on the lateral and medial surfaces of the human brain in 33 normal young adults. The colour bar is in units of a glycolytic index, a quantitative measure of glycolysis. The levels of aerobic glycolysis vary significantly within the brain. Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME 2010 Regional aerobic glycolysis in the human brain. Proc. Natl Acad. Sci. USA 107, 17 757–17 762. (doi:10.1073/pnas.1010459107) (b) Elements of glycolysis are highlighted by two coloured boxes to denote those elements involved in biosynthesis and neuroprotection (grey) and those involved in energy generation (blue). The symbiotic relationship between astrocytes and neurons which not only involves providing substrate (i.e. lactate) for energy generation via oxidative phosphorylation (reverse Warburg effect),but also, in so doing, how astrocyte lactate alters the redox potential of the neuron (redox switch) to divert neuronal glycolysis into biosynthesis and neuroprotection ((i.e. management of reactive oxygen species). Astrocytes also have been shown to regulate up and down states referring to the neurons subthreshold membrane potentials for action potential generation via KATP channels in the neuron. Biochemistry of exercise-induced metabolic acidosis American Journal of Physiology - Regulatory, Integrative and Comparative Physiology Published 1 September 2004 Vol. 287 no. 3, R502-R516 DOI: 10.1152/ajpregu.00114.2004 Glycolysis (EMDEN-MEYERHOF-pathway) is a multistep process that prepares the glucose molecule for oxidative phosphorylation and the generation of energy. Determined by the term and definition of glycolysis we ended to think at the point of pyruvate as final common pathway of dysoxic and anoxic states with lactate- induced acidosis in the 70s and 80s. We were unknown about the role of the so-called “aerobic glycolysis” with lactate as byproduct as one source of energy demands in astrocytes to help the neurons energetically by oxidation (Pellerin and Magistretti 1994). Therefore the decision came up to reevaluate and to use the background and the objectives of the mass of clinical data in a sample of 155 patients (mean age 54y) diagnosed as `organic´ seeking to find different syndromes correlating with brain metabolism. Documented data with the AMDP- rating scale system were prepared by principal and discriminant function analysis to form cluster derived groupings of patients with organic brain syndromes to correlate them with the results of cerebral rates of oxygen, glucose and lactate. The sample had to be divided on the base of clinical signs and symptoms in degenerative, vascular, alcohol toxic and other etiologies.   In conclusion we unconsciously predated the importance of lactate in the brain´s metabolism as indicator for cerebral insufficiency.   The difference between the neurocognitive impaired groups (N=52:personality change and N=45: dementia) and the N=42: depressives/N=8:delusionals with increased percent changes of CMR lactate and lactate-glucose indices was obvious (P=0.001). Only the nearly demented group (N=45) showed slightly reduced values of CMR O2.