title: A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.
abstract: Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.
authors.affiliation: Department of Clinical Neurosciences, Neurology Service, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Ximena
authors.initials: X
authors.lastname: Castillo
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Rosafio
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zürich, Switzerland.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Wyss
authors.affiliation: Center for Radiopharmaceutical Sciences, University Hospital, Zürich, Switzerland.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Drandarov
authors.affiliation: PET Center, Division of Nuclear Medicine, University Hospital, Zürich, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Buck
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Pellerin
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zürich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Weber
authors.affiliation: Department of Clinical Neurosciences, Neurology Service, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hirt
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D016923:Cell Death; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects; D002534:Hypoxia, Brain / Q000473:pathology; D007150:Immunohistochemistry; D007700:Kinetics; D019344:Lactic Acid / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000502:physiology; D013237:Stereoisomerism; D009687:Nuclear Proteins
chemical_list: D002352:Carrier Proteins; D005947:Glucose; D019344:Lactic Acid; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C484328:MAGEE1 protein, human; D009687:Nuclear Proteins