Lactate induced excitotoxicity in hippocampal slice cultures

• Published in: Experimental neurology 2004-03, Vol.186 (1), p.70-77
• Main Authors: Xiang, Zhongmin, Yuan, Maoli, Hassen, Getaw W., Gampel, Mordechai, Bergold, Peter J.
• Format: Article
• Language: English
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - therapeutic use; Acidosis - chemically induced; Acidosis - complications; Acidosis - drug therapy; Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Cell Death - drug effects; Cerebral ischemia; Dizocilpine Maleate - therapeutic use; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Excitatory Amino Acid Antagonists - therapeutic use; Excitotoxicity; Glucose - toxicity; Glutamate; Glutamic Acid - metabolism; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; Hydrogen-Ion Concentration; In Vitro Techniques; Intracellular Space - metabolism; Lactic Acid - toxicity; Medical sciences; Neuropharmacology; Neuroprotective agent; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - pathology; Pharmacology. Drug treatments; Propidium; Rats; Rats, Sprague-Dawley; Stroke; Time Factors; Toxicity: nervous system and muscle; Tritium - metabolism
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2003.10.015

During the initial minutes of cerebral ischemia, lactic acid accumulates and acidifies brain pH to 6.0–6.7. Glutamate is also released during ischemia that activates glutamate receptors and induces excitotoxicity. While glutamate excitotoxicity is well established to induce ischemic injury, a role of lactic acidosis in ischemic brain damage is poorly understood. This study analyzes acidosis neurotoxicity in hippocampal slice cultures in the presence or absence of lactate. At pH 6.7, neuronal loss was similar whether or not lactate was present. At pH 6.4, neuronal loss was significantly greater in the presence of lactate suggesting that lactate potentiates the acidosis toxicity. At pH 6.4 in the presence of lactate, NMDA or non-NMDA receptor antagonists reduced neuronal loss, while in the absence of lactate, NMDA or non-NMDA receptor antagonists had little effect. [3H]-Glutamate uptake was inhibited by acidic pH, and the amount of inhibition was significantly greater in the presence of lactate. These findings suggest that lactate plays a role in acidosis neurotoxicity by inducing excitotoxicity. Lactic acidosis and excitotoxicity have been previously thought to be independent events during ischemia. This study suggests that during ischemia, lactic acidosis contributes to excitotoxic neuronal loss.