Lactate induced excitotoxicity in hippocampal slice cultures.
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.
Department of Physiology and Pharmacology, State University New York-Downstate Medical Center, Brooklyn, NY 11203, USA.
Zhongmin
Z
Xiang
Maoli
M
Yuan
Getaw W
GW
Hassen
Mordechai
M
Gampel
Peter J
PJ
Bergold
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000627:therapeutic use; D000138:Acidosis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D005947:Glucose / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D014316:Tritium; D019344:Lactic Acid; D011419:Propidium; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D005947:Glucose