Xiang Zhongmin, Yuan Maoli, Hassen Getaw W, Gampel Mordechai, Bergold Peter J
Department of Physiology and Pharmacology, State University New York-Downstate Medical Center, Brooklyn, NY 11203, USA.
Exp Neurol. 2004 Mar;186(1):70-7. 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.
在脑缺血的最初几分钟内，乳酸会积聚并使脑内pH值酸化至6.0 - 6.7。缺血期间还会释放谷氨酸，其激活谷氨酸受体并诱导兴奋性毒性。虽然谷氨酸兴奋性毒性诱发缺血性损伤已得到充分证实，但乳酸酸中毒在缺血性脑损伤中的作用却知之甚少。本研究分析了在有或无乳酸存在的情况下海马切片培养物中的酸中毒神经毒性。在pH 6.7时，无论有无乳酸存在，神经元损失情况相似。在pH 6.4时，有乳酸存在时神经元损失明显更大，这表明乳酸增强了酸中毒毒性。在pH 6.4且有乳酸存在的情况下，NMDA或非NMDA受体拮抗剂可减少神经元损失，而在无乳酸时，NMDA或非NMDA受体拮抗剂几乎没有作用。酸性pH抑制了[3H] - 谷氨酸的摄取，且有乳酸存在时抑制量明显更大。这些发现表明乳酸通过诱导兴奋性毒性在酸中毒神经毒性中起作用。乳酸酸中毒和兴奋性毒性以前被认为在缺血期间是独立事件。本研究表明，在缺血期间，乳酸酸中毒促成了兴奋性毒性神经元损失。
