Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA, USA.
J Cereb Blood Flow Metab. 2012 Jun;32(6):1086-96. doi: 10.1038/jcbfm.2012.30. Epub 2012 Mar 28.
Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.
低血糖诱导的中枢神经病变可发生于试图严格控制血糖的糖尿病患者，可能导致认知功能障碍。越来越多的动物模型证据表明，低血糖诱导的神经元死亡不是葡萄糖剥夺的简单结果，而是多因素过程的最终结果。特别是，聚（ADP-核糖）聚合酶 1（PARP-1）的过度激活消耗细胞溶质烟酰胺腺嘌呤二核苷酸（NAD(+)），导致能量衰竭。在这项研究中，我们研究了在没有细胞溶质 NAD(+)的情况下，乳酸盐的给药是否能提供针对低血糖诱导的神经元死亡的神经保护作用。腹腔内注射 L-乳酸钠可纠正低血糖后的动脉血 pH 和血乳酸浓度。在没有葡萄糖的情况下给予乳酸盐不足以促进低血糖期间脑电图从等电状态恢复。然而，葡萄糖与乳酸盐的联合补充可将海马体中的神经元死亡减少约 80%。乳酸盐的给药还大大减少了低血糖诱导的超氧化物产生和小胶质细胞激活。总之，这些结果表明了一种有趣的可能性：低血糖后大脑中乳酸盐的增加可通过充当替代能量底物来抵消 PARP-1 过度激活导致的 NAD(+)减少，该底物可有效绕过糖酵解并直接进入柠檬酸循环以维持细胞 ATP 水平。
