The Neuroprotective Effect of Lactate Is Not Due to Improved Glutamate Uptake after Controlled Cortical Impact in Rats
The Neuroprotective Effect of Lactate Is Not Due to Improved Glutamate Uptake after Controlled Cortical Impact in Rats
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DOI：
10.1089/neu.2011.2067
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发表时间：
2012-08-01
影响因子：
4.2
通讯作者：
Kempski, Oliver
中科院分区：
文献类型：
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作者：
Alessandri, Beat;Schwandt, Eike;Kempski, Oliver
多年来，乳酸被认为是糖酵解的废物。越来越多的数据表明，乳酸是神经元激活过程中的重要能量底物。在严重创伤性脑损伤（TBI）中，谷氨酸释放和缺血性脑血流量（CBF）是能量需求和供应之间不匹配以及神经元细胞死亡的主要因素。虽然ATP和行为可以通过TBI后的乳酸盐治疗来改善，但没有组织学相关性，也没有与更好的星形胶质细胞谷氨酸摄取或CBF的任何联系作为可能的机制。我们对雄性大鼠进行了受控的皮质撞击（CCI; 5 m/sec，2.5 mm）。为了研究乳酸盐处理对病变体积、谷氨酸盐释放和CBF的影响，动物被输注NaCl或100 mM乳酸盐长达3小时。通过用α-氰基-4-羟基-肉桂酸（4-CIN; 90 mg/kg）抑制转运来研究内源性乳酸的作用。CCI后15分钟的乳酸盐治疗使CCI后第2天的病变体积从21.1 +/- 2.8 mm（3）减少到12.1 +/- 1.9 mm（3）。挫伤产生一个显着的三至四倍增加谷氨酸在微透析液，但有没有显着差异治疗开始前30分钟CCI。在本实验中，CCI后第7天，乳酸盐显著减少了病变体积（23.7 +/- 4至9.3 +/- 1-2 mm（3））。所有动物的CBF在CCI后立即增加，此后下降至基线以下。CCI后15分钟输注乳酸盐可使7/10只动物的CBF升高20分钟，而7/8只NaCl治疗的动物显示CBF进一步下降。脑挫伤后乳酸治疗可达到神经保护作用，而阻断内源性乳酸转运则无不良影响。神经保护并不是通过改善星形胶质细胞对谷氨酸的摄取来实现的，而是通过CCI后CBF的增加来支持的。由于其神经保护特性，乳酸盐可能是TBI患者的有益药物治疗。
For many years lactate was considered to be a waste product of glycolysis. Data are accumulating that suggest that lactate is an important energy substrate for neurons during activation. In severe traumatic brain injury (TBI) glutamate release and ischemic cerebral blood flow (CBF) are major factors for a mismatch between energy demand and supply and for neuronal cell death. Although ATP and behavior could be improved by lactate treatment after TBI, no histological correlate nor any linkage to better astrocytic glutamate uptake or CBF as possible mechanisms have been described. We subjected male rats to a controlled cortical impact (CCI; 5 m/sec, 2.5 mm). To study the effects of lactate treatment on lesion volume, glutamate release, and CBF, animals were infused with either NaCl or 100 mM lactate for up to 3 h. The role of endogenous lactate was investigated by inhibiting transport with alpha-cyano-4-hydroxy-cinnamic acid (4-CIN; 90 mg/kg). Lactate treatment 15 min post-CCI reduced lesion volume from 21.1 +/- 2.8 mm(3) to 12.1 +/- 1.9 mm(3) at day 2 after CCI. Contusion produced a significant three- to fourfold increase of glutamate in microdialysates, but there was no significant difference between treatments that began 30 min before CCI. In this experiment lesion volume was significantly reduced by lactate at day 7 post-CCI (23.7 +/- 4 to 9.3 +/- 1-2 mm(3)). CBF increased immediately after CCI and dropped thereafter below baseline in all animals. Lactate infusion 15 min post-CCI elevated CBF for 20 min in 7 of 10 animals, whereas 7 of 8 NaCl-treated animals showed a further CBF decline. Neuroprotection was achieved by lactate treatment following contusion injury, whereas blocking of endogenous lactate transport exerted no adverse effects. Neuroprotection was not achieved by improved glutamate uptake into astrocytes, but was supported by augmented CBF following CCI. Due to its neuroprotective property, lactate might be a beneficial pharmacological treatment for TBI patients.