Amitani Misato, Ohashi Akihiro, Hatazawa Jun, Gee Antony, Inoue Osamu
Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, Japan.
Synapse. 2008 Apr;62(4):253-8. doi: 10.1002/syn.20485.
PK11195, a selective PBR ligand, has been reported to exert a protective effect against the neuronal damage induced by the intrastriatal infusion of quinolinic acid, an excitatory amino acid. The neuroprotective effect of PK11195 observed at 48 h after the infusion was mediated by the inhibition of microglial activation. The aim of this study is to search the mechanism for the effect of PK11195 other than the inhibition of activation of microglia. In this study, the effect of PK11195 on glucose metabolism as well as neuroprotection in the early phase (2 h) after the injection of quinolinic acid was examined. Intrastriatal injection of quinolinic acid (60 nmol/microL) alone caused a significant enhancement of [(14)C]DG utilization in the infused striatum (about 160% vs. the contralateral side). This enhancement of glucose utilization might be due to an increase in phosphorylation rate of [(14)C]DG rather than delivery process from the plasma into the brain, since the initial uptake of [(14)C]DG (1 min) was not changed by quinolinic acid. Coinjection of PK11195 (10 nmol/microL) completely blocked the enhancement of [(14)C]DG uptake induced by quinolinic acid. The attenuating effect of PK11195 on glucose metabolic disturbance induced by quinolinic acid seemed to be related to voltage-dependent anion channels (VDAC), which are component of the PBR complex and associated with the regulation of hexokinase activity. PK11195 also showed neuroprotective effect at 2 h after the infusion of quinolinic acid, despite no significant activation of microglia was observed at this time-point. Thus, the neuroprotection of PK11195 might be related to normalization of the metabolic disturbance by the excitatory amino acid.
PK11195是一种选择性外周型苯二氮䓬受体（PBR）配体，据报道，它对纹状体内注射喹啉酸（一种兴奋性氨基酸）诱导的神经元损伤具有保护作用。输注后48小时观察到的PK11195的神经保护作用是由小胶质细胞活化的抑制介导的。本研究的目的是寻找PK11195除抑制小胶质细胞活化之外的作用机制。在本研究中，检测了PK11195对喹啉酸注射后早期（2小时）葡萄糖代谢以及神经保护的影响。单独纹状体内注射喹啉酸（60 nmol/μL）会导致注入的纹状体内[(14)C]DG利用率显著提高（与对侧相比约为160%）。葡萄糖利用率的这种提高可能是由于[(14)C]DG磷酸化速率增加，而不是从血浆到脑的转运过程，因为喹啉酸并未改变[(14)C]DG的初始摄取（1分钟）。共同注射PK11195（10 nmol/μL）完全阻断了喹啉酸诱导的[(14)C]DG摄取增加。PK11195对喹啉酸诱导的葡萄糖代谢紊乱的减弱作用似乎与电压依赖性阴离子通道（VDAC）有关，VDAC是PBR复合物的组成部分，与己糖激酶活性的调节相关。尽管在这个时间点未观察到小胶质细胞的显著活化，但PK11195在喹啉酸输注后2小时也显示出神经保护作用。因此，PK11195的神经保护作用可能与兴奋性氨基酸引起的代谢紊乱的正常化有关。
