Krisanova N, Sivko R, Kasatkina L, Borisova T
The Department of Neurochemistry, Palladin Institute of Biochemistry, Kiev, Ukraine.
Biochim Biophys Acta. 2012 Oct;1822(10):1553-61. doi: 10.1016/j.bbadis.2012.06.005. Epub 2012 Jun 17.
In our earlier work, a reduction of cholesterol content increased the extracellular glutamate level in rat brain nerve terminals (synaptosomes) that was a result of the lack of transporter-mediated glutamate uptake. The aim of this study was to assess transporter-mediated release of glutamate from cholesterol-deficient synaptosomes. In stroke, cerebral hypoxia/ischemia, and traumatic brain injury, the development of neurotoxicity is provoked by enhanced extracellular glutamate, which is released from nerve cells mainly by glutamate transporter reversal - a distinctive feature of these pathological states.
Laser scanning confocal microscopy, spectrofluorimetry, radiolabeled assay, and glutamate dehydrogenase assay.
Cholesterol acceptor methyl-β-cyclodextrin (15mM) reduced the cholesterol content in the synaptosomes by one quarter. Transporter-mediated glutamate release from synaptosomes: 1) stimulated by depolarization of the plasma membrane; 2) by means of heteroexchange with competitive transportable inhibitor of glutamate transporters dl-threo-β-hydroxyaspartate; 3) in low [Na(+)] medium; and 4) during dissipation of the proton gradient of synaptic vesicles by the protonophore cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP); was decreased under conditions of cholesterol deficiency by ~24, 28, 40, and 17%, respectively.
A decrease in the level of membrane cholesterol attenuated transporter-mediated glutamate release from nerve terminals. Therefore, lowering cholesterol may be used in neuroprotection in stroke, ischemia, and traumatic brain injury which are associated with an increase in glutamate uptake reversal. This data may explain the neuroprotective effects of statins in these pathological states and provide one of the mechanisms of their neuroprotective action. However, beside these disorders, lowering cholesterol may cause harmful consequences by decreasing glutamate uptake in nerve terminals.
在我们早期的研究中，胆固醇含量的降低会使大鼠脑神经末梢（突触体）中的细胞外谷氨酸水平升高，这是由于缺乏转运体介导的谷氨酸摄取所致。本研究的目的是评估转运体介导的胆固醇缺乏突触体释放谷氨酸的情况。在中风、脑缺氧/缺血和创伤性脑损伤中，神经毒性的发展是由细胞外谷氨酸水平升高引发的，谷氨酸主要通过谷氨酸转运体逆转从神经细胞释放，这是这些病理状态的一个显著特征。
激光扫描共聚焦显微镜、荧光分光光度法、放射性标记测定法和谷氨酸脱氢酶测定法。
胆固醇受体甲基-β-环糊精（15mM）使突触体中的胆固醇含量降低了四分之一。转运体介导的突触体谷氨酸释放：1）受质膜去极化刺激；2）通过与谷氨酸转运体的竞争性可转运抑制剂dl-苏式-β-羟基天冬氨酸进行异源交换；3）在低[Na⁺]培养基中；4）在质子载体氰化物-p-三氟甲氧基苯基腙（FCCP）使突触小泡质子梯度消散期间；在胆固醇缺乏的情况下分别降低了约24%、28%、40%和17%。
膜胆固醇水平的降低减弱了转运体介导的神经末梢谷氨酸释放。因此，降低胆固醇可用于与谷氨酸摄取逆转增加相关的中风、缺血和创伤性脑损伤的神经保护。这些数据可能解释了他汀类药物在这些病理状态下的神经保护作用，并提供了其神经保护作用的机制之一。然而，除了这些疾病外，降低胆固醇可能会因减少神经末梢的谷氨酸摄取而导致有害后果。
