Ryu Jae K, Choi Hyun B, McLarnon James G
Department of Pharmacology and Therapeutics, Faculty of Medicine, 2176 Health Sciences Mall, The University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Neurobiol Dis. 2005 Nov;20(2):550-61. doi: 10.1016/j.nbd.2005.04.010.
The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.
在给予喹啉酸（QUIN）后，研究了外周苯二氮䓬受体（PBR）配体PK11195对大鼠纹状体的影响。免疫组织化学分析表明，纹状体内注射QUIN可导致损伤纹状体中PBR表达增加。双重免疫荧光染色显示，PBR主要表达于ED1免疫反应性小胶质细胞，而不表达于GFAP免疫反应性星形胶质细胞或NeuN免疫反应性神经元。PK11195处理显著降低了QUIN注射纹状体中小胶质细胞的激活水平以及促炎细胞因子和诱导型一氧化氮合酶的表达。PK11195给药显著减轻了以脂质过氧化标志物（4-HNE）和氧化性DNA损伤标志物（8-OHdG）表达增加为特征的氧化性介导的纹状体QUIN损伤。此外，纹状体内注射PK11195与QUIN可显著减少兴奋性氨基酸诱导的纹状体损伤，并减少QUIN介导的纹状体神经元中半胱天冬酶-3的激活。这些结果表明，激活的小胶质细胞引起的炎症反应对纹状体神经元具有损害作用，在小胶质细胞中对PBR进行药物靶向治疗可能是保护亨廷顿舞蹈病等神经疾病中神经元的有效策略。
