Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: Astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase
Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: Astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase
复制标题
DOI：
10.1097/01.jnen.0000195941.48033.eb
复制
发表时间：
2006-01-01
影响因子：
3.2
通讯作者：
Kim, SU
中科院分区：
文献类型：
--
作者：
Ishida, Y;Nagai, A;Kim, SU
在本研究中，我们用免疫细胞化学和逆转录聚合酶链式反应(RT-PCR)检测了凝血酶受体(PAR)在帕金森病(PD)脑黑质致密部(SNPC)和培养的人神经元、星形胶质细胞、少突胶质细胞和小胶质细胞中的表达。PAR-I仅在SNPC的胶质纤维酸性蛋白阳性的星形胶质细胞中表达，而在PD的SNPC中表达PAR-1的星形胶质细胞数量较非神经对照脑增多。凝血酶和凝血酶原免疫反应在帕金森病大鼠脑内星形胶质细胞和血管壁较强。RT-PCR检测到PAR-1在人脑星形胶质细胞和神经元中表达，但在少突胶质细胞和小胶质细胞中不表达。我们研究了凝血酶介导的人星形胶质细胞的激活。凝血酶治疗可激活人脑星形胶质细胞，并诱导星形胶质细胞的形态改变和明显的增殖增加。在凝血酶/PAR激活的星形胶质细胞中，神经生长因子和炎性细胞因子/趋化因子(IL-1β、IL-6、IL-8、MCPA)的表达无明显变化，而胶质细胞系衍生生长因子和谷胱甘肽过氧化物酶(GPX)的表达增加。接下来，我们研究了凝血酶激活的星形胶质细胞对人脑神经元X人神经母细胞瘤杂交神经元的神经保护作用。尽管凝血酶以剂量依赖的方式显示出对人类混合神经元的神经毒性，但来自凝血酶处理的星形胶质细胞培养物的条件培养液促进了人类混合神经元的存活。这种保护作用可被GPX抑制剂--硫代琥珀酸完全抑制，这表明凝血酶/PAR激活的星形胶质细胞释放的GPX参与了混合型神经元对抗凝血酶细胞毒性的神经保护作用。本研究提示帕金森病大鼠SNPC区星形胶质细胞PAR-I表达增加是帕金森病病理发展过程中大脑对伤害性损伤引起的多巴胺能神经元变性和细胞死亡提供神经保护的恢复性举措。
In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-I was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1 beta, IL-6, IL-8, MCPA) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron X human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-I in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.