Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Neuroscience. 2010 May 19;167(3):929-45. doi: 10.1016/j.neuroscience.2010.02.047. Epub 2010 Feb 26.
A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.
越来越多的证据表明，纤溶酶原激活物（PAs）参与了中枢神经系统（CNS）中的许多生理和病理事件。在癫痫的不同实验模型中观察到组织纤溶酶原激活物（tPA）和尿激酶纤溶酶原激活物（uPA）的诱导，并且 tPA 已被牵连到导致癫痫活动的机制中。我们研究了几种致痫性病变中 tPA 和 uPA 的表达和细胞分布，包括海马硬化（HS；n=6），以及发育性神经胶质病变，如局灶性皮质发育不良（FCD；n=6）、结节性硬化症患者的皮质结节（TSC；n=6）和神经节细胞瘤（GG；n=6），使用免疫细胞化学、western blot 和实时定量 PCR 分析。与对照标本相比，tPA 和 uPA 免疫染色在致痫病变中的神经胶质和神经元细胞（HS 中的海马神经元和 FCD、TSC 和 GG 标本中的发育不良神经元）中显示出增加的表达。共聚焦激光扫描显微镜证实了这两种蛋白质在星形胶质细胞和小胶质细胞以及微血管内皮细胞中的表达。免疫印迹还证明了 uPA 受体（uPAR）的上调（P<0.05）。PCR 分析还在不同的致痫性病变中检测到 tPA、uPA、uPAR 和组织 PA 抑制剂型 mRNA 水平的增加表达（P<0.05）。我们的数据支持 PA 系统成分在不同的人类局灶性致痫性病变中的作用，这可能会严重影响神经元活动、炎症反应，并有助于发生在致痫性病变中的神经元网络的复杂重塑。
