Experimental Epilepsy Research, Department of Neurosurgery, University of Freiburg, Freiburg, Germany.
Exp Neurol. 2012 Jul;236(1):141-50. doi: 10.1016/j.expneurol.2012.04.009. Epub 2012 Apr 19.
Activated astrocytes display a broad spectrum of properties, ranging from neuroprotection to active contribution to demise of neural tissue. To investigate if activation of astrocytes by a single, defined stimulus enhances neuroprotective properties, we tested whether injection of ciliary neurotrophic factor (CNTF) can ameliorate epilepsy-related brain damage. Intrahippocampal CNTF injection in mice induced a rapid (within 2 days) and persistent (3 weeks) activation of astrocytes reflected by strong upregulation of glial fibrillary acidic protein (GFAP) mRNA synthesis and GFAP immunoreactivity. Moreover, CNTF signaling via phosphorylation and nuclear translocation of STAT3 (signal transducer and activator of transcription 3) was specifically activated in GFAP-positive astrocytes. CNTF-mediated activation of astrocytes 2 days prior to an epileptogenic intrahippocampal injection of kainate (KA) resulted in strongly reduced cell death in the hilus and CA3 region of the hippocampus, revealed by Fluoro-Jade B staining. Granule cell dispersion, the pathological widening of the granule cell layer, was also significantly reduced 16 days after KA injection. Importantly, intrahippocampal in vivo recordings 3 weeks after KA injection showed that the occurrence of high frequency oscillations (fast ripples, FR), a surrogate marker for epileptic activity, was significantly reduced in CNTF+KA-injected mice as compared to KA-injected animals. However, when CNTF was applied in the chronic epileptic phase at 3 weeks after KA injection, no reduction of FR activity was observed. In summary, our results indicate that the activation of astrocytes prior to an excitotoxic injury effectively reduces neuronal damage and the severity of epileptiform activity, whereas activation in the chronic phase is no longer protective.
活化的星形胶质细胞表现出广泛的特性，从神经保护到积极促进神经组织死亡。为了研究单一的、明确的刺激是否能增强星形胶质细胞的激活，我们测试了睫状神经营养因子（CNTF）是否能改善与癫痫相关的脑损伤。在小鼠海马内注射 CNTF 可迅速（2 天内）和持久（3 周）激活星形胶质细胞，表现为胶质纤维酸性蛋白（GFAP）mRNA 合成和 GFAP 免疫反应性的强烈上调。此外，CNTF 通过 STAT3（信号转导和转录激活因子 3）的磷酸化和核易位特异性激活 GFAP 阳性星形胶质细胞中的信号通路。在癫痫发作性海马内注射海人藻酸（KA）前 2 天，CNTF 介导的星形胶质细胞激活导致海马齿状回和 CA3 区的细胞死亡明显减少，这一点通过 Fluoro-Jade B 染色得到证实。颗粒细胞分散，即颗粒细胞层病理性增宽，在 KA 注射后 16 天也明显减少。重要的是，KA 注射后 3 周的海马内体内记录显示，高频振荡（快涟漪，FR）的发生，即癫痫活动的替代标志物，在 CNTF+KA 注射小鼠中明显低于 KA 注射动物。然而，当 CNTF 在 KA 注射后 3 周的慢性癫痫期应用时，未观察到 FR 活性的降低。总之，我们的结果表明，在兴奋性损伤前激活星形胶质细胞可有效减少神经元损伤和癫痫样活动的严重程度，而在慢性期激活则不再具有保护作用。
