CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy
CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy
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DOI：
10.1016/j.expneurol.2012.04.009
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Haas, Carola A.
中科院分区：
文献类型：
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作者：
Bechstein, Matthias;Haeussler, Ute;Haas, Carola A.
激活的星形胶质细胞表现出广泛的特性，从神经保护到对神经组织死亡的积极贡献。为了研究单一、明确的刺激激活星形胶质细胞是否增强了神经保护特性，我们测试了注射睫状神经营养因子(CNTF)是否可以改善癫痫相关的脑损伤。小鼠海马区注射CNTF可诱导星形胶质细胞快速(2天内)、持续(3周)激活，表现为胶质纤维酸性蛋白(GFAP)mRNA合成和GFAP免疫反应增强。此外，在GFAP阳性的星形胶质细胞中，CNTF信号通过信号转导和转录激活子3(STAT3)的磷酸化和核转位被特异性地激活。海人藻酸(KA)致痫前2天，CNTF介导的星形胶质细胞活化导致海马门区和CA3区细胞死亡明显减少，荧光Jade B染色显示。注射KA后16天，颗粒细胞弥散、颗粒细胞层的病理增宽也明显减少。重要的是，注射KA后3周的体内海马区记录显示，与注射KA的小鼠相比，CNTF+KA注射的小鼠的高频振荡(快速涟漪，FR)的发生显著减少。而在注射KA后3周慢性癫痫期应用CNTF，未见FR活性降低。综上所述，我们的结果表明，星形胶质细胞在兴奋性毒性损伤之前的激活有效地减少了神经元的损伤和癫痫样活动的严重程度，而慢性期的激活不再具有保护作用。(C)2012 Elsevier Inc.保留所有权利。
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. (C) 2012 Elsevier Inc. All rights reserved.