CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy
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CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy. / Bechstein, Matthias; Häussler, Ute; Neef, Matthias; Hofmann, Hans-Dieter; Kirsch, Matthias; Haas, Carola A.
in: EXP NEUROL, Jahrgang 236, Nr. 1, 07.2012, S. 141-50.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy
AU - Bechstein, Matthias
AU - Häussler, Ute
AU - Neef, Matthias
AU - Hofmann, Hans-Dieter
AU - Kirsch, Matthias
AU - Haas, Carola A
N1 - Copyright © 2012 Elsevier Inc. All rights reserved.
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
KW - Animals
KW - Astrocytes/drug effects
KW - Ciliary Neurotrophic Factor/physiology
KW - Disease Models, Animal
KW - Epilepsy, Temporal Lobe/chemically induced
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Neurons/drug effects
KW - Neuroprotective Agents/pharmacology
U2 - 10.1016/j.expneurol.2012.04.009
DO - 10.1016/j.expneurol.2012.04.009
M3 - SCORING: Journal article
C2 - 22542945
VL - 236
SP - 141
EP - 150
JO - EXP NEUROL
JF - EXP NEUROL
SN - 0014-4886
IS - 1
ER -