Insulin-like growth factor-1 (IGF-1) is known to promote neurogenesis and survival. However, recent studies have suggested that IGF-1 regulates neuronal firing and excitatory neurotransmission. In the present study, focusing on temporal lobe epilepsy, we found that IGF-1 levels and IGF-1 receptor activation are increased in human epileptogenic tissues, and pilocarpine- and pentylenetetrazole-treated rat models. Using an acute model of seizures, we showed that lateral cerebroventricular infusion of IGF-1 elevates IGF-1 receptor (IGF-1R) signalling before pilocarpine application had proconvulsant effects. In vivo electroencephalogram recordings and power spectrogram analysis of local field potential revealed that IGF-1 promotes epileptiform activities. This effect is diminished by co-application of an IGF-1R inhibitor. In an in vitro electrophysiological study, we demonstrated that IGF-1 enhancement of excitatory neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor- and N-methyl-D-aspartate receptor-mediated currents is inhibited by IGF-1R inhibitor. Finally, activation of extracellular signal-related kinase (ERK)-1/2 and protein kinase B (Akt) in seizures in rats is increased by exogenous IGF-1 and diminished by picropodophyllin. A behavioural study reveals that the ERK1/2 or Akt inhibitor attenuates seizure activity. These results indicate that increased IGF-1 levels after recurrent hippocampal neuronal firings might, in turn, promote seizure activity via IGF-1R-dependent mechanisms. The present study presents a previously unappreciated role of IGF-1R in the development of seizure activity.
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September 24 2015
Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain
Guohui Jiang;
Guohui Jiang
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
†Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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Wei Wang;
Wei Wang
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
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Qingqing Cao;
Qingqing Cao
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
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Juan Gu;
Juan Gu
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
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Xiujuan Mi;
Xiujuan Mi
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
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Kewei Wang;
Kewei Wang
‡Department of Pharmacology, Peking University School of Medicine, Beijing, China
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Guojun Chen;
Guojun Chen
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
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Xuefeng Wang
*Department of Neurology, First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
Correspondence: Xuefeng Wang ([email protected]) or Guojun Chen ([email protected]).
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Publisher: Portland Press Ltd
Received:
April 28 2015
Revision Received:
July 15 2015
Accepted:
August 18 2015
Accepted Manuscript online:
August 18 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (12): 1047–1060.
Article history
Received:
April 28 2015
Revision Received:
July 15 2015
Accepted:
August 18 2015
Accepted Manuscript online:
August 18 2015
Citation
Guohui Jiang, Wei Wang, Qingqing Cao, Juan Gu, Xiujuan Mi, Kewei Wang, Guojun Chen, Xuefeng Wang; Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain. Clin Sci (Lond) 1 December 2015; 129 (12): 1047–1060. doi: https://doi.org/10.1042/CS20150312
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