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Role of Elevated Thrombospondin-1 in Kainic Acid-Induced Status Epilepticus

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Abstract

Previous studies have suggested that thrombospondin-1 (TSP-1) regulates the transforming growth factor beta 1 (TGF-β1)/phosphorylated Smad2/3 (pSmad2/3) pathway. Moreover, TSP-1 is closely associated with epilepsy. However, the role of the TSP-1-regulated TGF-β1/pSmad2/3 pathway in seizures remains unclear. In this study, changes in this pathway were assessed following kainic acid (KA)-induced status epilepticus (SE) in rats. The results showed that increases in the TSP-1/TGF-β1/pSmad2/3 levels spatially and temporally matched the increases in glial fibrillary acidic protein (GFAP)/chondroitin sulfate (CS56) levels following KA administration. Inhibition of TSP-1 expression by small interfering RNA or inhibition of TGF-β1 activation with a Leu-Ser-Lys-Leu peptide significantly reduced the severity of KA-induced acute seizures. These anti-seizure effects were accompanied by decreased GFAP/CS56 expression and Smad2/3 phosphorylation. Moreover, inhibiting Smad2/3 phosphorylation with ponatinib or SIS3 also significantly reduced seizure severity, alongside reducing GFAP/CS56 immunoreactivity. These results suggest that the TSP-1-regulated TGF-β1/pSmad2/3 pathway plays a key role in KA-induced SE and astrogliosis, and that inhibiting this pathway may be a potential anti-seizure strategy.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81573412), the Key Research and Development Plan (2018GSF121004), and the Natural Science Foundation of Shandong Province, China (ZR2014JL055).

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  1. Yurong Zhang and Mengdi Zhang have contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, China

    Yurong Zhang, Mengdi Zhang, Xiaohong Pan, Qiaoyun Wang, Xue Gao, Chaoyun Wang, Xiuli Zhang, Yuxia Liu, Shucui Li & Hongliu Sun

  2. Shandong Academy of Medical Sciences, Jinan, 250062, China

    Wei Zhu

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  1. Yurong Zhang
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Zhang, Y., Zhang, M., Zhu, W. et al. Role of Elevated Thrombospondin-1 in Kainic Acid-Induced Status Epilepticus. Neurosci. Bull. 36, 263–276 (2020). https://doi.org/10.1007/s12264-019-00437-x

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