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Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish

Author

Listed:
  • Wenwei Sun

    (South China University of Technology)

  • Meimei Wang

    (South China University of Technology)

  • Jun Zhao

    (South China University of Technology)

  • Shuang Zhao

    (South China University of Technology)

  • Wenchao Zhu

    (South China University of Technology)

  • Xiaoting Wu

    (Guangdong Pharmaceutical University)

  • Feifei Li

    (South China University of Technology)

  • Wei Liu

    (South China University of Technology)

  • Zhuo Wang

    (South China University of Technology)

  • Meng Gao

    (South China University of Technology)

  • Yiyue Zhang

    (South China University of Technology)

  • Jin Xu

    (South China University of Technology)

  • Meijia Zhang

    (South China University of Technology)

  • Qiang Wang

    (South China University of Technology)

  • Zilong Wen

    (Clear Water Bay, Kowloon
    Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center)

  • Juan Shen

    (Guangdong Pharmaceutical University)

  • Wenqing Zhang

    (South China University of Technology
    Shenzhen Bay Laboratory)

  • Zhibin Huang

    (South China University of Technology)

Abstract

Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.

Suggested Citation

  • Wenwei Sun & Meimei Wang & Jun Zhao & Shuang Zhao & Wenchao Zhu & Xiaoting Wu & Feifei Li & Wei Liu & Zhuo Wang & Meng Gao & Yiyue Zhang & Jin Xu & Meijia Zhang & Qiang Wang & Zilong Wen & Juan Shen &, 2023. "Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41114-y
    DOI: 10.1038/s41467-023-41114-y
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    References listed on IDEAS

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    1. J. Gray Camp & Keisuke Sekine & Tobias Gerber & Henry Loeffler-Wirth & Hans Binder & Malgorzata Gac & Sabina Kanton & Jorge Kageyama & Georg Damm & Daniel Seehofer & Lenka Belicova & Marc Bickle & Ric, 2017. "Multilineage communication regulates human liver bud development from pluripotency," Nature, Nature, vol. 546(7659), pages 533-538, June.
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