2. Academic Validation
  3. Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish

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

  • Nat Commun. 2023 Sep 2;14(1):5351. doi: 10.1038/s41467-023-41114-y.
Wenwei Sun # 1,  Meimei Wang # 1,  Jun Zhao 1,  Shuang Zhao 1,  Wenchao Zhu 2,  Xiaoting Wu 3,  Feifei Li 1,  Wei Liu 1,  Zhuo Wang 1,  Meng Gao 2,  Yiyue Zhang 1,  Jin Xu 1,  Meijia Zhang 1,  Qiang Wang 1,  Zilong Wen 4 5,  Juan Shen 6,  Wenqing Zhang 7 8,  Zhibin Huang 9
Affiliations

Affiliations

  • 1 Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
  • 2 National Engineering Research Center for Tissue Restoration and Reconstruction, Key Laboratory of Biomedical Engineering of Guangdong Province, Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, Innovation Center for Tissue Restoration Reconstruction, South China University of Technology, Guangzhou, 510006, China.
  • 3 Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
  • 4 Division of Life Science, State Key Laboratory of Molecular Neuroscience and Center of Systems Biology and Human Health, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China.
  • 5 Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518055, China.
  • 6 Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China. [email protected].
  • 7 Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, China. [email protected].
  • 8 Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, 518055, China. [email protected].
  • 9 Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, China. [email protected].
  • # Contributed equally.
PMID: 37660128 DOI: 10.1038/s41467-023-41114-y
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.

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