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.

非甾体抗炎药是使用最广泛的药物类别之一，但早期开发的风险仍然存在争议，特别是在神经系统中。在这里，我们利用斑马鱼幼虫来评估非甾体抗炎药的潜在毒性作用，发现舒林酸可以选择性诱导斑马鱼幼虫大脑中GABA能神经元的凋亡。斑马鱼幼虫在接触舒林酸后表现出过度活跃的行为。我们还发现 akt1 在 GABA 能神经元中选择性表达，SC97（一种 Akt1 激活剂）和外源 akt1 mRNA 可以逆转舒林酸引起的细胞凋亡。进一步的研究表明，舒林酸与视黄酸 X 受体 α (RXRα) 结合，诱导 GABA 能神经元自噬，从而激活线粒体凋亡途径。最后，我们验证了舒林酸可以导致小鼠多动症并选择性诱导 GABA 能神经元凋亡。这些发现表明，过量使用舒林酸可能会导致早期神经发育毒性并增加多动的风险，这可能与 GABA 能神经元的损伤有关。