Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish.
Wenwei SunMeimei WangJun ZhaoShuang ZhaoWenchao ZhuXiaoting WuFeifei LiWei LiuZhuo WangMeng GaoWenqing ZhangJin XuMeijia ZhangQiang WangZilong WenJuan ShenWenqing ZhangZhibin HuangPublished in: Nature communications (2023)
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.
Keyphrases
- oxidative stress
- cell death
- endoplasmic reticulum stress
- cell cycle arrest
- anti inflammatory drugs
- spinal cord
- signaling pathway
- cell proliferation
- pi k akt
- aedes aegypti
- type diabetes
- metabolic syndrome
- binding protein
- risk assessment
- physical activity
- high fat diet induced
- skeletal muscle
- body mass index
- nuclear factor
- case control
- anti inflammatory
- oxide nanoparticles