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•CREB activation protected Sb-induced neuronal apoptosis.•JNK pathway activation contributed to Sb-stimulated CREB phosphorylation.•JNK/CREB activation alleviates Sb-induced neuronal apoptosis through Bcl-2 regulation.
Antimony (Sb) is a potentially toxic chemical element abundantly found in the environment. We previously reported that Sb promoted neuronal deathvia reactive oxygen species-dependent autophagy. Here, we assessed the role of cyclic adenosine monophosphate response element-binding protein (CREB) in Sb-induced neuronal damage. We found that Sb treatment induced CREB phosphorylation and neuronal apoptosis both in vitro and in vivo. Interestingly, inhibition of CREB’s transcriptional activity with 666−15 dramatically enhanced apoptosis in PC12 cells by downregulating B-cell lymphoma 2 (Bcl-2). Additionally, Sb activated ERK, JNK, and p38 signaling ; however, only JNK promoted CREB phosphorylation. In conclusion, our findings suggest that CREB phosphorylation by JNK attenuates Sb-induced neuronal apoptosis via Bcl-2 upregulation. These data suggest that JNK-dependent CREB activation prevents neurons from Sb-induced apoptosis and guides the development of novel strategies to prevent Sb-induced neurotoxicity.