The protective effect of low-dose nicotine on ischemia stroke by maintaining the integrity of the blood-brain barrier

• Published in: Nicotine & tobacco research 2025-02
• Main Authors: Pang, Qianqian, Yan, Xinyang, Chen, Zheng, Yun, Liang, Qian, Jiang, Dong, Zeyi, Wang, Miao, Deng, Wei, Fu, Yao, Hai, Tao, Chen, Zhichao, Rong, Xianfang
• Format: Article
• Language: English
• ISSN: 1469-994X; 1469-994X
• DOI: 10.1093/ntr/ntaf034

Increasing evidence has shown that low-dose nicotine could have preventive and therapeutic effects on ischemic stroke (IS). Nevertheless, direct evidence is still missing, especially key molecules and signal pathways.INTRODUCTIONIncreasing evidence has shown that low-dose nicotine could have preventive and therapeutic effects on ischemic stroke (IS). Nevertheless, direct evidence is still missing, especially key molecules and signal pathways.Mice were randomly assigned to one of three groups: the sham group, the control group, and the nicotine-treated group. In the control group, mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). In the nicotine-treated group, mice were exposed to 12 μg/ml nicotine in their drinking water for 1 month prior to undergoing surgery. For in vitro blood-brain barrier (BBB) model, hCMEC/D3 monolayers were prepared on Transwells and pre-treated with nicotine for 48 hours and then subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, RNA-seq was adopted to explore the potential targets and signaling pathways regarding the protective role of nicotine.METHODSMice were randomly assigned to one of three groups: the sham group, the control group, and the nicotine-treated group. In the control group, mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). In the nicotine-treated group, mice were exposed to 12 μg/ml nicotine in their drinking water for 1 month prior to undergoing surgery. For in vitro blood-brain barrier (BBB) model, hCMEC/D3 monolayers were prepared on Transwells and pre-treated with nicotine for 48 hours and then subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Moreover, RNA-seq was adopted to explore the potential targets and signaling pathways regarding the protective role of nicotine.MCAO/R resulted in significantly compromised BBB integrity and serious brain damage. Notably, pretreatment of mice with 12μg/ml nicotine for one month significantly reduced IS-induced BBB damage and its associated brain injury. In addition, the permeability of hCMEC/D3 monolayer endothelial cells was significantly reduced under OGD/R conditions, which could be ameliorated by nicotine pretreatment. The RNA-seq results showed that TGF-β and Wnt signaling pathways were associated with pathways associated with DEGs between OGD/R and OGD/R plus nicotine treatment. Finally, the activation of Wnt/β-catenin pathways could be antagonized by the α7 nicotine acetylcho