Pang Qianqian, Yan Xinyang, Chen Zheng, Yun Liang, Qian Jiang, Dong Zeyi, Wang Miao, Deng Wei, Fu Yao, Hai Tao, Chen Zhichao, Rong Xianfang
Research and Development Center, IMiracle (Shenzhen) Innovation Technology Co., Ltd, Shenzhen, China.
Dongguan Hongfu Biological Technology Co., Ltd, Dongguan, China.
Nicotine Tob Res. 2025 Jul 22;27(8):1420-1429. doi: 10.1093/ntr/ntaf034.
INTRODUCTION: 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. METHODS: 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. RESULTS: MCAO/R resulted in significantly compromised BBB integrity and serious brain damage. Notably, pretreatment of mice with 12 μg/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 acetylcholine receptor (α7 nAChR) inhibitor α-BTX. CONCLUSIONS: These results demonstrate that nicotine treatment could alleviates the IS-compromised integrity of BBB by regulating the Wnt signal pathway through α7 nAChR. IMPLICATIONS: The study demonstrates that nicotine at low concentrations exerts neuro-protective effects by supporting the integrity of BBB and subsequent endothelial viability after ischemic stroke. This finding suggests that targeting the BBB, especially endothelial cells, with nicotine treatment is a promising therapeutic strategy for brain injury after ischemic stroke.
引言：越来越多的证据表明，低剂量尼古丁对缺血性中风（IS）可能具有预防和治疗作用。然而，直接证据仍然缺失，尤其是关键分子和信号通路方面。 方法：将小鼠随机分为三组之一：假手术组、对照组和尼古丁处理组。在对照组中，小鼠接受大脑中动脉闭塞/再灌注（MCAO/R）。在尼古丁处理组中，小鼠在手术前1个月饮用含12μg/ml尼古丁的水。对于体外血脑屏障（BBB）模型，在Transwells上制备hCMEC/D3单层细胞，并用尼古丁预处理48小时，然后进行氧糖剥夺/复氧（OGD/R）。此外，采用RNA测序来探索与尼古丁保护作用相关的潜在靶点和信号通路。 结果：MCAO/R导致BBB完整性显著受损和严重脑损伤。值得注意的是，用12μg/ml尼古丁预处理小鼠1个月可显著降低IS诱导的BBB损伤及其相关的脑损伤。此外，在OGD/R条件下，hCMEC/D3单层内皮细胞的通透性显著降低，尼古丁预处理可改善这一情况。RNA测序结果表明，TGF-β和Wnt信号通路与OGD/R和OGD/R加尼古丁处理之间的差异表达基因相关的通路有关。最后，α7尼古丁乙酰胆碱受体（α7 nAChR）抑制剂α-BTX可拮抗Wnt/β-连环蛋白通路的激活。 结论：这些结果表明，尼古丁处理可通过α7 nAChR调节Wnt信号通路，减轻IS导致的BBB完整性受损。 启示：该研究表明，低浓度尼古丁通过支持缺血性中风后BBB的完整性和随后的内皮细胞活力发挥神经保护作用。这一发现表明，用尼古丁处理靶向BBB，尤其是内皮细胞，是缺血性中风后脑损伤的一种有前景的治疗策略。
Cell Mol Life Sci. 2025-6-28
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