Nicotine Alleviates Cortical Neuronal Injury by Suppressing Neuroinflammation and Upregulating Neuronal PI3K-AKT Signaling in an Eclampsia-Like Seizure Model
Nicotine Alleviates Cortical Neuronal Injury by Suppressing Neuroinflammation and Upregulating Neuronal PI3K-AKT Signaling in an Eclampsia-Like Seizure Model
复制标题
尼古丁通过抑制子痫样癫痫模型中的神经炎症和上调神经元 PI3K-AKT 信号传导来减轻皮质神经元损伤
DOI：
10.1007/s12640-020-00265-2
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发表时间：
2020-08-07
影响因子：
3.7
通讯作者：
Liu, Huishu
中科院分区：
文献类型：
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作者：
Han, Xinjia;Zhou, Ning;Liu, Huishu
我们之前的研究表明，用α 7尼古丁乙酰胆碱受体（α 7nAChR）激动剂尼古丁治疗可以减轻全身炎症，减少海马神经元的损失和癫痫发作的严重程度。在本研究中，我们进一步研究了子痫发作后皮层是否也存在神经元损伤，阐明了尼古丁在子痫中神经保护作用的潜在机制。回顾性分析重度子痫前期（SPE）患者的MRI资料。采用脂多糖注射液建立子痫前期模型（PE组），戊四氮唑诱导子痫发作（E组）。采用α 7nAChR激动剂尼古丁及其拮抗剂（α - bgt）和PI3K抑制剂wortmannin给药。采用尼氏染色检测神经元损伤，免疫组化和western blotting检测皮层神经元炎症、神经元凋亡、α - 7nAChR表达和PI3K-AKT信号的变化。MRI显示，SPE患者的异常信号多位于大脑皮层。E组皮层神经元存活率低于海马神经元存活率；与对照组相比，E组和PE组大脑皮层的这一比例明显较低。尼古丁显著降低炎症细胞因子的产生和E组皮质小胶质细胞的激活。此外，尼古丁增加了皮质神经元的p-AKT水平，降低了cleaved caspase-3水平。用α - bgt治疗可以逆转尼古丁的作用。Wortmannin还能阻断尼古丁的抗神经元凋亡作用。我们的研究结果表明，尼古丁可能通过抑制神经炎症和激活神经元PI3K-AKT通路来保护子痫后皮层的神经元损伤。
Our previous studies showed that treatment with alpha7 nicotinic acetylcholine receptor (alpha 7nAChR) agonist nicotine could alleviate systemic inflammation and reduce neuronal loss in the hippocampus and seizure severity in eclampsia. In this study, we further investigated whether there is also neuronal damage in the cortex after eclamptic seizure, elucidated the potential mechanisms underlying the neuroprotective roles of nicotine in eclampsia. Retrospective analysis of MRI data of severe preeclampsia (SPE) patients was conducted. A preeclampsia model was established by lipopolysaccharide injection (PE group), and pentylenetetrazol was used to induce eclamptic seizure (E group). alpha 7nAChR agonist nicotine and its antagonist (alpha-BGT) and PI3K inhibitor wortmannin were used for drug administration. Neuronal damage was detected by Nissl staining, and changes in neuroinflammation, neuronal apoptosis, alpha 7nAChR expression, and PI3K-AKT signaling on cortical neurons were detected by immunohistochemistry and western blotting. MRI images showed that most abnormal signals from the brain of SPE patients were located in the cortex. The neuron survival ratio was lower in the cortex than in the hippocampus within the E group; such ratios in the cortex were significantly lower in the E and PE groups compared with those of the control group. Nicotine markedly decreased the production of inflammatory cytokines and microglial activation in the cortex of the E group. Moreover, nicotine increased p-AKT levels and decreased cleaved caspase-3 levels in cortical neurons. Treatment with alpha-BGT reversed effects of nicotine. Wortmannin also blocked the anti-neuronal apoptosis action of nicotine. Our results suggest that nicotine protects against neuronal injury in the cortex following eclampsia possibly by inhibiting neuroinflammation and activating neuronal PI3K-AKT pathway.