Tang Hui, Shao Chuan, Wang Xiaoya, Cao Yi, Li Zhou, Luo Xiaoquan, Yang Xiang, Zhang Yuekang
Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, SC, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, SC, China.
Front Pharmacol. 2022 Aug 25;13:882121. doi: 10.3389/fphar.2022.882121. eCollection 2022.
Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally 1 hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.
众多研究已阐明6-姜酚在中枢神经系统疾病中的神经保护作用。然而，6-姜酚对蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的潜在作用及机制仍知之甚少。在此，我们报告6-姜酚通过GBP2/PI3K/AKT途径对SAH诱导的EBI发挥神经保护作用。通过向大鼠脑大池注入股动脉血建立SAH大鼠模型。在SAH诱导后1小时腹腔注射6-姜酚或溶剂。我们发现，6-姜酚治疗后SAH大鼠的神经功能评分和脑水肿显著改善，并且通过尼氏染色法和TUNEL法检测发现SAH大鼠的神经元凋亡减少。为了进一步探索与6-姜酚相关的潜在分子机制，进行了RNA测序以研究6-姜酚治疗组和未治疗组SAH大鼠转录组的差异；结果发现，与溶剂组相比，6-姜酚治疗明显抑制了鸟苷酸结合蛋白2（GBP2）的表达。此外，还采用双免疫荧光法研究6-姜酚治疗后神经元、星形胶质细胞和小胶质细胞的变化。结果显示GBP2在神经元中表达，而在星形胶质细胞或小胶质细胞中不表达。蛋白质免疫印迹分析结果表明，6-姜酚治疗的SAH大鼠中PI3K/AKT途径被激活。此外，重组GBP2蛋白和LY294002（PI3K抑制剂）处理逆转了6-姜酚对SAH大鼠的治疗效果。这些结果表明，6-姜酚通过抑制GBP2的表达来激活PI3K/AKT途径，改善神经功能结局，减轻脑水肿和神经元凋亡。总之，我们的研究结果表明，6-姜酚可减轻大鼠SAH后的EBI，6-姜酚可能成为SAH诱导的EBI的新型神经保护候选药物。
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