Gastroenterology Department, National Clinical Research Center for Child Health, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China; Institute of Systemic medicine, Zhejiang University School of Medicine, Hangzhou, China; Department of Zoology, Faculty of Science, Aswan University, Egypt.
Gastroenterology Department, National Clinical Research Center for Child Health, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Phytomedicine. 2022 Sep;104:154298. doi: 10.1016/j.phymed.2022.154298. Epub 2022 Jun 27.
A blockage in a blood vessel can cause reduced blood flow to the brain, which eventually leads to the death of surrounding tissue. Several studies have attempted to develop an effective intervention to reverse this process and improve the health status of affected individuals. Due to its indirect effect on cellular functions and metabolism, the hypoxia-inducible factor (HIF-1α) protein has been proposed as a promising transcription factor in the treatment of stroke.
The current study aims to explore the relation between HIF-1 α and thymoquinone (TQ) in the attenuation of ischemic brain damage and the possible mechanism of this relation to reduce cell death.
For this purpose, dimethyloxallyl glycine (DMOG), 8 mg/kg, Acriflavine (ACF), 1.5 mg/kg, and both combined with TQ (5 mg/kg) were assessed. Male C57 mice were used to establish an ischemic stroke model by using endothelin-1 (ET-1) (400 pmole/μl) intra- cranial injection. The ultrastructure alterations of neuronal soma, axons, and mitochondria after stroke and treatment were well addressed. Besides, the expression levels of VEGF, HIF-1α, Nrf2, and HO-1 were evaluated. Meanwhile, apoptosis and autophagy-related proteins were also investigated.
Treatment of ischemic stroke by TQ can activate the HIF-1α pathway and its downstream genes such as VEGF, TrkB, and PI3K, which in turn enhance angiogenesis and neurogenesis. Our study revealed that TQ has the same effect as DMOG to activate HIF-1 α and can improve motor dysfunction after ischemic stroke. Further, we demonstrated that both TQ and DMOG effectively attenuate the organelle's damage following ischemic stroke, which was confirmed by the cryogenic transmission electron microscope. The synergistic effect of TQ and DMOG may lead to a chemo-modulation action in the autophagy process after stroke onset and this result is validated by the western blot and rt-qPCR techniques.
Our finding revealed the potential role of TQ as a HIF-1 α activator to reduce cell death, modulate autophagy and decrease the infarct volume after ischemic stroke onset. The neuroprotective effect of TQ is achieved by decreasing the inflammation and increasing angiogenesis as well as neurogenesis via induction of the HIF-1α-VEGF/Nrf2-HO-1-TrkB-PI3K pathway.
血管阻塞会导致大脑血流减少，最终导致周围组织死亡。已有多项研究试图开发有效的干预措施来逆转这一过程，改善受影响个体的健康状况。由于其对细胞功能和代谢的间接影响，缺氧诱导因子（HIF-1α）蛋白被提议作为治疗中风的一种有前途的转录因子。
本研究旨在探讨 HIF-1α与百里醌（TQ）在减轻缺血性脑损伤中的关系，以及这种关系降低细胞死亡的可能机制。
为此，评估了二甲基氧代甘氨酸（DMOG）、8mg/kg、吖啶黄素（ACF）、1.5mg/kg 以及两者与 TQ（5mg/kg）联合使用。使用内皮素-1（ET-1）（400pmole/μl）颅内注射建立雄性 C57 小鼠缺血性中风模型。很好地解决了中风和治疗后神经元体、轴突和线粒体的超微结构改变。此外，还评估了 VEGF、HIF-1α、Nrf2 和 HO-1 的表达水平。同时，还研究了细胞凋亡和自噬相关蛋白。
TQ 治疗缺血性中风可激活 HIF-1α 通路及其下游基因，如 VEGF、TrkB 和 PI3K，从而促进血管生成和神经发生。我们的研究表明，TQ 与 DMOG 具有相同的激活 HIF-1α 的作用，并能改善缺血性中风后的运动功能障碍。此外，我们还证明，TQ 和 DMOG 都能有效地减轻缺血性中风后细胞器的损伤，这一点通过低温透射电子显微镜得到了证实。TQ 和 DMOG 的协同作用可能导致中风发作后自噬过程中的化学调节作用，这一结果通过 western blot 和 rt-qPCR 技术得到了验证。
我们的发现揭示了 TQ 作为 HIF-1α 激活剂的潜在作用，可减少细胞死亡，调节自噬，减少缺血性中风后的梗死体积。TQ 的神经保护作用是通过降低炎症、增加血管生成和神经发生来实现的，其机制是诱导 HIF-1α-VEGF/Nrf2-HO-1-TrkB-PI3K 通路。
