Kaur Navpreet, Aran Khadga Raj
Department of Pharmacy Practice, ISF College of Pharmacy, Moga, 142001, Punjab, India.
Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
Mol Biol Rep. 2025 Sep 2;52(1):858. doi: 10.1007/s11033-025-10944-y.
Hypoxia is an inadequate oxygen supply to the tissues, which hinders the brain's ability to produce energy and causes unconsciousness, followed by death in a matter of minutes. Upon detecting oxygen deprivation, the body initiates a cardiorespiratory response that includes increased lung ventilation, vasoconstriction, and an increased heart rate to improve oxygen supply. Moreover, during hypoxia, there is stabilization of hypoxia inducible factor (HIF), including HIF-1α and HIF-2α, where HIF-1α predominantly regulates genes involved in metabolic reprogramming and immediate stress response, and HIF-2α is engaged in sustaining vascular endothelial growth factor (VEGF) and erythropoietin (EPO) gene expression. The brain is an extremely oxygen-dependent organ, as it uses one-fifth of the body's oxygen at rest, making it particularly vulnerable during hypoxia. According to the literature, it results in metabolic changes in neurons via impacting various enzymatic activities, which further trigger inflammatory responses and oxidative stress, resulting in Parkinson's disease (PD). PD is a progressive neurodegenerative disease, characterised by α-synuclein aggregation, Lewy body formation, and dopaminergic neuronal loss in the substantia nigra. HIF-1α is involved in various pathological mechanisms underlying PD, including α-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and proteasomal degradation. Emerging evidence from several preclinical studies demonstrates that HIF-1α could be a promising therapeutic target due to its active involvement in PD pathology. This review aims to elucidate the interconnection between hypoxia and the development of PD by evaluating the role of HIF-1α in the pathogenesis of PD and summarizing possible therapeutic strategies based on modifying the activity of the HIF-1α signaling.
缺氧是指组织的氧气供应不足，这会阻碍大脑产生能量的能力，导致昏迷，随后在几分钟内死亡。一旦检测到缺氧，身体就会启动心肺反应，包括增加肺通气、血管收缩和心率加快，以改善氧气供应。此外，在缺氧期间，缺氧诱导因子（HIF）会稳定下来，包括HIF-1α和HIF-2α，其中HIF-1α主要调节参与代谢重编程和即时应激反应的基因，而HIF-2α则参与维持血管内皮生长因子（VEGF）和促红细胞生成素（EPO）的基因表达。大脑是一个极其依赖氧气的器官，因为它在休息时消耗身体五分之一的氧气，这使得它在缺氧时特别脆弱。根据文献，缺氧通过影响各种酶活性导致神经元代谢变化，进而引发炎症反应和氧化应激，导致帕金森病（PD）。PD是一种进行性神经退行性疾病，其特征是α-突触核蛋白聚集、路易小体形成以及黑质中多巴胺能神经元丢失。HIF-1α参与了PD的各种病理机制，包括α-突触核蛋白聚集、神经炎症、线粒体功能障碍和蛋白酶体降解。来自几项临床前研究的新证据表明，由于HIF-1α积极参与PD病理过程，它可能是一个有前景的治疗靶点。本综述旨在通过评估HIF-1α在PD发病机制中的作用，并总结基于调节HIF-1α信号活性的可能治疗策略，阐明缺氧与PD发展之间的联系。
