Neuroprotective effects and mechanisms of ischemic/hypoxic preconditioning on neurological diseases

Abstract

As the organ with the highest demand for oxygen, the brain has a poor tolerance to ischemia and hypoxia. Despite severe ischemia/hypoxia induces the occurrence and development of various central nervous system (CNS) diseases, sublethal insult may induce strong protection against subsequent fatal injuries by improving tolerance. Searching for potential measures to improve brain ischemic/hypoxic is of great significance for treatment of ischemia/hypoxia related CNS diseases. Ischemic/hypoxic preconditioning (I/HPC) refers to the approach to give the body a short period of mild ischemic/hypoxic stimulus which can significantly improve the body's tolerance to subsequent more severe ischemia/hypoxia event. It has been extensively studied and been considered as an effective therapeutic strategy in CNS diseases. Its protective mechanisms involved multiple processes, such as activation of hypoxia signaling pathways, anti-inflammation, antioxidant stress, and autophagy induction, etc. As a strategy to induce endogenous neuroprotection, I/HPC has attracted extensive attention and become one of the research frontiers and hotspots in the field of neurotherapy. In this review, we discuss the basic and clinical research progress of I/HPC on CNS diseases, and summarize its mechanisms. Furthermore, we highlight the limitations and challenges of their translation from basic research to clinical application.

Keywords: hypoxia; ischemia; neurological diseases; neuroprotection; preconditioning.

FIGURE 1

Neuroprotective mechanisms of IPC/HPC/RIPC treatment in neurological diseases. IPC/HPC/RIPC could prevent from several neurological diseases, such as cerebrovascular diseases, neurodegenerative diseases, multiple sclerosis, and spinal cord injury. There protective machenisms including activating hypoxic signaling pathway, antioxidant stress, anti‐inflammation, anti‐apoptosis, reducing excitotoxicity, and activating autophagy. HPC, hypoxic preconditioning; IPC, ischemic preconditioning; RIPC, remote ischemic preconditioning

FIGURE 2

Molecular mechanisms of IPC/HPC/RIPC treatment. Various critical molecules and mechanisms are involved in neuroprotective effects of IPC/HPC/RIPC treatment. AKT, protein kinase B; BAX, Bcl‐2‐associated X; BBB, blood brain barrier; Bcl‐2, B‐cell lymphoma‐2; CAT, catalase; EPO, erythropoietin; GLT, glutamate transporter; GPx, glutathione peroxidase; HIF, hypoxia inducible factor; HPC, hypoxic preconditioning; HSP70, heat‐shock protein 70; IFN, interferon; IL, interleukin; IPC, ischemic preconditioning; NCX, Na⁺–Ca²⁺ exchanger; NF‐κB, nuclear factor‐kappa B; Nrf2, erythroid 2‐related factor 2; NO, nitric oxide; PI3K, phosphatidylinositol 3‐kinase; PKC, protein kinase C; S1P, sphingosine‐1‐phosphate; SOD, superoxide dismutase; Sphk1, sphingosine kinase; Rab, ras‐related in brain; RIPC, remote ischemic preconditioning; TLR, toll‐like receptor; TNF, tumor necrosis factor; TRAIL, TNF‐related apoptosis inducing ligand; VEGF, vascular endothelial growth factor

FIGURE 3

Molecular mechanisms of HIF‐1α mediated hypoxia response. Under normoxic conditions, HIF‐1α subunit is hydroxylated by PHD, which further promotes its binding with VHL complex, resulting in its ubiquitin and proteasomal degradation. Under hypoxic conditions, HIF‐1α combines with HIF‐1β to form a complex, which translocates to the nucleus and binds to HRE resulting in the transcription of multiple genes, such as EPO, VEGF, and Glut. EPO, erythropoietin; HIF, hypoxia inducible factor; HRE, hypoxia response element; PHD, proline hydroxylase; VEGF, vascular endothelial growth factor

FIGURE 4

IPC/HPC/RIPC relieve neuroinflammation induced through central and peripheral immune cells. Neuroinflammation is involved in the pathogenesis of many neurological diseases. In the CNS, microglia or astrocytes activation could result in the release of inflammatory factors, such as TNF‐α, IL‐1β, and IL‐6. In addition, peripheral immune cells such as T lymphocytes and monocytes also infiltrate into CNS through BBB, which is usually destructive in most neurological diseases. The above process could be relieved by IPC/HPC/RIPC. BBB, blood brain barrier; CNS, central nervous system; HPC, hypoxic preconditioning; IL, interleukin; IPC, ischemic preconditioning; RIPC, remote ischemic preconditioning; TNF, tumor necrosis factor