Neuroprotective effect of ischemic postconditioning against hyperperfusion and its mechanisms of neuroprotection

Abstract

Background: In recent years, stroke and ischemia-reperfusion injury has motivated researchers to find new ways to reduce the complications. Although reperfusion is essential for brain survival, it is like a double-edged sword that may cause further damage to the brain. Ischemic postconditioning (IPostC) refers to the control of blood flow in postischemia-reperfusion that can reduce ischemia-reperfusion injuries.

Materials and methods: Articles were collected by searching for the terms: Ischemic postconditioning and neuroprotective and ischemic postconditioning and hyperperfusion. Suitable articles were collected from electronic databases, including ISI Web of Knowledge, Medline/PubMed, ScienceDirect, Embase, Scopus, Biological Abstract, Chemical Abstract, and Google Scholar.

Results: New investigations show that IPostC has protection against hyperperfusion by reducing the amount of blood flow during reperfusion and thus reducing infarction volume, preventing the blood-brain barrier damage, and reducing the rate of apoptosis through the activation of innate protective systems. Numerous mechanisms have been suggested for IPostC, which include reduction of free radical production, apoptosis, inflammatory factors, and activation of endogenous protective pathways.

Conclusion: It seems that postconditioning can prevent damage to the brain by reducing the flow and blood pressure caused by hyperperfusion. It can protect the brain against damages such as stroke and hyperperfusion by activating various endogenous protection systems. In the present review article, we tried to evaluate both useful aspects of IPostC, neuroprotective effects, and fight against hyperperfusion.

Keywords: Ischemic postconditioning; neuroprotective; reperfusion injury.

Figure 1

Schematic of the effect of reperfusion on the opening of mitochondrial membrane pores called permeability transition pore (PTP). During reperfusion following prolonged ischemic, the accumulation of Ca2 + in the mitochondrial matrix causes the matrix chaperones to move to the inner mitochondrial membrane, which in turn causes PTP to open

Figure 2

Triggers of complement activation after cerebral ischemia–reperfusion injury. Ischemic insult induces the expression of neoepitopes or danger-associated molecular patterns (DAMPs) on the surface of stressed endothelial cells. The exposed DAMPs are recognized by circulating natural self-reactive antibodies, principally immunoglobulin M (IgM), which triggers complement activation. Although IgM binds C1q, it appears to be the binding of mannose-binding lectin and activation of the lectin pathway that drives ischemia and reperfusion injury in the organ systems examined, including the brain. Complement can be also activated through direct binding of C1q to apoptotic cells, as well as through C-reactive protein-induced complement activation

Figure 3

Mechanism of anti-apoptotic effects of ischemic postconditioning. Stress in the endoplasmic reticulum is closely related to mitochondrial function. In fact, ischemic postconditioning causes a kind of stress on the cell, thereby activating the endogenous defense mechanisms and thus protecting the mitochondria. This process reduces apoptosis in nerve cells. P-eif2α: Phospho- eukaryotic initiation factor 2 alpha, GRP78: Glucose-regulated protein78, CHOP: C/EBP homologous protein, ER: Endoplasmic reticulum, Bim: Bcl-2-like protein, Bcl-2: B-cell lymphoma 2, NF-ҝB: Nuclear factor kappa-light-chain-enhancer of activated B-cells, JNK: c-Jun N-terminal kinase, pAKT: Phosphorylated protein kinase B, ERK: Extracellular signal-related kinase, Bad: Bcl-2-associated death promoter, mitokATP: Mitochondrial ATP-sensitive potassium channels, Cyto C: Cytochrome C

Figure 4

Mechanism of anti-inflammatory effects of post-conditional ischemic. Ischemic postconditioning stimulates endogenous defense mechanisms. Decreased mitochondrial cytochrome C leads to suppression of the immune system, which in turn reduces the levels of inflammatory cytokines and chemokines. IL-1β: Interleukin-1 beta, TNF-α: Tumor necrosis factor-alpha, TLR-2: Toll-like receptor 2, TLR-4: Toll-like receptor 4, Cyto C: Cytochrome C, NF-ҝB: Nuclear factor kappa-light-chain-enhancer of activated B-cells

Figure 5

Schematic diagram illustrating the impact of endogenous neuroprotective mechanisms on neuron rescue after injury