Relationship Between Cerebral Ischemia-Reperfusion Injury And Cell Apoptosis
Apr 21, 2023
The brain is one of the most important organs of the human body. In recent years, with the continuous increase in the incidence of cardiovascular and cerebrovascular diseases, this disease together with heart disease and malignant tumors constitute the three major fatal diseases. Cerebral ischemia is the main cause of cardiovascular and cerebrovascular diseases, which can damage local brain tissue and its function, and the degree of damage is related to the length of ischemia time and the amount of residual blood flow.
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After cerebral ischemia restores the blood supply within a certain period, brain function does not recover, and more serious neurological impairment of brain function occurs. This phenomenon is called cerebral ischemia-reperfusion injury[1][2]. The pathogenic mechanism of cerebral ischemia-reperfusion injury is mainly related to various effects such as excitatory amino acid toxicity, excessive free radical formation, and inflammatory response, and after cerebral ischemia, a large number of neurons around the reperfusion injury area will appear Apoptotic death, that is, cerebral ischemia-reperfusion injury is closely related to apoptosis. This paper describes the current research progress.
Relationship Between Cerebral Ischemia-Reperfusion Injury and Neuronal Apoptosis
Studies have shown that there are two forms of cell death caused by cerebral ischemia-reperfusion injury: necrosis and apoptosis. The duration of ischemic injury and the distance between nerve cells and the ischemic center jointly determine the form of cell death: when the duration of ischemia is longer, that is, when the cells are insufficiently supplied with oxygen for a long time due to severe ischemia and are located in the ischemic center, A sharp drop in blood flow generally causes cell necrosis; short duration of ischemia only causes mild to moderate hypoxic-ischemia, and the nerve cells located in the penumbra of the ischemic central area, that is, the nerve cells around the ischemic central area, are mostly apoptotic.
When the cell dies[3], the volume of the cell shrinks, and the connection with the surrounding cells disappears, so it will be separated from the surrounding cells, the cytoplasm density of the cell will increase, the potential of the mitochondrial membrane will disappear, and then the permeability will change, releasing cytochrome C reaches the cytoplasm, the nucleoplasm is condensed, the nuclear membrane and nucleolus are broken, the DNA is degraded into fragments, and finally forms apoptotic bodies, which are phagocytized by adjacent cells or phagocytes[4].
Pathways of neuronal cell apoptosis caused by cerebral ischemia-reperfusion injury
2.1 Endogenous mitochondria-mediated apoptosis pathway
When nerve cells are stimulated by ischemia, the mitochondrial apoptotic pathway inside the nerve cells can be activated, resulting in the depolarization of the mitochondrial membrane and the decrease of the membrane potential, increasing the permeability of the outer mitochondrial membrane and the release of cytochrome C from the mitochondria.
After cytochrome C is released into the cell, it interacts with Apaf-1 to form an apoptotic complex with the assistance of ATP and dATP. The apoptotic complex recruits and activates Pro-Caspase 9 to form a Caspase 9 holoenzyme, and the Caspase 9 holoenzyme further Activate the effector Caspase3 and Caspase7, starting the caspase cascade reaction, and cut more than 100 kinds of substrates in cells, such as α-tubulin, Actin, PARPA, Lamin, etc., thereby causing nerve cell apoptosis [5].
2.2 Endogenous endoplasmic reticulum-mediated apoptosis pathway
The endoplasmic reticulum is the main processing site for protein synthesis and a storehouse of Ca2+. Cerebral ischemia-reperfusion injury can lead to the disorder of intracellular Ca2+ level, thus causing the stress response of the endoplasmic reticulum. Endoplasmic reticulum stress can reduce protein synthesis in cells, increase protein folding, and maintain Ca2+ homeostasis, but excessive stress can disrupt the Ca2+ homeostasis in the endoplasmic reticulum and a large amount of Ca2+ will enter the cell Inside and inside the mitochondria, on the one hand, it will affect the activity of mitochondria and Bcl-2 family proteins, making the cells go to apoptosis, and on the other hand, activate the intracellular neutral cysteine endopeptidase Calpain. The activated Calpain may activate Caspase Cascade reactions that affect apoptosis [6][7].
2.3 Exogenous death receptor pathway
The death receptor (DR) family on the surface of nerve cells belongs to the superfamily of tumor necrosis factor receptors (TNFR). The death domain (DD) is composed of residues and has the function of hydrolyzing protein. When the death receptor binds to a specific death ligand, it receives an extracellular death signal, activates the intracellular apoptosis mechanism, and induces apoptosis.
Currently, known death receptor ligands mainly include Fas-FasL, TNFR1-TNF, TRAILR1-TRAIL, TRAILR2-TRAIL, and DR3-TL1A. The well-studied death receptor signaling pathways are Fas, TNFR1, and TRAIL[8]. Initiation of Fas-FasL-mediated apoptosis in the external death receptor pathway when the FasL homotrimeric complex binds to Fas; TNF trimer binding to TNFR1 induces the death domain of TNFR1 to gather adapter proteins TRADD, TRADD Signaling molecules such as TRAF2, RIP, and FADD can be recruited.
TRAF2 and RIP can activate NF-κB and JNK/AP signaling pathways, while FADD can activate the Caspase cascade reaction. The difference in the recruitment of signaling molecules by the adapter protein TRADD determines the survival or survival of cells. Death; TRAILR1 and TRAILR2 are highly expressed in cancer cells.
After binding to the ligand TRAIL, they bind to FADD through the death domain, recruit pro-caspase8, and form DISC. Pro-caspase8 in DISC self-cleaves into active Caspase8, and Caspase8 activates Caspase3 through a Caspase pathway similar to Fas and a mitochondria-dependent pathway, thereby mediating apoptosis [9].
Summary
The injury caused by cerebral ischemia-reperfusion is formed by a variety of complex mechanisms. This article only discusses a small part of neuronal apoptosis. At present, there are many studies on cerebral ischemia-reperfusion injury at home and abroad, including the use of traditional Chinese medicine or acupuncture points to regulate related proteins and signaling pathways in multiple ways to repair nerve cells and achieve brain damage. protective effect [10]. However, the mechanism of action of the relevant treatment methods is still unclear, and a large number of clinical studies are still needed to achieve new results as soon as possible to benefit patients.
What is the mechanism of Cistanche's treating ischemia-reperfusion injury?
Cistanche is a traditional herbal medicine that has been used in China for centuries. It contains several bioactive compounds, including echinacoside, acteoside, and verbascoside, which have been shown to possess antioxidant, anti-inflammatory, and immunomodulatory properties.
Studies have shown that Cistanche can protect against ischemia-reperfusion injury by inhibiting oxidative stress, inflammation, and apoptosis. It does this by increasing the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase while reducing the production of reactive oxygen species (ROS) and lipid peroxidation.
Moreover, Cistanche can suppress the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and reduce the recruitment of neutrophils and macrophages to the site of injury. By modulating the immune response, Cistanche can prevent further tissue damage and promote tissue repair. Overall, Cistanche exerts its beneficial effects on ischemia-reperfusion injury through multiple mechanisms, making it a promising candidate for the development of new therapeutic agents for this condition.
References
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[7] Solaroglu I, Tsubokawa T, Cahill J, et al. Anti-apoptotic effect of granulocyte colony-stimulating factor after focal cerebral ischemia in the rat. Neuroscience, 2006, 143(4): 965-974.
[8] Nijboer CH, Heijnen CJ, Groenendaal F, et al. A dual role of the NF-kappaB pathway in neonatal hypoxic-ischemic brain damage［J］． Stroke, 2008, 39(9): 2578-2586.
[9] Wajant H, Scheurich P. TNFR1-induced activation of the classical NF-κB pathway[J].The FEBS Journal,2015,278(6):862-876.
[10] Zhou Jiaojiao, Wu Chengting, Li Guo, Zhang Qingping, He Yehui. Research progress of traditional Chinese medicine intervention on autophagy to protect cerebral ischemia-reperfusion injury [J]. Hunan Journal of Traditional Chinese Medicine, 2021, 37(09): 191-194.
