Endothelial Progenitor Cell Transplantation Attenuated Synaptic Loss by Enhancing CR3 Dependent Microglial Phagocytosis in Mice

2021 ◽  
Author(s):  
Yuanyuan Ma ◽  
Lu Jiang ◽  
Liping Wang ◽  
Yongfang Li ◽  
Yanqun Liu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Progenitor Cell ◽  
Focal Ischemia ◽  
Complement Receptor ◽  
Primary Microglia ◽  
Synaptic Loss ◽  
Ischemic Brain ◽  
Microglial Phagocytosis ◽  
Complement Receptor 3

Abstract Background: Endothelial progenitor cell (EPC) transplantation has been shown to have therapeutic effects in cerebral ischemia. However, whether the therapeutic effect of EPCs is a result of the modulation of microglia activity remain elusive. Methods: Adult male mice (n=184) underwent 90 minute-middle cerebral artery occlusion and EPCs were transplanted into the peri-infarct region immediately after the surgery. Microglia migration and phagocytosis were evaluated in the ischemic brain in vivo and underwent oxygen-glucose-deprivation culture condition in vitro. Complement receptor 3 was examined in ischemic brain and cultured primary microglia. Complement receptor 3 agonist leukadherin-1 was intraperitoneally injected to mice immediately after ischemia to imitate the EPC effect. Expression of synapse remodeling related synaptophysin and PSD-95 proteins was detected in the EPC and leukadherin-1 treated mice, separately. Results: EPC transplantation increased the number of microglia in the peri-infarct region of the brain at 3 days after focal ischemia (p<0.05). The ability of phagocytizing apoptotic cells of microglia was higher in EPCs transplanted group at 3 days after ischemia compared to the controls (p<0.05). In vitro study showed that cultured microglia displayed a higher migration (p<0.05) and phagocytosis ability (p<0.05) under the stimulation of EPC conditioned medium or cultured EPCs compared to the controls. Complement receptor 3 expression in the ischemic mouse brain with EPC transplantation (p<0.05), and primary microglia treated by EPC conditioned medium or cultured EPCs was up-regulated (p<0.05). Leukadherin-1 reduced brain atrophy volume at 14 days (p<0.05) and ameliorated neurological deficiency during 14 days after cerebral ischemia (p<0.05). Both EPC transplantation and leukadherin-1 injection increased synaptophysin (p<0.05) and PSD-95 expressions (p<0.05) at 14 days after focal ischemia. Conclusion: We concluded that EPC transplantation promoted regulating complement receptor 3 mediated microglial phagocytosis at acute phase, and subsequently benefited for attenuating synaptic loss at the recovery phase of ischemic stroke, which provided a novel therapeutic mechanism of EPC for cerebral ischemia.

scholarly journals Prolonged Fasting Improves Endothelial Progenitor Cell-Mediated Ischemic Angiogenesis in Mice

2016 ◽  
Vol 40 (3-4) ◽  
pp. 693-706 ◽  
Author(s):  
Bao Xin ◽  
Chun-Long Liu ◽  
Hong Yang ◽  
Cheng Peng ◽  
Xiao-Hui Dong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Endothelial Progenitor Cell ◽  
Progenitor Cell ◽  
Ischemic Injury ◽  
Prolonged Fasting ◽  
Endothelial Progenitor ◽  
Ischemic Brain ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Background/Aims: Prolonged fasting (PF) was shown to be of great potency to promote optimal health and reduce the risk of many chronic diseases. This study sought to determine the effect of PF on the endothelial progenitor cell (EPC)-mediated angiogenesis in the ischemic brain and cerebral ischemic injury in mice. Methods: Mice were subjected to PF or periodic PF after cerebral ischemia, and histological analysis and behavioral tests were performed. Mouse EPCs were isolated and examined, and the effects of EPC transplantation on cerebral ischemic injury were investigated in mice. Results: It was found that PF significantly increased the EPC functions and angiogenesis in the ischemic brain, and attenuated the cerebral ischemic injury in mice that was previously subjected to cerebral ischemia. Periodic PF might reduce cortical atrophy and improve long-term neurobehavioral outcomes after cerebral ischemia in mice. The eNOS and MnSOD expression and intracellular NO level were increased, and TSP-2 expression and intracellular O2- level were reduced in EPCs from PF-treated mice compared to control. In addition, transplanted EPCs might home into ischemic brain, and the EPCs from PF-treated mice had a stronger ability to promote angiogenesis in ischemic brain and reduce cerebral ischemic injury compared to the EPCs from control mice. The EPC-conditioned media from PF-treated mice exerted a stronger effect on cerebral ischemic injury reduction compared to that from control mice. Conclusion: Prolonged fasting promoted EPC-mediated ischemic angiogenesis and improved long-term stroke outcomes in mice. It is implied that prolonged fasting might potentially be an option to treat ischemic vascular diseases.

Blood—Brain Barrier Permeability and Brain Concentration of Sodium, Potassium, and Chloride during Focal Ischemia

1994 ◽  
Vol 14 (1) ◽  
pp. 29-37 ◽  
Author(s):  
A. Lorris Betz ◽  
Richard F. Keep ◽  
Mary E. Beer ◽  
Xiao-Dan Ren
Keyword(s):  
Cerebral Ischemia ◽  
Brain Edema ◽  
Relative Permeability ◽  
Sodium Transport ◽  
Focal Ischemia ◽  
Edema Formation ◽  
Ischemic Brain ◽  
Early Stages ◽  
Brain Edema Formation ◽  
Rate Of Accumulation

Brain edema formation during the early stages of focal cerebral ischemia is associated with an increase in both sodium content and blood–brain barrier (BBB) sodium transport. The goals of this study were to determine whether chloride is the principal anion that accumulates in ischemic brain, how the rate of BBB transport of chloride compares with its rate of accumulation, and whether the stimulation seen in BBB sodium transport is also seen with other cations. Focal ischemia was produced by occlusion of the middle cerebral artery (MCAO) in anesthetized rats. Over the first 6 h after MCAO, the amount of brain water in the center of the ischemic cortex increased progressively at a rate of 0.15 ± 0.02 (SE) g/g dry wt/h. This was accompanied by a net increase in brain sodium (48 ± 12 μmol/g dry wt/h) and a loss of potassium (34 ± 7 μmol/g dry wt/h). The net rate of chloride accumulation (16 ± 1 μmol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions (22Na, 36Cl, and 86Rb) and two passive permeability tracers {[3H]α-aminoisobutyric acid (3H]AIB) and [14C]urea} was determined. Permeability to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36Cl influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in ischemic brain. The BBB permeability to 22Na relative to that of [3H]AIB was significantly increased in the ischemic cortex, the relative permeability to 86Rb was significantly decreased, and the relative permeability to 36Cl was unchanged. These results indicate that the stimulation in BBB sodium transport is specific for sodium. Further, chloride accumulates with sodium in brain during the early stages of ischemia; however, its rate of accumulation is low compared with its rate of transport from blood to brain. Therefore, inhibition of BBB sodium transport is more likely to reduce edema formation than is inhibition of BBB chloride transport. This study demonstrates that chloride is the principal anion that accompanies the accumulation of sodium in ischemic brain, but its rate of accumulation in brain is much less than its rate of movement into brain, and therefore inhibition of chloride uptake would have little effect on brain edema formation. There is a specific acceleration of blood-to-brain sodium transport during ischemia that is not seen with another positively charged ion, 86Rb. This is consistent with stimulation of brain capillary Na,K-ATPase activity in response to the elevated extracellular potassium concentration. Inhibition of potassium influx across the BBB would probably be more successful in lessening edema formation than accelerating potassium efflux. However, inhibition of blood-to-brain sodium transport is likely to be a more effective approach to reducing brain edema formation during the early stages of cerebral ischemia.

scholarly journals The Vi Capsular Polysaccharide Prevents Complement Receptor 3-Mediated Clearance ofSalmonella entericaSerotype Typhi

2010 ◽  
Vol 79 (2) ◽  
pp. 830-837 ◽  
Author(s):  
R. Paul Wilson ◽  
Sebastian E. Winter ◽  
Alanna M. Spees ◽  
Maria G. Winter ◽  
Jessalyn H. Nishimori ◽  
...  
Keyword(s):  
Capsular Polysaccharide ◽  
Immune Serum ◽  
Complement Receptor ◽  
Immune Recognition ◽  
Bacterial Binding ◽  
Intraperitoneal Infection ◽  
Complement Receptor 3 ◽  
Vi Capsular Polysaccharide

ABSTRACTCapsular polysaccharides are important virulence factors of invasive bacterial pathogens. Here we studied the role of the virulence (Vi) capsular polysaccharide ofSalmonella entericaserotype Typhi (S.Typhi) in preventing innate immune recognition by complement. Comparison of capsulatedS.Typhi with a noncapsulated mutant (ΔtviBCDE vexABCDEmutant) revealed that the Vi capsule interfered with complement component 3 (C3) deposition. Decreased complement fixation resulted in reduced bacterial binding to complement receptor 3 (CR3) on the surface of murine macrophagesin vitroand decreased CR3-dependent clearance of Vi capsulatedS.Typhi from the livers and spleens of mice. Opsonization of bacteria with immune serum prior to intraperitoneal infection increased clearance of capsulatedS.Typhi from the liver. Our data suggest that the Vi capsule prevents CR3-dependent clearance, which can be overcome in part by a specific antibody response.

Induction of Caspase-Activated Deoxyribonuclease Activity after Focal Cerebral Ischemia and Reperfusion

2002 ◽  
Vol 22 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Yumin Luo ◽  
Guodong Cao ◽  
Wei Pei ◽  
Cristine O'Horo ◽  
Steven H. Graham ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Caspase 3 ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Brain Cell ◽  
Ischemic Brain ◽  
Cell Extracts ◽  
Apoptosis Assay ◽  
Deoxyribonuclease Activity

Deoxyribonucleic acid fragmentation at nucleosomal junctions is a hallmark of neuronal apoptosis in ischemic brain injury, for which the mechanism is not fully understood. Using the in vitro cell-free apoptosis assay, the authors found that caspase-3–dependent deoxyribonuclease activity caused internucleosomal DNA fragmentation in brain-cell extracts in a rat model of transient focal ischemia. This in vitro deoxyribonuclease activity was completely inhibited by purified inhibitor of caspase-activated deoxyribonuclease protein, the specific endogenous inhibitor of caspase-activated deoxyribonuclease, or by caspase-activated deoxyribonuclease immunodepletion. The induction of the deoxyribonuclease activity was correlated with caspase-3 activation and caspase-3–mediated degradation of inhibitor of caspase-activated deoxyribonuclease. Furthermore, inhibiting caspase-3–like protease activity prevented the endogenous induction of internucleosomal DNA fragmentation in the ischemic brain. These results suggest that caspase-3–dependent caspase-activated deoxyribonuclease activity plays an important role in mediating DNA fragmentation after focal ischemia.

scholarly journals Cleaved β-Actin May Contribute to DNA Fragmentation Following Very Brief Focal Cerebral Ischemia

2018 ◽  
Vol 77 (3) ◽  
pp. 260-265
Author(s):  
Zhouheng Ye ◽  
Bradley P Ander ◽  
Frank R Sharp ◽  
Xinhua Zhan
Keyword(s):  
Cerebral Ischemia ◽  
Dna Fragmentation ◽  
Structural Changes ◽  
Focal Cerebral Ischemia ◽  
Fragment Size ◽  
Granzyme B ◽  
Focal Ischemia ◽  
Degraded Dna ◽  
Ischemia Group

Abstract Our previous study demonstrated caspase independent DNA fragmentation after very brief cerebral ischemia, the mechanism of which was unclear. In this study, we explore whether actin is cleaved following focal cerebral ischemia, and whether these structural changes of actin might modulate DNA fragmentation observed following focal ischemia. Results showed that a cleaved β-actin fragment was identified in brains of rats 24 hours following 10-minute and 2-hour focal ischemia. Though granzyme B and caspase-3 cleaved β-actin in vitro, the fragment size of β-actin cleaved by granzyme B was the same as those found after 10-minute and 2-hour focal ischemia. This was consistent with increases of granzyme B activity after 10-minute and 2-hour ischemia compared with controls. Cerebral extracts from 10-minute and 2-hour ischemic brains degraded DNA in vitro. Adding intact β-actin to these samples completely abolished DNA degradation from the 10-minute ischemia group but not from the 2-hour ischemia group. We concluded that β-actin is likely cleaved by granzyme B by 24 hours following 10-minute and 2-hour focal cerebral ischemia. Intact β-actin inhibits DNase, and cleavage of β-actin activates DNase, which leads to DNA fragmentation observed in the brain following very brief focal ischemia.

scholarly journals Early Endonuclease Activation following Reversible Focal Ischemia in the Rat Brain

1995 ◽  
Vol 15 (3) ◽  
pp. 385-388 ◽  
Author(s):  
C. Charriaut-Marlangue ◽  
I. Margaill ◽  
M. Plotkine ◽  
Y. Ben-Ari
Keyword(s):  
Cerebral Ischemia ◽  
Dna Fragmentation ◽  
Cortical Neurons ◽  
Structural Changes ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Dna Separation ◽  
Ischemic Brain Injury ◽  
Dna Ladder ◽  
Ischemic Brain

The structural changes that occur in chromatin DNA after ischemic brain injury are poorly understood. The presence of oligonucleosome fragments that are recognized as the characteristic DNA ladder has been demonstrated in global and focal ischemia, associated or not with random DNA fragmentation. Using pulsed-field gel electrophoresis, which improves DNA separation, we have now detected initial stages of DNA fragmentation that occur already 6 h after reversible focal cerebral ischemia in rats. This result confirms that internucleosomal DNA fragmentation precedes random DNA fragmentation in vulnerable striatal and cortical neurons following reversible focal cerebral ischemia.

scholarly journals Maraviroc, An Inhibitor of Chemokine Receptor Type 5, Alleviates Neuroinflammatory Response after Cerebral Ischemia/Reperfusion Injury via Regulating JNK Signaling

2021 ◽  
Author(s):  
Beilei Chen ◽  
Pingping Cao ◽  
Xin Guo ◽  
Xiaobo Li ◽  
Li Jiang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Chemokine Receptor ◽  
Ischemia Reperfusion ◽  
Primary Microglia ◽  
Neuroprotective Effects ◽  
Jnk Signaling ◽  
Cerebral Ischemia Reperfusion ◽  
Different Doses

Abstract Neuroinflammation is a key factor that contributes to the secondary injury after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5(CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC,APEXBIO,UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion(MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) with different doses (5, 20, or 50 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia were stimulated with different doses of MVC (0.2, 2, 20 or 200nM) for 12h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after (OGD/R). The expression of pro-inflammatory cytokines (IL-1β and IL-6) in microglia were down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of IL-1β and IL-6 by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN，Beyotime，SC0132-5mg) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials.

scholarly journals Neuroprotective Effects of Resveratrol in Ischemic Brain Injury

NeuroSci ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 305-319
Author(s):  
Noelia D. Machado ◽  
Gorka Villena Armas ◽  
Mariana A. Fernández ◽  
Santiago Grijalvo ◽  
David Díaz Díaz
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
De Novo ◽  
Neuroprotective Effect ◽  
Ischemic Brain Injury ◽  
In Vivo Models ◽  
Ischemic Brain ◽  
Number Of Patients

Cerebral ischemia represents the third cause of death and the first cause of disability in adults. This process results from decreasing cerebral blood flow levels as a result of the occlusion of a major cerebral artery. This restriction in blood supply generates low levels of oxygen and glucose, which leads to a decrease in the energy metabolism of the cell, producing inflammation, and finally, neurological deterioration. Currently, blood restoration of flow is the only effective approach as a therapy in terms of ischemic stroke. However, a significant number of patients still have a poor prognosis, probably owing to the increase in the generation of reactive oxygen species (ROS) during the reperfusion of damaged tissue. Oxidative stress and inflammation can be avoided by modulating mitochondrial function and have been identified as potential targets for the treatment of cerebral ischemia. In recent years, the beneficial actions of flavonoids and polyphenols against cerebrovascular diseases have been extensively investigated. The use of resveratrol (RSV) has been shown to markedly decrease brain damage caused by ischemia in numerous studies. According to in vitro and in vivo experiments, there is growing evidence that RSV is involved in several pathways, including cAMP/AMPK/SIRT1 regulation, JAK/ERK/STAT signaling pathway modulation, TLR4 signal transduction regulation, gut/brain axis modulation, GLUT3 up-regulation inhibition, neuronal autophagy activation, and de novo SUR1 expression inhibition. In this review, we summarize the recent outcomes based on the neuroprotective effect of RSV itself and RSV-loaded nanoparticles in vitro and in vivo models focusing on such mechanisms of action as well as describing the potential therapeutic strategies in which RSV plays an active role in cases of ischemic brain injury.

scholarly journals In Vivo and in Vitro Evaluation of the Anti-inflammatory Effect of Thymoquinone Toward Ischemic Brain Injury Alleviation via Nrf2/HO-1 Pathway

2020 ◽  
Author(s):  
Nashwa Amin ◽  
Xiaoxue Du ◽  
Shijia Chen ◽  
Qiannan Ren ◽  
Azhar Badry ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Chronic Dose ◽  
The Brain

Abstract Background - In recent years, considerable efforts have been devoted to exploring effective therapy for cerebral ischemia. Reactive oxygen species (ROS) mediated - inflammation plays a crucial role in ischemic brain injury. Triptolide (TP) has been widely used for ischemic therapy although administrating a chronic dose of this therapy may cause serious drawbacks and higher liver toxicity. Considering these critical side effects, here we demonstrate the employment of thymoquinone (TQ) as a new alternative drug for alleviating ischemic brain damage via suppression of inflammatory cytokines by inducing Nrf2/HO-1 under a chronic dose without toxicity. Methods- We assessed a photo-thrombosis mouse model of focal cerebral ischemia to investigate the impact of the chronic dose of TQ to alleviates ischemic brain damage, meanwhile, we used Pc12 to determine the efficiency of TQ to attenuate the OGD/R induces cell death. Results- Our in vivo and in vitro results indicate that the administration of TQ drug can sufficiently mitigate the brain damage after stroke by increasing the Nrf2/HO-1 expression and thereby modulate the cell death and inflammation resulting from cerebral ischemia. The observation based on YFP mice elucidates the role of TQ therapy in recovering the brain status after injury through increasing the dendrite spines density and the ratio of YFP reporter cells with NeuN expression. Conclusions- Our study is the first to focus on the crucial role of the Nrf2/HO-1 pathway as a promising ischemic therapy under a chronic dose of TQ by increasing proliferating protein expression, decreasing inflammation and neuronal cell death as well as controlling the autophagy process.

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