scholarly journals Functionalized nanoparticles with monocyte membranes and rapamycin achieve synergistic chemoimmunotherapy for reperfusion-induced injury in ischemic stroke

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yanyun Wang ◽  
Yi Wang ◽  
Shuyu Li ◽  
Yuliang Cui ◽  
Xiping Liang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Animal Studies ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Functionalized Nanoparticles ◽  
Injury Model ◽  
Secondary Tissue

Abstract Background Ischemic stroke is an acute and severe neurological disease, and reperfusion is an effective way to reverse brain damage after stroke. However, reperfusion causes secondary tissue damage induced by inflammatory responses, called ischemia/reperfusion (I/R) injury. Current therapeutic strategies that control inflammation to treat I/R are less than satisfactory. Results We report a kind of shield and sword nano-soldier functionalized nanoparticles (monocyte membranes-coated rapamycin nanoparticles, McM/RNPs) that can reduce inflammation and relieve I/R injury by blocking monocyte infiltration and inhibiting microglia proliferation. The fabricated McM/RNPs can actively target and bind to inflammatory endothelial cells, which inhibit the adhesion of monocytes to the endothelium, thus acting as a shield. Subsequently, McM/RNPs can penetrate the endothelium to reach the injury site, similar to a sword, and release the RAP drug to inhibit the proliferation of inflammatory cells. In a rat I/R injury model, McM/RNPs exhibited improved active homing to I/R injury areas and greatly ameliorated neuroscores and infarct volume. Importantly, in vivo animal studies revealed good safety for McM/RNPs treatment. Conclusion The results demonstrated that the developed McM/RNPs may serve as an effective and safe nanovehicles for I/R injury therapy. Graphic abstract

scholarly journals Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 2938-2951 ◽  
Author(s):  
Yating He ◽  
Xiaofeng Ma ◽  
Daojing Li ◽  
Junwei Hao
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Bv2 Cells ◽  
Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

scholarly journals Platelet necrosis mediates ischemic stroke outcome in mice

Blood ◽  
2020 ◽  
Vol 135 (6) ◽  
pp. 429-440 ◽  
Author(s):  
Frederik Denorme ◽  
Bhanu Kanth Manne ◽  
Irina Portier ◽  
Alicia S. Eustes ◽  
Yasuhiro Kosaka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Similar Degree ◽  
Cyclophilin D ◽  
Wild Type ◽  
Neutrophil Depletion

Abstract Dysregulated platelet functions contribute to the development and progression of ischemic stroke. Utilizing mice with a platelet-specific deletion of cyclophilin D (CypD), a mediator of necrosis, we found that platelet necrosis regulates tissue damage and outcomes during ischemic stroke in vivo. Mice with loss of CypD in platelets (CypDplt−/−mice) exhibited significantly enhanced cerebral blood flow, improved neurological and motor functions, and reduced ischemic stroke infarct volume after cerebral ischemia-reperfusion injury. These effects were attributable, at least in part, to platelet-neutrophil interactions. Twenty-four hours after stroke, significantly more circulating platelet-neutrophil aggregates (PNAs) were found in CypDplt+/+ mice. Underscoring the role of platelet necrosis in PNA formation, we observed a significant number of phosphatidylserine (PS)+ platelets in PNAs in CypDplt+/+ mice. In contrast, significantly fewer platelets in PNAs were PS+ in CypDplt−/− counterparts. Accordingly, mice with CypD-deficient platelets had fewer neutrophils and PNAs recruited to their brain following stroke relative to wild-type counterparts. Neutrophil depletion in wild-type mice conferred protection from ischemic stroke to a similar degree as observed in mice with CypD-deficient platelets. Neutrophil depletion in CypDplt−/− mice did not further reduce infarct size. Transmission electron microscopy of ex vivo–formed PNAs revealed a propensity of necrotic platelets to interact with neutrophils. These results suggest that necrotic platelets interact with neutrophils to exacerbate brain injury during ischemic stroke. Because inhibiting platelet necrosis does not compromise hemostasis, targeting platelet CypD may be a potential therapeutic strategy to limit brain damage following ischemic stroke.

scholarly journals Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury

2011 ◽  
Vol 32 (2) ◽  
pp. 242-247 ◽  
Author(s):  
Amy E B Packard ◽  
Jason C Hedges ◽  
Frances R Bahjat ◽  
Susan L Stevens ◽  
Michael J Conlin ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Cortical Cells ◽  
Polycytidylic Acid ◽  
Populations At Risk

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

scholarly journals Up-regulation of miR-499a-5p decreases cerebral ischemia/reperfusion injury by targeting PDCD4

2021 ◽  
Author(s):  
Weifeng Shan ◽  
Huifeng Ge ◽  
Bingquan Chen ◽  
Linger Huang ◽  
Shaojun Zhu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Tunel Staining ◽  
Cerebral Ischemia Reperfusion

Abstract MiR-499a-5p was significantly down-regulated in degenerative tissues and correlated with apoptosis. Nonetheless, the biological function of miR-499a-5p in acute ischemic stroke has been still unclear. In this study, we found the plasma levels of miR-499a-5p were significantly down-regulated in 64 ischemic stroke patients and negatively correlated with the National Institutes of Health Stroke Scale score. Then, we constructed cerebral ischemia/reperfusion (I/R) injury in rats after middle cerebral artery occlusion and subsequent reperfusion and oxygen-glucose deprivation and reoxygenation (OGD/R) treated SH-SY5Y cell model. Transfection with miR-499a-5p mimic was accomplished by intracerebroventricular injection in the in vivo I/R injury model. We further found miR-499a-5p overexpression decreased infarct volumes and cell apoptosis in the in vivo I/R stroke model using TTC and TUNEL staining. PDCD4 was a direct target of miR-499a-5p by luciferase report assay and western blotting. Knockdown of PDCD4 reduced the infarct damage and cortical neuron apoptosis caused by I/R injury. MiR-499a-5p exerted neuroprotective roles mainly through inhibiting PDCD4-mediated apoptosis by CCK-8 assay, LDH release assay and flow cytometry analysis. These findings suggest that miR-499a-5p might represent a novel target that regulates brain injury by inhibiting PDCD4-mediating apoptosis.

scholarly journals Large Animal Studies to Reduce the Foreign Body Reaction in Brain–Computer Interfaces: A Systematic Review

Biosensors ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 275
Author(s):  
Shan Yasin Mian ◽  
Jonathan Roy Honey ◽  
Alejandro Carnicer-Lombarte ◽  
Damiano Giuseppe Barone
Keyword(s):  
Foreign Body ◽  
Animal Studies ◽  
Foreign Body Reaction ◽  
Inflammatory Cells ◽  
Anatomical Location ◽  
Large Animal ◽  
Brain Computer Interfaces ◽  
Computer Interfaces ◽  
Electrode Insertion

Brain–computer interfaces (BCI) are reliant on the interface between electrodes and neurons to function. The foreign body reaction (FBR) that occurs in response to electrodes in the brain alters this interface and may pollute detected signals, ultimately impeding BCI function. The size of the FBR is influenced by several key factors explored in this review; namely, (a) the size of the animal tested, (b) anatomical location of the BCI, (c) the electrode morphology and coating, (d) the mechanics of electrode insertion, and (e) pharmacological modification (e.g., drug eluting electrodes). Trialing methods to reduce FBR in vivo, particularly in large models, is important to enable further translation in humans, and we systematically reviewed the literature to this effect. The OVID, MEDLINE, EMBASE, SCOPUS and Scholar databases were searched. Compiled results were analysed qualitatively. Out of 8388 yielded articles, 13 were included for analysis, with most excluded studies experimenting on murine models. Cats, rabbits, and a variety of breeds of minipig/marmoset were trialed. On average, over 30% reduction in inflammatory cells of FBR on post mortem histology was noted across intervention groups. Similar strategies to those used in rodent models, including tip modification and flexible and sinusoidal electrode configurations, all produced good effects in histology; however, a notable absence of trials examining the effect on BCI end-function was noted. Future studies should assess whether the reduction in FBR correlates to an improvement in the functional effect of the intended BCI.

scholarly journals Non-Invasive Multimodality Imaging Directly Shows TRPM4 Inhibition Ameliorates Stroke Reperfusion Injury

2018 ◽  
Vol 10 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Bo Chen ◽  
Gandi Ng ◽  
Yahui Gao ◽  
See Wee Low ◽  
Edwin Sandanaraj ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Transient Receptor Potential ◽  
Multimodality Imaging ◽  
Infarct Volume ◽  
Triphenyltetrazolium Chloride ◽  
In Vivo Evaluation ◽  
Transient Receptor Potential Melastatin ◽  
Imaging Results ◽  
Trpm4 Channel

Abstract The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control. T2-weighted MRI suggests that TRPM4 inhibition successfully reduces edema by 30% and concomitantly salvages functionally active brain, measured by 18F-FDG-PET. These in vivo imaging results correlate well with post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining which exhibits a 34.9% reduction in infarct volume after siRNA treatment. Furthermore, in a permanent stroke model, large areas of brain tissue displayed both edema and significant reductions in metabolic activity which was not shown in transient models with or without TRPM4 inhibition, indicating that tissue salvaged by TRPM4 inhibition during stroke reperfusion may survive. Evans Blue extravasation and hemoglobin quantification in the ipsilateral hemisphere were greatly reduced, suggesting that TRPM4 inhibition can improve BBB integrity after ischemic stroke reperfusion. Our results support the use of TRPM4 blocker for early stroke reperfusion.

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hazem F Elewa ◽  
Anna Kozak ◽  
David Rychly ◽  
Adviye Ergul ◽  
Reginald Frye ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Methyl Cellulose ◽  
The United States ◽  
Experimental Stroke ◽  
High Risk Population ◽  
Protective Agent ◽  
Oral Gavage

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

Abstract WMP76: Interleukin-33 Protects Against Transient Ischemic Stroke by Enhancing Regulatory T-Cell Expansion and Accumulation

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Xinjing Liu ◽  
Ruiyao Hu ◽  
Lulu Pei ◽  
Yuming Xu ◽  
Bo Song
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cell Expansion ◽  
Neuronal Apoptosis ◽  
Infarct Volume ◽  
Intraperitoneal Administration

Background: The interleukin (IL)-33 could promote proliferation of regulatory T lymphocytes (Tregs) which are negatively related with brain damage after ischemic stroke. How IL-33 works on Tregs after stroke is unclear. The purpose of this study was to investigate the role of IL-33 for Tregs-mediated neuroprotection and further expounded the mechanisms of protection in mice. Methods: In vitro study, primary mice neuronal cells were subjected to 3h oxygen-glucose deprivation (OGD). The vehicle or drug conditioned Tregs were applied to neurons at the time of induction of hypoxia respectively. Neuronal apoptosis, Tregs related cytokines were measured by MTT assay, Western blotting and enzyme-linked immune-sorbent assay (ELISA). In vivo study, Tregs were depleted by intraperitoneal administration of anti-CD25Ab. Intraperitoneal injection of IL-33 immediately post 60 min transient middle cerebral artery occlusion (tMCAO) modeling. The neurological function test at days 1, 3, 5, 7 and 14 after tMCAO. Infarct volume, Brain edema, cell death, percentage of Tregs and related cytokines were respectively measured by 2,3,5-triphenyltetrazolium chloride or MAP2 staining, dry-wet method, TUNEL staining, flow cytometry and immunofluorescence, Western blotting and ELISA. Results: The supernatant of IL-33-treated Tregs reduced neuronal apoptosis in the OGD model meanwhile elevated the production of Tregs related cytokines IL-10, IL-35 and TGF- β in vitro. Intraperitoneal administration of IL-33 significantly reduced infarct volume and stroke-induced cell death and improved sensorimotor functions. Notably, the protective effect of IL-33 was abolished in mice depleted of Tregs. IL-33 increased CD4+CD25+Foxp3+ Tregs in spleens, blood, and brain in vivo. Yet, ST2 blocking muted these IL-33 activities. Mechanistically, the protection of IL-33 was associated with reduced apoptosis protein and production of Tregs related cytokine. Conclusions: This study elucidated that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation, which suggested a promising immune modulatory target for the treatment of stroke.

scholarly journals AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β)

Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 469-477 ◽  
Author(s):  
Candela Diaz-Cañestro ◽  
Martin F. Reiner ◽  
Nicole R. Bonetti ◽  
Luca Liberale ◽  
Mario Merlini ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Acute Ischemic Stroke ◽  
Peripheral Blood ◽  
Ischemia Reperfusion ◽  
Interleukin 1Β ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes

Background and Purpose— Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD—a member of the AP-1 (activated protein-1) family of transcription factors—was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods— WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti–IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results— In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti–IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions— JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.

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