Abstract 158: Pre-existing Cancer Exacerbates Cerebral Ischemic Stroke in Mice via Regulatory T Cell Redistribution

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Long Wang ◽  
Yuxi Zhou ◽  
Weifeng Yu ◽  
Peiying Li
Keyword(s):  
Colon Cancer ◽  
Ischemic Stroke ◽  
Immune Cell ◽  
Infarct Volume ◽  
Ischemic Brain Injury ◽  
Stroke Patients ◽  
Ischemic Brain ◽  
Cerebral Ischemic Stroke ◽  
Neuro Inflammation ◽  
Cerebral Ischemic

Background and purpose: Accumulating epidemic evidence suggest that a considerable number of ischemic stroke patients had 1 or more cancer diagnosis before stroke attack. How the pre-existing cancer impact the cerebral ischemic injury is remarkably unknown. We tested the hypothesis that pre-existing cancer exacerbates cerebral ischemic stroke via regulatory T cell (Treg) redistribution. Methods: MC38 colon cancer cells or B16 melanoma cells were injected subcutaneously at the dose of 5*10 5 cells in 200μl PBS 3 weeks before distal middle cerebral artery occlusion (d-MCAO) surgery. Infarct volume was assessed at 3 days after surgery by staining the mice brain with 2,3,5-triphenyltetrazolium chloride. Sensorimotor assessments, such as body proprioception, climbing, forelimb walking, lateral turning, foot fault and adhesive removal were examined at 3, 5, 7, 14, 21 and 28 days after stroke. Neuro-inflammation was examined by measuring inflammatory cytokines with RT-PCR and immune cell infiltration using immunofluorescence and flow cytometry. Results: Pre-existing colon cancer and melanoma both exacerbated infarct volume growth in d-MCAO mice at 3 days after surgery. Mice with colon cancer exhibited prominently deterioration in their performance in sensorimotor functions after stroke compared with mice without cancer. Pre-existing colon cancer augmented peripheral immune cell infiltration into the ischemic brain but hindered Tregs’ recruitment into the brain. Cerebral ischemic stroke induced reduction in the number of Tregs in the peripheral blood were significantly aggravated in mice with pre-existing colon cancer. Depletion of Tregs with CD25 monoclonal antibody increased infarct volume in stroke mice but did not further exacerbate infarct growth in colon cancer stroke mice. Conclusion: Pre-existing cancer exacerbates ischemic brain injury and neuro-inflammation after stroke. Tregs redistribution plays an indispensable role in the cancer related deterioration of ischemic brain injury and may represent a promising target for treating stroke patients with pre-existing cancer.

EDA-Containing Fibronectin Aggravates Ischemic Brain Injury In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 330-330
Author(s):  
Anil Chauhan ◽  
Mohammad M Khan ◽  
Chintan Gandhi ◽  
Neelam Chauhan ◽  
Asgar Zaheer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Experimental Model ◽  
Vascular Injury ◽  
Laser Doppler Flowmetry ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Doppler Flowmetry ◽  
Ischemic Brain

Abstract Abstract 330 Background: Fibronectin (FN) is a dimeric glycoprotein that plays an important role in several cellular processes, such as embryogenesis, malignancy, hemostasis, wound healing and maintenance of tissue integrity. FN is a ligand for many members of the integrin family (e.g. αIIbβ3, α5β1, α4β1, α9β1, αvβ3 and αvβ5) and also binds to thrombosis-related proteins including heparin, collagen and fibrin. FN generates protein diversity as a consequence of alternative processing of a single primary transcript. Two forms of FN exist; soluble plasma FN (pFN), which lacks the alternatively-spliced Extra Domain A (EDA); and insoluble cellular FN (cFN), which contains EDA. FN containing EDA (EDA+FN) is normally absent in plasma of human and mouse but EDA+FN has been found in patients with vascular injury secondary to vasculitis, sepsis, acute major trauma or ischemic stroke. We tested the hypothesis that elevated levels of plasma EDA+FN increase brain injury in an experimental model of ischemic stroke in mice. Model and Method: We used two genetically modified mouse strains: EDA+/+ mice contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+FN, whereas EDA-/- mice contain an EDA-null allele of the EDA exon and express only FN lacking EDA. Control EDAwt/wt mice contain the wild-type FN allele. Transient focal cerebral ischemia was induced by 60 minutes of occlusion of the right middle cerebral artery with a 7.0 siliconized filament in male mice (8-10 weeks in age). Mice were anesthetized with 1–1.5% isoflurane mixed with medical air. Body temperature was maintained at 37°C ± 1.0 using a heating pad. Laser Doppler flowmetry was used to confirm induction of ischemia and reperfusion. At 23 hours after MCAO, mice were evaluated for neurological deficits as a functional outcome and were sacrificed for quantification of infarct volume. For morphometric measurement eight 1 mm coronal sections were stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride (TTC). Sections were digitalized and infarct areas were measured blindly using NIS elements. Result: In EDA+/+ mice the percentage of infarct volume (mean ± SEM: 37.25 ± 4.11, n= 12,) in the ipsilateral (ischemic) hemisphere was increased by approximately two-fold compared to EDA wt/wt mice (mean ± SEM: 22.33 ± 3.39, n=11; P< 0.05, ANOVA) or EDA-/- mice (mean ± SEM: 21.72 ± 2.94, n=9). Regional cerebral blood flow during ischemia was not different among groups as assessed by laser Doppler flowmetry. The percentage increase in infarct volume in the EDA+/+ mice correlated well with severe neurological deficits (motor-deficit assessed by a four-point neurological score scale) compared to EDA wt/wt or EDA-/- mice. Because both thrombosis and inflammation contributes to brain injury during ischemic stroke, we investigated the time to form an occlusive thrombus in ferric-chloride carotid artery injury model by intravital microscopy. EDA+/+ mice demonstrated significantly faster time to occlusion (mean ± SEM: 12.35 ± 1.51 n=12,) compared to EDAwt/wt (Mean ± SEM: 17.27 ± 1.72 min, n=13, P<0.05, ANOVA) or EDA-/- (Mean ± SEM: 15.61 ± 1.76, n=11) mice. Additionally, the inflammatory response in the ischemic region was increased by two fold in EDA+/+ mice compared to EDA wt/wt and EDA-/- mice as sensed by myeloperoxidase activity and immunohistochemical analysis of neutrophils. Conclusion: EDA-containing FN is pro-thrombotic and pro-inflammatory, and aggravates ischemic brain injury in an experimental model of stroke in mice. The presence of EDA+FN in plasma may be a risk factor for vascular injury secondary to ischemic stroke. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Stepwise-Targeting Strategy For The Treatment of Cerebral Ischemic Stroke

2021 ◽  
Author(s):  
Jing-Bo Hu ◽  
Xueying Tan ◽  
Dongwei Wang ◽  
Hongze Liang ◽  
Jiejun Peng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Infarct Volume ◽  
Stress Injury ◽  
Therapeutic Outcomes ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic ◽  
In Cis ◽  
Brain Tissues

Abstract Background: Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood-brain barrier (BBB), resulting in the poor therapeutic outcomes. Results: In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals.Conclusions: These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS.

scholarly journals A stepwise-targeting strategy for the treatment of cerebral ischemic stroke

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingbo Hu ◽  
Xueying Tan ◽  
Dongwei Wang ◽  
Yixuan Li ◽  
Hongze Liang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Infarct Volume ◽  
Stress Injury ◽  
Therapeutic Outcomes ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic ◽  
In Cis ◽  
Brain Tissues

Abstract Background Effective amelioration of neuronal damages in the case of cerebral ischemic stroke (CIS) is essential for the protection of brain tissues and their functional recovery. However, most drugs can not penetrate the blood–brain barrier (BBB), resulting in the poor therapeutic outcomes. Results In this study, the derivatization and dual targeted delivery technologies were used to actively transport antioxidant melatonin (MLT) into the mitochondria of oxidative stress-damaged cells in brain tissues. A mitochondrial targeting molecule triphenylphosphine (TPP) was conjugated to melatonin (TPP-MLT) to increase the distribution of melatonin in intracellular mitochondria with the push of mitochondrial transmembrane potential. Then, TPP-MLT was encapsulated in dual targeted micelles mediated by TGN peptide (TGNYKALHPHNG) with high affinity for BBB and SHp peptide (CLEVSRKNG) for the glutamate receptor of oxidative stress-damaged neural cells.TGN/SHp/TPP-MLT micelles could effectively scavenge the overproduced ROS to protect neuronal cells from oxidative stress injury during CIS occurrence, as reflected by the improved infarct volume and neurological deficit in CIS model animals. Conclusions These promising results showed this stepwise-targeting drug-loaded micelles potentially represent a significant advancement in the precise treatment of CIS. Graphical Abstract

scholarly journals The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Mrinal K. Ghosh ◽  
Dipankar Chakraborty ◽  
Sibani Sarkar ◽  
Arijit Bhowmik ◽  
Malini Basu
Keyword(s):  
Ischemic Stroke ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Early Stage ◽  
Significant Risk ◽  
Patient Death ◽  
Stroke Patients ◽  
Increased Risk ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Abstract Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences, ~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.

Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Junaith S Mohamed ◽  
Peter J Ferrandi ◽  
Paez G Hector ◽  
Christopher R Pitzer ◽  
Stephen E Alway
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Rna Seq ◽  
Stroke Patients ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.

Infarct volume, neurological severity and PAF binding to platelets of patients with acute cerebral ischemic stroke

1999 ◽  
Vol 21 (7) ◽  
pp. 645-648 ◽  
Author(s):  
Abraham Adunsky ◽  
Moshe Hershkowitz ◽  
Eli Atar ◽  
Mathi Bakoun ◽  
Amir Poreh
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

scholarly journals Efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke

2020 ◽  
Author(s):  
Anil Gulati ◽  
Nilesh Agrawal ◽  
Deepti Vibha ◽  
U.K. Misra ◽  
Birinder Paul ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Ischemic Stroke ◽  
Odds Ratio ◽  
Controlled Study ◽  
Stroke Patients ◽  
Neurological Outcomes ◽  
Number Of Patients ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Background: Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective: To determine safety, tolerability and efficacy of sovateltide as an adjuvant to standard of care (SOC) in acute cerebral ischemic stroke patients. Methods: A prospective, multi-centric, randomized, double-blind, controlled study to compare efficacy of sovateltide in patients with acute cerebral ischemic stroke was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients who had stroke within the last 24 hours with a radiologic confirmation of ischemic stroke were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. All patients in both groups received SOC for stroke. Patients randomized in the sovateltide group received three doses of sovateltide (each dose 0.3 μg/kg) administered as an IV bolus over 1 minute at an interval of 3 hours ± 1 hour on day 1, day 3 and day 6 (total dose of 0.9 μg/kg/day). Patients randomized in the placebo group received equal volume of saline. Efficacy was evaluated by neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scales. Quality of Life was measured by EuroQoL (EQ-5D) and stroke specific quality-of-life (SS-QoL). Results: Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. The baseline characteristics and SOC in both cohorts was similar. Sovateltide treatment resulted in a significantly quicker recovery as measured by improvements in neurological outcomes in mRS and BI scales on day 6 compared to day 1 (p<0.0001). Moreover, sovateltide increased the frequency of favorable outcomes in all scales at 3 months. An improvement of ≥2 points in mRS was observed in 60% and 40% patients in sovateltide and saline groups, respectively (p=0.0519; odds ratio 5.25). BI improvement of ≥40 points was 64% and 36% in sovateltide and saline groups, respectively (p=0.0112; odds ratio 12.44). An improvement of ≥6 points was seen in NIHSS in 56% of patients in sovateltide vs 43% in saline groups (p=0.2714; odds ratio 2.275). Number of patients with complete recovery achieving NIHSS score of 0 and BI of 100 were significantly more (p<0.05) in sovateltide group compared to saline group. Sovateltide treatment resulted in improved Quality of Life as measured by EuroQoL and SS-QoL (stroke specific quality-of-life) on day 90. Sovateltide was well tolerated and all patients received complete treatment with no incidence of drug related adverse event reported. Hemodynamic, biochemical or hematological parameters were not affected with sovateltide. Conclusion: Sovateltide was safe, well tolerated, and resulted in quicker recovery and improved neurological outcome in acute cerebral ischemic stroke patients 90 days post-treatment.

scholarly journals Change of intestinal microbiota in cerebral ischemic stroke patients

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Na Li ◽  
Xingcui Wang ◽  
Congcong Sun ◽  
Xinwei Wu ◽  
Mei Lu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intestinal Microbiota ◽  
Stroke Patients ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic
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