Abstract TP100: Pharmacological Inhibition of ACC1 Restrains Peripheral T Cell Activation and Protects Against Cerebral Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Peiying Li ◽  
Long Wang ◽  
Yuxi Zhou ◽  
Xing Wang ◽  
Weifeng Yu
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Ischemic Brain ◽  
Soraphen A ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Adhesive Removal

Background and purpose: T cell activation, which is detrimental to the ischemic brain, requires metabolic reprogramming to meet the increased fuel demanding. ACC1 is an enzyme catalyzing the carboxylation of acetyl-CoA to malonyl CoA, a key substrate in the glycolytic-lipogenic pathway, which is extremely critical for T cell differentiation and phenotype polarization. We tested the hypothesis that pharmacologically inhibiting the enzyme ACC1 early after stroke may restrain T cell activation and protect against cerebral ischemic injury. Methods: Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 60 minutes in C57/B6 mice. Soraphen A, the specific pharmacological inhibitor of ACC1 was administered at 1 hour after reperfusion at the dose of 1mg/kg, 5mg/kg, 10mg/kg and 50mg/kg intraperitoneally. Infarct volume was assess at 3 days after surgery by staining with 2,3,5-triphenyltetrazolium chloride. Behavior 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. T cell infiltration into the ischemic brain was examined by immunofluorescent staining. Results: Mice treated with 5mg/kg or 10mg/kg soraphen A exhibited significantly smaller infarct volume at 3 days after stroke. 5mg/kg was chosen as the dose for further experiments. Soraphen A treatment improved the overall neurological assessment and enhanced the performance of mice in adhesive removal test and grid walking test. Soraphen A treatment significantly attenuated the CD3+ T cell and Gr-1+ neutrophil infiltration in the ischemic mice brain at 3 days after surgery. Conclusion: Pharmacological inhibition of T cell activation by soraphen A is protective against cerebral ischemic injury and may represent a novel strategy for stroke therapy.

scholarly journals Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Zun-Jing Liu ◽  
Wei Liu ◽  
Lei Liu ◽  
Cheng Xiao ◽  
Yu Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Ischemic Injury ◽  
Ppar Gamma ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPARγagonist in that it upregulated PPARγexpression and PPARγ-PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1β, TNF-α, PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed IκB degradation that was caused by cerebral ischemia. The present data also showed that PPARγinteracted with NF-κB-p65 and thus inhibited NF-κB activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPARγ. Our results as described above suggested that PPARγinduced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat

1991 ◽  
Vol 261 (6) ◽  
pp. H2051-H2057 ◽  
Author(s):  
S. Lindsay ◽  
T. H. Liu ◽  
J. A. Xu ◽  
P. A. Marshall ◽  
J. K. Thompson ◽  
...  
Keyword(s):  
Free Radical ◽  
Xanthine Oxidase ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Primary Source ◽  
Ischemic Injury ◽  
Xanthine Dehydrogenase ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

The role of xanthine dehydrogenase and oxidase as a source of free radicals contributing to focal cerebral ischemic injury was evaluated in Long-Evans rats after the middle cerebral artery was permanently occluded and both carotid arteries were clamped for 90 min. The fraction of xanthine dehydrogenase present as the free radical producing oxidase increased slightly from 22% in control cortex to 30% in the ischemic right cortex during the first 3 h of reperfusion and then remained relatively unchanged over the next 24 h. This increase may in part be due to entrapped plasma, which contained 4.5 +/- 0.8 nmol.min-1.ml-1 xanthine oxidase entirely in the free radical-producing form. Infarct volume was unaffected by pretreatment with 50 mg allopurinol/kg per day over 3 days before surgery but was decreased by 8% with 100 mg/kg and 24% with 150 mg/kg of allopurinol (P less than 0.05). However, inhibition of xanthine oxidase by dietary depletion of the essential molybdenum cofactor increased infarct volume by 19%, suggesting that protection by allopurinol at higher dosages was independent of xanthine oxidase inhibition. Neither xanthine oxidase present in rat brain nor circulating in plasma appears to be the primary source of oxygen radicals that contributes to infarction in focal 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.

A preventive injection of endothelial progenitor cells prolongs lifespan in stroke-prone spontaneously hypertensive rats

2018 ◽  
Vol 132 (16) ◽  
pp. 1797-1810 ◽  
Author(s):  
Cheng Peng ◽  
Xiao-Hui Dong ◽  
Jia-Lin Liu ◽  
Yu-Long Tao ◽  
Chun-Fang Xu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Spontaneously Hypertensive Rats ◽  
Single Injection ◽  
Ischemic Injury ◽  
Hypertensive Rats ◽  
Ischemic Brain ◽  
Spontaneously Hypertensive ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

There is a pressing need for new approaches to prevent stroke. Endothelial progenitor cells (EPCs) promote vascular repair and revascularization in the ischemic brain. The present study sought to evaluate whether preventive delivery of EPCs could prevent or protect against stroke. Stroke-prone spontaneously hypertensive rats (SHR-SP) received a single injection of EPCs, and their survival time was monitored. In addition, at 28 and/or 42 days after a single injection of EPCs, SHR-SP and mice were subjected to cerebral ischemia, and cerebral ischemic injury, local angiogenesis and in vivo EPC integration were determined. Other experiments examined the effects of EPC conditioned medium, and the distribution of donor EPCs taken from GFP transgenic mice. It was found that EPC-pretreated SHR-SP showed longer lifespans than untreated controls. A single preventive injection of EPCs could produce persistent protective effects against cerebral ischemic injury (lasting at least 42 days), and promote local angiogenesis in the ischemic brain, in two types of animals (SHR-SP and normotensive mice). EPCs of donor origin could be detected in the recipient peripheral blood, and integrated into the recipient ischemic brains. Furthermore, it was suggested that mouse EPCs might exert paracrine effects on cerebral ischemic injury in addition to their direct angiogenic effects. In conclusion, a single preventive injection of EPCs prolonged the lifespan of SHR-SP, and protected against cerebral ischemic injury for at least 7 weeks. It is implied that EPC injection might be a promising candidate for a preventive role in patients at high risk for stroke.

scholarly journals CELSR1 Promotes Neuroprotection in Cerebral Ischemic Injury Mainly through the Wnt/PKC Signaling Pathway

2020 ◽  
Vol 21 (4) ◽  
pp. 1267 ◽  
Author(s):  
Li-Hong Wang ◽  
Geng-Lin Zhang ◽  
Xing-Yu Liu ◽  
Ai Peng ◽  
Hai-Yuan Ren ◽  
...  
Keyword(s):  
Motor Function ◽  
Cell Apoptosis ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion

Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.

scholarly journals Prdx6 Upregulation by Curcumin Attenuates Ischemic Oxidative Damage via SP1 in Rats after Stroke

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Gongwei Jia ◽  
Botao Tan ◽  
Jingxi Ma ◽  
Lina Zhang ◽  
Xinhao Jin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Specific Protein ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Neuroprotective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Background. The role of Peroxiredoxin 6 (Prdx6) in brain ischemia remains unclear. Curcumin (Cur) treatment elicits neuroprotective effects against cerebral ischemic injury, and the associated mechanisms may involve Prdx6. In this study, we investigated whether Prdx6 and the transcription factor specific protein 1 (SP1) were involved in the antioxidant effect of Cur after stoke. Methods. Focal cerebral ischemic injury was induced by transient middle cerebral artery occlusion for 2 hours in male Sprague-Dawley rats treated with or without Prdx6 siRNA. Expression of Prdx6 in the penumbra was assessed by Real-Time PCR (RT-PCR), Western blot analysis, and immunoflourescent staining. In addition, infarct volume, neurological deficit score, and oxidative stress were evaluated. Prdx6 levels were also determined in the presence and absence of SP1 antagonist mithramycin A (MTM-A). Results. Cur treatment upregulated Prdx6 protein expression and the number of Prdx6-positive neuronal cells 24 hours after reperfusion. Cur treatment also attenuated oxidative stress and induced neuroprotective effects against ischemic damage, whereas the beneficial effects of Cur treatment were lost in animals treated with Prdx6-siRNA. Prdx6 upregulation by Cur treatment was abolished by SP1 antagonists MTM. Conclusions. Prdx6 upregulation by Cur treatment attenuates ischemic oxidative damage through SP1 induction in rats after stroke. This represents a novel mechanism of Cur-induced neuroprotection against cerebral ischemia.

scholarly journals Peripheral Administration of Fetuin-A Attenuates Early Cerebral Ischemic Injury in Rats

2009 ◽  
Vol 30 (3) ◽  
pp. 493-504 ◽  
Author(s):  
Haichao Wang ◽  
Wei Li ◽  
Shu Zhu ◽  
Jianhua Li ◽  
Jason D'Amore ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Tissue ◽  
Immune Cells ◽  
Ischemic Injury ◽  
Dependent Manner ◽  
Ischemic Brain ◽  
Fetuin A ◽  
Ischemic Brain Tissue ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Cerebral ischemia-elicited inflammatory responses are driven by inflammatory mediators produced both by central (e.g., neurons and microglia) and infiltrating peripheral immune cells (e.g., macrophage/monocyte), and contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is released from injured cells, and counter-regulates release of various proinflammatory cytokines. However, the spermine-mediated anti-inflammatory activities are dependent on the availability of fetuin-A, a liver-derived negative acute-phase protein. Using an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), we found that levels of fetuin-A in the ischemic brain tissue were elevated in a time-dependent manner, starting between 2 and 6 h, peaking around 24 to 48 h, and returning to baseline 72 h after MCAo. When administered peripherally, exogenous fetuin-A gained entry across the BBB into the ischemic brain tissue, and dose dependently reduced brain infarct volume at 24 h after MCAo. Meanwhile, fetuin-A effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue. Taken together, these experimental data suggest that fetuin-A protects against early cerebral ischemic injury partly by attenuating the brain inflammatory response.

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