scholarly journals Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

2021 ◽  
Vol 22 (14) ◽  
pp. 7495
Author(s):  
Eun-Hye Kim ◽  
Eun-Sun Kim ◽  
Donggeun Shin ◽  
Donghyun Kim ◽  
Sungbin Choi ◽  
...  
Keyword(s):  
Brain Injury ◽  
Matrix Metalloproteinases ◽  
Brain Damage ◽  
Infarct Volume ◽  
Treatment Options ◽  
Gelatin Zymography ◽  
Enzyme Assays ◽  
Ischemic Brain ◽  
Cerebral Ischemic

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.

scholarly journals Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

2012 ◽  
Vol 32 (9) ◽  
pp. 1810-1819 ◽  
Author(s):  
Jesus M Pradillo ◽  
Adam Denes ◽  
Andrew D Greenhalgh ◽  
Herve Boutin ◽  
Caroline Drake ◽  
...  
Keyword(s):  
Risk Factors ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Brain Damage ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Experimental Stroke ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Interleukin 1 Receptor Antagonist

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood–brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

scholarly journals Lipopolysaccharide worsens the prognosis of experimental cerebral ischemia via interferon gamma-induced protein 10 recruit in the acute stage

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Ping Wang ◽  
Jiaqi Zhang ◽  
Feifei Guo ◽  
Shuang Wang ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Damage ◽  
Interferon Gamma ◽  
Infarct Volume ◽  
Brain Homogenate ◽  
Acute Stage ◽  
Ischemic Brain Injury ◽  
Ppi Network ◽  
Ischemic Brain ◽  
The Brain

Abstract Background Infection is an important clinical complication facing stroke-patients and triples the risk of death within 30 days post-stroke via mechanisms which are poorly understood. Aims We tried to explore the mechanisms that inflammation caused by infections aggravated the ischemic brain injury after middle cerebral artery occlusion (MCAO). Methods We used lipopolysaccharide (LPS) as systemic inflammatory stimuli to explore the mechanisms of aggravated ischemic brain injury after Sprague-Dawley male rats subjected to MCAO. Brain damage was evaluated by cerebral blood perfusion, Longa-5 scores, infarct volume and edema degree. Systemic cytokine responses and inflammatory changes in the plasma and brain were analyzed by ELISA kit, RT2 Profiler™ PCR array, and quantitative real-time PCR. The differential genes were subjected to Gene Ontology enrichment analysis and protein–protein interaction (PPI) network construction. Results Lipopolysaccharide profoundly aggravated the brain damage after 24 h post-MCAO. At the acute stage (ischemia/reperfusion 90 min/3 h), the brain homogenate gene expression of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and Interferon gamma-induced protein 10 (IP-10) was significantly up-regulated and the contents in plasma and brain homogenate were significantly increased in MCAO and MCAO + LPS group. IP-10 was the only gene with significant difference between MCAO and MCAO + LPS group, which was also in an important position with degrees of ≥ 14 in PPI network. Conclusions It was possible that trace LPS aggravated the ischemic brain injury by induction of excessive IP-10 secretion in the acute stage, leading to excessive inflammatory response, which consequently increased the infarct volume and edema degree 24 h post-MCAO.

Abstract 3535: CD36 Impacts Stroke Injury In Hyperlipidemia Through MCP-1/CCR2 Axis.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Eunhee Kim ◽  
Maria Febbraio ◽  
Yi Bao ◽  
Aaron T Tolhurst ◽  
Sunghee Cho
Keyword(s):  
Brain Injury ◽  
Bone Marrow Cells ◽  
Infarct Volume ◽  
Scavenger Receptor ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Mrna Levels ◽  
Ischemic Brain ◽  
Ccr2 Expression

Hyperlipidemia increases ischemic injury. The exacerbation is associated with elevated expression of CD36, a class B scavenger receptor, in peripheral monocytes/macrophages as well as ischemic brain (Kim et al., 2008). This study investigates whether and how peripheral and brain CD36 contribute to stroke-induced brain injury in hyperlipidemia. Bone marrow cells (BM) were exchanged between CD36-expressing (AKO) and CD36-deficient (DKO) mice. The experimental mice were fed a high fat diet for 11 weeks and then subjected to transient ischemic stroke by middle cerebral artery occlusion. Ischemic outcome, MCP-1, CCR2 in the brain, and plasma MCP-1 levels were determined at 3 days post-ischemia. Compared to AKO mice received AKO BM (control transplant), the AKO mice received DKO BM resulted in 30% reduction in infarct volume (IV) ( n =12-14, p<0.05, Fig. 1 left), 27% in MCP-1 (p<0.05) and 35% CCR2 (p<0.05) mRNA levels. In contrast, DKO mice received AKO BM did not increase IV ( Fig. 1 right), MCP-1 or CCR2 mRNA levels compared to DKO mice received DKO BM ( n =11-15, ns ). Correlation analyses of MCP-1 vs IV or CCR2 vs IV showed significant reductions in slope elevations in DKO mice compared to AKO (MCP-1 vs IV, p<0.05; CCR2 vs IV, p<0.01, n =23-25/group). In spite of blunted MCP-1 expression in ischemic brain, plasma MCP-1 levels were significantly higher in DKO mice (DKO, 441.5±33.6pg/ml vs AKO, 235.8±15.9pg/ml, n =25, p<0.001). We further addressed in vitro the importance of CD36 in splenocytes for CCR2 expression. In a given AKO or DKO serum, CCR2 expression was higher in AKO splenocytes compared to DKO splenocytes ( Fig. 2 ). This study demonstrates several findings; i) peripheral CD36 contributes ischemic injury in hyperlipidemia; ii) brain (host) CD36 is additionally required for the peripheral CD36 effect take place iii) DKO host displays reduced MCP-1/CCR2 expression in the post-ischemic brain but higher plasma MCP-1 levels iv) CD36 regulates CCR2 expression in splenocytes. The findings suggest that host and peripheral CD36 synergistically regulates immune cells trafficking through modulating MCP-1/CCR2 axis. Thus, targeting CD36 may serve as a novel neuro-immune strategy to achieve neuroprotection from stroke-induced acute brain injury in hyperlipidemia.

scholarly journals Lipopolysaccharide Worsens the Prognosis of Experimental Cerebral Ischemia via Interferon Gamma-Induced Protein 10 Recruit in the Acute Stage

2019 ◽  
Author(s):  
Ping Wang ◽  
Jiaqi Zhang ◽  
Feifei Guo ◽  
Shuang Wang ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Damage ◽  
Interferon Gamma ◽  
Infarct Volume ◽  
Brain Homogenate ◽  
Acute Stage ◽  
Ischemic Brain Injury ◽  
Ppi Network ◽  
Ischemic Brain ◽  
The Brain

Abstract Background: Infection is an important clinical complication facing stroke-patients and triples the risk of death within 30 days post-stroke via mechanisms which are poorly understood . Aims: We tried to explore the mechanisms that infections aggravated the ischemic brain injury after middle cerebral artery occlusion (MCAO). Methods: We used lipopolysaccharide (LPS) as systemic inflammatory stimuli to explore the mechanisms of aggravated ischemic brain injury after Sprague-Dawley male rats subjected to MCAO. Brain damage was evaluated by cerebral blood perfusion, Longa-5 scores, infarct volume and edema degree. Systemic cytokine responses and inflammatory changes in the plasma and brain were analyzed by ELISA kit, RT 2 Profiler TM PCR array, and quantitative real-time PCR.The differential genes were subjected to Gene Ontology enrichment analysis and Protein-protein interaction (PPI) network construction. Results: LPS profoundly aggravated the brain damage after 24 hrs post-MCAO . At the acute stage (Ischemia/ Reperfusion 90min/3h), the brain homogenate gene expression of Interleukin 6 (IL-6), Tumor necrosis factor a ( TNF- a ), Interleukin 1 b (IL-1 b ) and Interferon Gamma-Induced Protein 10 (IP-10) was significantly up-regulated and the contents in plasma and brain homogenate were significantly increased in MCAO and MCAO+LPS group. IP-10 was the only gene with significant difference between MCAO and MCAO+LPS group, which was also in an important position with degrees of ³ 14 in PPI network. Conclusions: It was possible that trace LPS aggravated the ischemic brain injury by induction of excessive IP-10 secretion in the acute stage, leading to excessive inflammatory response, which consequently increased the infarct volume and edema degree 24 hrs post-MCAO.

scholarly journals Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

2010 ◽  
Vol 31 (4) ◽  
pp. 1107-1118 ◽  
Author(s):  
Slavianka G Moyanova ◽  
Federica Mastroiacovo ◽  
Lidia V Kortenska ◽  
Rumiana G Mitreva ◽  
Erminia Fardone ◽  
...  
Keyword(s):  
Brain Damage ◽  
Metabotropic Glutamate Receptors ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Protective Role ◽  
Ischemic Brain Damage ◽  
Systemic Injection ◽  
Ischemic Brain ◽  
Metabotropic Glutamate ◽  
Transient Focal Ischemia

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

scholarly journals Macamide B Pretreatment Attenuates Neonatal Hypoxic-Ischemic Brain Damage of Mice Induced Apoptosis by Regulates Autophagy Via The PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Xiaoxia Yang ◽  
Mengxia Wang ◽  
Qian Zhou ◽  
Yanxian Bai ◽  
Jing Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Brain Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Induced Apoptosis ◽  
The Impact

Abstract Lepidium meyenii (Maca) is an annual or biennial herb from South America that is a member of the genus Lepidium L. in the family Cruciferae. This herb has antioxidant, anti-apoptotic, and enhances autophagy functions and can prevent cell death, and protect neurons from ischemic damage. Macamide B, an effective active ingredient of maca, has a neuroprotective role in neonatal hypoxic-ischemic brain damage (HIBD), and the underlying mechanism of its neuroprotective effect is not yet known. The purpose of this study is to explore the impact of macamide B on HIBD-induced autophagy and apoptosis and its potential mechanism for neuroprotection. The modified Rice-Vannucci method was used to induce HIBD on 7-day-old (P7) macamide B and vehicle-pretreated pups. TTC staining was used to evaluate the cerebral infarct volume of pups, brain water content was measured to evaluate the neurological function of pups, neurobehavioral testing was used to assess functional recovery after HIBD, TUNEL and FJC staining was used to detect cell autophagy and apoptosis, and western blot analysis was used to detect the expression levels of the pro-survival signaling pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and autophagy and the apoptosis-related proteins. The results show that macamide B pretreatment can significantly decrease brain damage, improve the recovery of neural function after HIBD. At the same time, macamide B pretreatment can induce the activation of PI3K/AKT signaling pathway after HIBD, enhance autophagy, and reduce hypoxic-ischemic (HI)-induced apoptosis. In addition, 3-methyladenine (3-MA), an inhibitor of PI3K/AKT signaling pathway, significantly inhibits the increase in autophagy levels, aggravates HI-induced apoptosis, and reverses the neuroprotective effect of macamide B on HIBD. Our data indicate that macamide B pretreatment might regulate autophagy through PI3K/AKT signaling pathway, thereby reducing HIBD-induced apoptosis and exerting neuroprotective effects on neonatal HIBD. Macamide B may become a new drug for the prevention and treatment of HIBD.

scholarly journals Adipocytes as an Important Source of Serum S100B and Possible Roles of This Protein in Adipose Tissue

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Carlos Alberto Gonçalves ◽  
Marina Concli Leite ◽  
Maria Cristina Guerra
Keyword(s):  
Adipose Tissue ◽  
Brain Injury ◽  
Brain Damage ◽  
Current Knowledge ◽  
Biological Significance ◽  
Serum Levels ◽  
Serum S100b ◽  
Definitive Evidence ◽  
Astroglial Activation

Adipocytes contain high levels of S100B and in vitro assays indicate a modulated secretion of this protein by hormones that regulate lipolysis, such as glucagon, adrenaline, and insulin. A connection between lipolysis and S100B release has been proposed but definitive evidence is lacking. Although the biological significance of extracellular S100B from adipose tissue is still unclear, it is likely that this tissue might be an important source of serum S100B in situations related, or not, to brain damage. Current knowledge does not preclude the use of this protein in serum as a marker of brain injury or astroglial activation, but caution is recommended when discussing the significance of changes in serum levels where S100B may function as an adipokine, a neurotrophic cytokine, or an alarmin.

The LPA-CDK5-Tau Pathway Mediates Neuronal Injury in an In Vitro Model of Ischemia-Reperfusion Insult

2021 ◽  
Author(s):  
Yaya Wang ◽  
Jie Zhang ◽  
Liqin Huang ◽  
Yanhong Mo ◽  
Changyu Wang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemic Brain ◽  
Pathophysiological Process ◽  
Vitro Model

Abstract Lysophosphatidic acid (LPA) is a common glycerol phospholipid and an important extracellular signaling molecule. LPA binds to its receptors and mediates a variety of biological effects, including the pathophysiological process underlying ischemic brain damage and traumatic brain injury. However, the molecular mechanisms mediating the pathological role of LPA are not clear. Here, we found that LPA activates cyclin-dependent kinase 5 (CDK5). CDK5 phosphorylates tau, which leads to neuronal cell death. Inhibition of LPA production or blocking its receptors reduced the abnormal activation of CDK5 and phosphorylation of tau, thus reversing the death of neurons. Our data indicate that the LPA-CDK5-Tau pathway plays an important role in the pathophysiological process after ischemic stroke. Inhibiting the LPA pathway may be a potential therapeutic target for treating ischemic brain injury.

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