Abstract 2966: Role of the Cerebral Vascular Toll-Like Receptor Signaling Pathway in Neuroprotection Induced by Combination Therapy of VELCADE and TPA

Background and Purpose: Toll-like receptors (TLRs) and their family members including IL-1 receptor-associated kinase-1 (IRAK1) mediate ischemic cell damage. MicroRNAs (miRNAs) including miR-146a regulate TLRs. The present study investigated whether treatment of stroke in older animals with VELCADE in combination with tPA affects expression of TLRs and miR-146a in cerebral endothelial cells. Methods: Wistar rats at the age of 16-18 months were subjected to right embolic middle cerebral artery occlusion (MCAo). VELCADE (0.1mg/kg) and tPA (5mg/kg) were intravenously administered 2h after MCAo (n=16). Ischemic rats treated with tPA alone (n=14) or saline (n=15) were used as control groups. Levels of TLRs and miR-146a in cerebral endothelial cells were measured. Cultured primary cerebral endothelial cells (PCECs) were used for investigating the direct effect of VELCADE on expression of miR-146a. Results: Quantitative RT-PCR analysis revealed that VELCADE in combination with tPA significantly increased miR-l46a levels (11±3 fold) in the cerebral endothelial cells isolated by laser capture microdissection compared with that in ischemic rats treated with tPA monotherapy (2±1). Concurrently, immunostaining showed that the combination therapy suppressed tPA monotherapy-upregulated TLR2 (44±7 vs 93±8/mm 2 in tPA), TLR4 (39±6vs 91±8), IRAK1 (16±3 vs 46±5), fibrin (17±6 vs 40±3), and NF-kB (9±2 vs 22±3) immunoreactive vessels, leading to reduction of infarct volume (14±2 vs 28±3% in tPA, and 30±3% in saline, p<0.05). These in vivo data indicate that combination therapy-upregulated miR-146a is inversely related with TLRs levels and ischemic cell damage. In vitro, Western blots showed that incubation of PCECs with fibrin at 1.5 µg/ml increased levels of IRAK1 (1.4 fold) and myeloid differentiation factor 88 (MyD88, 1.4 fold). RT-PCR analysis of PCECs showed that fibrin reduced miR-146a levels by 30 %. However, PCECs treated with VELCADE (10 ng/ml) in the presence of fibrin elevated miR-146 levels by 80% and abolished fibrin-elevated IRAK1 and MyD88 proteins. Moreover, overexpression of miR146a in PCECs downregulated IRAK1 protein, a miR-146a target, by 40%. Conclusion: Our data demonstrate that fibrin activates endothelial TLRs and that VELCADE-upregulated miR-146a abolishes tPA-induced TLRs, suggesting that miRNAs and the TLR signaling pathway in cerebral endothelial cells play an important role in the neuroprotective effect of the combination therapy of VELCADE and tPA for acute stroke.

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

10.21203/rs.3.rs-952715/v1 ◽

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.

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Abstract WP272: A Powerful Combination Therapy for Stroke: Post-Ischemia Ethanol Administration and Normobaric Oxygenation on Ischemic Rats

Stroke ◽

10.1161/str.44.suppl_1.awp272 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Christopher Sy ◽

Xiaokun Geng ◽

Paul Fu ◽

Changya Peng ◽

Vance Fredrickson ◽

...

Keyword(s):

Combination Therapy ◽

Protein Expression ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Artery Occlusion ◽

Neurological Deficits ◽

Ethanol Administration ◽

Acute Administration ◽

Sprague Dawley ◽

Acute Cerebral Ischemia

Objectives: Normobaric oxygenation (NBO) has been reported to be neuroprotective against acute cerebral ischemia. Recently, a clinical trial was terminated because beneficial outcomes were not definitive. Our recent study ( Stroke. 2012 43(1):205-10 ) demonstrated a strong neuroprotective effect induced by acute administration of ethanol (EtOH) at 1.5g/kg. In this study, we assessed the therapeutic influence of EtOH in combination with NBO. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 2h. Ischemic animals received either an intraperitoneal injection of EtOH (1.0g/kg), a course of NBO (100% for 2h), or a combination of both immediately prior to reperfusion onset. Brain injury was determined by infarct volume and behavioral outcomes at 48h post-reperfusion. Metabolic dysfunction was investigated by assessing ADP/ATP ratios, reactive oxygen species (ROS) levels, NADPH oxidase (NOX) activity, and protein expression of NOX subunits (p47 phox , gp91 phox , and p67 phox ), as well as the protein expression and enzyme activity of pyruvate dehydrogenase (PDH), at both 3h and 24h after reperfusion. Results: Combination therapy led to a significant decrease in infarct volumes (Saline: 48±4%, EtOH: 38±3%, NBO: 37±4%, Combination: 19±3% ) and in neurological deficits (Belayev Scale 0-12, Saline: 8.4±0.7; EtOH: 6.5±0.7; NBO: 6.4±0.6; Combination: 4.4±0.3 ). At 3h and 24h post-reperfusion the decrease in ADP/ATP ratio was significantly enhanced, reflecting a preservation of cellular energy. A greater decrease in NOX activity and protein expression was observed, in association with decreased ROS levels, suggesting that improved glycolysis may contribute to neuroprotection. PDH activity and protein expression was dramatically increased, making the facilitation of aerobic metabolism a probable mechanism for preserving cellular ATP. Conclusions: Our findings demonstrate that a synergistic relationship exists between EtOH and NBO. Both are promising neuroprotective agents when used together, even at low doses. Moreover, both are inexpensive, widely available, easy to administer, and have little side effects. Thus, combination therapy could be an effective and efficient approach to future stroke treatments.

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Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20040998 ◽

2019 ◽

Vol 20 (4) ◽

pp. 998 ◽

Cited By ~ 11

Author(s):

Yao-Chung Chuang ◽

Shang-Der Chen ◽

Chung-Yao Hsu ◽

Shu-Fang Chen ◽

Nai-Ching Chen ◽

...

Keyword(s):

Status Epilepticus ◽

Signaling Pathway ◽

Mitochondrial Biogenesis ◽

Neuronal Damage ◽

Cell Damage ◽

Neuroprotective Effect ◽

Neuronal Cell ◽

Protective Mechanism ◽

Protective Effects ◽

Prolonged Seizure

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway.

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Tissue Kallikrein Alleviates Cerebral Ischemia-Reperfusion Injury by Activating the B2R-ERK1/2-CREB-Bcl-2 Signaling Pathway in Diabetic Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/1843201 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 7

Author(s):

Ruifeng Shi ◽

Kunxiong Yuan ◽

Bin Hu ◽

Hongfei Sang ◽

Lizhi Zhou ◽

...

Keyword(s):

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Camp Response Element Binding ◽

Diabetic Rats ◽

Tissue Kallikrein ◽

Inflammatory Reactions ◽

Beneficial Effects

Diabetes mellitus (DM) substantially increases the risk of ischemic stroke and reduces the tolerance to ischemic insults. Tissue kallikrein (TK) has been demonstrated to protect neurons from ischemia/reperfusion (I/R) injury in orthoglycemic model by activating the bradykinin B2 receptor (B2R). Considering the differential effects of B2R or bradykinin B1 receptor (B1R) on cardioprotection and neuroprotection in I/R with or without diabetes, this study was designed to investigate the role of TK during cerebral I/R injury in streptozotocin-induced diabetic rats. Intravenous injection of TK inhibited apoptosis in neurons, alleviated edema and inflammatory reactions after focal cerebral I/R, significantly reduced the infarct volume, and improved functional recovery. These beneficial effects were accompanied by activation of the extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding (CREB), and Bcl-2 signal proteins. Inhibition of the B2R or ERK1/2 pathway abated the effects of TK, whereas an antagonist of B1R enhanced the effects. These findings reveal that the neuroprotective effect of TK against cerebral I/R injury in streptozotocin-induced diabetic rats mainly involves the enhancement of B2R and ERK1/2-CREB-Bcl-2 signaling pathway activity.

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Autophagy is Involved in Neuroprotective Effect of Alpha7 Nicotinic Acetylcholine Receptor on Ischemic Stroke

Frontiers in Pharmacology ◽

10.3389/fphar.2021.676589 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhe-Qi Xu ◽

Jing-Jing Zhang ◽

Ni Kong ◽

Guang-Yu Zhang ◽

Ping Ke ◽

...

Keyword(s):

Ischemic Stroke ◽

Signaling Pathway ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Autophagy Flux ◽

Nicotinic Acetylcholine

The α7 nicotinic acetylcholine receptor (α7nAChR) belongs to the superfamily of cys loop cationic ligand-gated channels, which consists of homogeneous α7 subunits. Although our lab found that activation of α7nAChR could alleviate ischemic stroke, the mechanism is still unknown. Herein, we explored whether autophagy is involved in the neuroprotective effect mediated by α7nAChR in ischemic stroke. Transient middle cerebral artery occlusion (tMCAO) and oxygen and glucose deprivation (OGD/R) exposure were applied to in vivo and in vitro models of ischemic stroke, respectively. Neurological deficit score and infarct volume were used to evaluate outcomes of tMCAO in the in vivo study. Autophagy-related proteins were detected by Western blot, and autophagy flux was detected by using tandem fluorescent mRFP-GFP-LC3 lentivirus. At 24 h after tMCAO, α7nAChR knockout mice showed worse neurological function and larger infarct volume than wild-type mice. PNU282987, an α7nAChR agonist, protected against OGD/R-induced neuronal injury, enhanced autophagy, and promoted autophagy flux. However, the beneficial effects of PNU282987 were eliminated by 3-methyladenine (3-MA), an autophagy inhibitor. Moreover, we found that PNU282987 treatment could activate the AMPK-mTOR-p70S6K signaling pathway in the in vitro study, while the effect was attenuated by compound C, an AMPK inhibitor. Our results demonstrated that the beneficial effect on neuronal survival via activation of α7nAChR was associated with enhanced autophagy, and the AMPK-mTOR-p70S6K signaling pathway was involved in α7nAChR activation–mediated neuroprotection.

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Endothelial CXCL5 negatively regulates myelination and repair after white matter stroke

10.1101/664953 ◽

2019 ◽

Author(s):

Guanxi Xiao ◽

Rosie Kumar ◽

Yutaro Komuro ◽

Jasmine Burguet ◽

Visesha Kakarla ◽

...

Keyword(s):

Risk Factors ◽

Endothelial Cells ◽

White Matter ◽

Signaling Pathway ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Oligodendrocyte Progenitor ◽

Vessel Disease ◽

Cerebral Endothelial Cells

AbstractCerebral small vessel disease and resulting white matter pathologies are worsened by cardiovascular risk factors including obesity. The molecular changes in cerebral endothelial cells caused by chronic cerebrovascular risk factors remain unknown. We developed a novel approach for molecular profiling of chronically injured cerebral endothelial cells using cell-specific translating ribosome affinity purification (RiboTag) with RNA-seq in Tie2-Cre:RiboTag mice. We used this approach to identify the transcriptome of white matter endothelial cells after the onset of diet-induced obesity (DIO). DIO induces an IL-17B signaling pathway that acts on the cerebral endothelia through IL-17Rb to increase levels of both circulating CXCL5 and local endothelial expression of CXCL5 in both the DIO mouse model and in humans with imaging or pathologic evidence of cerebral small vessel disease. In the white matter, endothelial CXCL5 acts as a chemoattractant and promotes the association of oligodendrocyte progenitor cells (OPCs) with cerebral endothelia increasing vessel-associated OPC cell number and triggers OPC gene expression programs regulating migration and chemokine receptor activation. Targeted blockade of IL-17B with peripheral antibody administration reduced the population of vessel-associated OPCs by reducing endothelial CXCL5 expression. CXCL5-mediated sequestration of OPCs to white matter vasculature impairs OPC differentiation after a focal white matter ischemic lesion. DIO promotes a unique white matter endothelial-to-oligodendrocyte progenitor cell signaling pathway that compromises brain repair after stroke.

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[D-Ala2, D-Leu5] Enkephalin Inhibits TLR4/NF-κB Signaling Pathway and Protects Rat Brains against Focal Ischemia-Reperfusion Injury

Mediators of Inflammation ◽

10.1155/2021/6661620 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Danyun Fu ◽

Haitong Liu ◽

Jiang Zhu ◽

Hongjiao Xu ◽

Junyan Yao

Keyword(s):

Cerebral Ischemia ◽

Signaling Pathway ◽

Western Blotting ◽

Neurological Deficit ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Cerebral Infarct ◽

Brain Inflammation ◽

Tnf Α

Background. Cerebral ischemia-reperfusion (I/R) injury is the main cause of acute brain injury, which is a life-threatening disease due to the lack of effective treatments. [D-Ala2, D-Leu5] enkephalin (DADLE) is a synthetic delta-opioid receptor agonist that is reported to confer neuroprotective effect; however, the underlying mechanism is still being explored. The purpose of the present study is to determine whether DADLE administrated intracerebroventricularly could attenuate the cerebral I/R injury, to determine if this is through inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway and therefore inhibiting neuroinflammation in an ischemic stroke model. Methods. Rats were subjected to 120 minutes of ischemia by transient middle cerebral artery occlusion (MCAO). At 45 minutes after ischemia, DADLE or control vehicle (artificial cerebrospinal fluid, ACSF) was given to the rats intracerebroventricularly. Neurological deficit, cerebral infarct volume, and histopathological changes were assessed at 24 hours after reperfusion. Brain inflammation was assessed by measuring tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the ischemic penumbra by ELISA. The expression of TLR4 was determined by immunohistochemistry staining and western blotting. The expression of NF-κB was investigated by western blotting. Results. Compared with the vehicle-treatment (ACSF), DADEL improved neurological deficit ( 9.6 ± 2.1 versus 13.8 ± 1.9 ), reduced cerebral infarct volume ( 18.74 ± 3.30 % versus 10.57 ± 2.50 % ), and increased the number of normal neurons ( 29.72 ± 8.53 % versus 51.37 ± 9.18 % ) after cerebral I/R injury in rats (all P < 0.05 ). Expressions of inflammatory molecules including TNF-α and IL-6 were highly expressed in the vehicle-treated rats, whereas treatment with DADLE downregulated these expressions ( P < 0.05 ). Additionally, cerebral I/R injury significantly increased the TLR4 and NF-κB expression in vehicle-control group, which was markedly inhibited by DADLE ( P < 0.05 ). Conclusions. DADLE, administrated intracerebroventricularly at 45 minutes after cerebral ischemia, significantly ameliorated I/R-induced brain damage in rats. This kind of neuroprotective effect appears to be related to the downregulation of TLR4-mediated inflammatory responses.

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Soluble Thrombomodulin Antigen in Conditioned Medium Is Increased by Damage of Endothelial Cells

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648199 ◽

1991 ◽

Vol 65 (05) ◽

pp. 618-623 ◽

Cited By ~ 235

Author(s):

Hidemi Ishii ◽

Hiroyuki Uchiyama ◽

Mutsuyoshi Kazama

Keyword(s):

Hydrogen Peroxide ◽

Endothelial Cells ◽

Conditioned Medium ◽

Intracellular Transport ◽

Cell Damage ◽

Sodium Dodecyl ◽

Cellular Damage ◽

Release Mechanism ◽

Dependent Manner ◽

Western Blots

SummaryThrombomodulin (TM) exists not only in endothelial cells but also in circulating plasma as soluble heterogeneous fragments. A release mechanism of soluble TM antigen from endothelial cells was investigated. Cultured human umbilical vein endothelial cells released about 0.6% of total cellular TM antigen into conditioned medium during 24 h. The release of TM antigen was not influenced by addition of various concentrations (0.01-5.0 μM) of monensin, which inhibits intracellular transport of secretory proteins, though the secretion of plasminogen activator inhibitor-1 from the cells was inhibited. The release of TM antigen was not increased when total cellular TM level increased 1.3- or 1.4-fold relative to control cells after stimulation with 0.1-1.0 U/ml thrombin or 3 mM dibutyryl cAMP, respectively. Exposure of endothelial cells for 6 h to mixture of 1 μM N-formyl-methionyl-leucyl-phenylalanine (FMLP) and 100 ng/ml lipopolysaccharide (LPS) decreased cellular TM level by 30% relative to control cells without increase in the TM release. The FMLP and LPS-stimulated leukocyte treatment of the cells increased the release of TM antigens into the medium in a time-dependent manner and the increased release of TM antigen paralleled the extent of cell damage as measured by 51Cr release. Hydrogen peroxide treatment of the cells increased the release of TM antigens into the medium in a time- and concentration-dependent manner. The increased release of TM antigen by hydrogen peroxide also paralleled the extent of cell damage. Soluble TM antigen in conditioned medium from the untreated control cells was composed of six heterogeneous fragments of 105, 56, 48, 33, 31 and 28 kDa observed on Western blots after sodium dodecyl sulfatepolyacrylamide gel electrophoresis under reducing conditions, and the soluble TM antigen from the hydrogen peroxide-treat-ment cells was composed of five heterogeneous fragments of 80, 56, 33, 31 and 28 kDa. These compositions were quite similar to that observed for soluble TM fragments in human plasma. It is suggested that soluble TM antigen is not secreted from endothelial cells, but results from cellular damage.

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Punicalagin alleviates brain injury and inflammatory responses, and regulates HO-1/Nrf-2/ARE signaling in rats after experimental intracerebral haemorrhage

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.8 ◽

2020 ◽

Vol 19 (4) ◽

pp. 727-737

Author(s):

Fuchi Zhang ◽

Kang Wu ◽

Xiaolin Wu ◽

Can Xin ◽

Minghui Zhou ◽

...

Keyword(s):

Brain Injury ◽

Signaling Pathway ◽

Intracerebral Haemorrhage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Cell Damage ◽

Neuroprotective Effect ◽

Serum Levels ◽

Underlying Mechanism ◽

Sprague Dawley

Purpose: To investigate the effect of punicalagin, an ellagitannin present in pomegranates, on intracerebral haemorrhage (ICH)-induced inflammatory responses and oxidative stress, and also unravel the underlying mechanism(s) of action. Methods: Collagenase type IV (0.2 U) was used to induce ICH in adult male Sprague-Dawley rats. Punicalagin was given to the rats at doses of 25, 50, and 75 mg/kg body weight via oral gavage for 15 days before ICH induction. The animals were sacrificed 24h following induction of ICH, and their brains were excised immediately and used for analysis. Histological changes were determined with Haematoxylin and Eosin (H&E) staining. Permeability to blood-brain barrier (BBB) was determined by quantifying the extent of extravasation of Evan Blue (EB). Protein expressions of HO-1/Nrf-2/ARE and NF-κB signaling were assayed using immunoblotting and RT-PCR. Levels of reactive oxygen species (ROS) and serum levels of cytokines were also determined. Results: Punicalagin treatment reduced inflammatory cell infiltration and cell damage, improved brain tissue architecture and BBB integrity. The punicalagin treatment increased the activities of antioxidant enzymes, and enhanced antioxidant status via activation of Nrf-2/ARE/HO-1 signaling pathway (p < 0.05). The treatment upregulated the expressions of HO-1 to 174 %, relative to 127 % in ICH control rats. Furthermore, it enhanced NF-κB levels and reversed the ICH injury-induced upregulations of IL-6, IL-18 and IL-1β. Conclusion: These findings indicate that punicalagin exerts neuroprotective effect in rats after experimental ICH through regulation of theHO-1/Nrf-2/ARE signaling pathway. Thus, punicalagin has therapeutic potential for ICH. Keywords: Brain injury, Haemoxygenase-1, Intracerebral haemorrhage, Inflammatory responses, Nrf2/ARE signalling, Punicalagin

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