scholarly journals Astragaloside IV for Experimental Focal Cerebral Ischemia: Preclinical Evidence and Possible Mechanisms

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Hui-Lin Wang ◽  
Qi-Hui Zhou ◽  
Meng-Bei Xu ◽  
Xiao-Li Zhou ◽  
Guo-Qing Zheng
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Quality Score ◽  
Neurological Deficits ◽  
Study Quality ◽  
Astragaloside Iv ◽  
Anti Inflammatory

Astragaloside IV (AST-IV) is a principal component of Radix Astragali seu Hedysari (Huangqi) and exerts potential neuroprotection in experimental ischemic stroke. Here, we systematically assessed the effectiveness and possible mechanisms of AST-IV for experimental acute ischemic stroke. An electronic search in eight databases was conducted from inception to March 2016. The study quality score was evaluated using the CAMARADES. Rev Man 5.0 software was used for data analyses. Thirteen studies with 244 animals were identified. The study quality score of included studies ranged from 3/10 to 8/10. Eleven studies showed significant effects of AST-IV for ameliorating the neurological function score (P<0.05); seven studies for reducing the infarct volume (P<0.05); and three or two studies for reducing the brain water content and Evans blue leakage (P<0.05), respectively, compared with the control. The mechanisms of AST-IV for ischemic stroke are multiple such as antioxidative/nitration stress reaction, anti-inflammatory, and antiapoptosis. In conclusion, the findings of present study indicated that AST-IV could improve neurological deficits and infarct volume and reduce the blood-brain barrier permeability in experimental cerebral ischemia despite some methodological flaws. Thus, AST-IV exerted a possible neuroprotective effect during the cerebral ischemia/reperfusion injury largely through its antioxidant, anti-inflammatory, and antiapoptosis properties.

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.

VWF-Cleaving Protease ADAMTS13 Reduces Brain Injury Following Ischemic Stroke in Mice: Essential Role for VWF in Stroke

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 259-259
Author(s):  
Bing-Qiao Zhao ◽  
Anil kumar Chauhan ◽  
Ian S. Patten ◽  
Michael Dockal ◽  
Friedrich Scheiflinger ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Essential Role ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Protective Role ◽  
Artery Occlusion ◽  
Type I ◽  
Deficient Mice

Abstract Ischemic stroke is the second leading cause of death and disability. The only approved therapy available is recombinant tissue plasminogen activator (tPA), but its use remains limited. Therefore, there is a need for an alternative drug. Platelets and their adhesion receptors play a crucial role in modulating infarct size during ischemic stroke. ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) is a plasma metalloprotease that cleaves von Willebrand factor (VWF) an important adhesion molecule for platelets at sites of vascular injury. In patients, an increase in circulating levels of VWF and a decrease in ADAMTS13 activity are considered risk factors for ischemic stroke. By using genetically-modified mice we have previously shown that ADAMTS13 down regulates both thrombosis and inflammation and recombinant human ADAMTS13 down regulates platelet thrombi in injured arterioles. All these processes were dependent on VWF. We therefore hypothesize that ADAMTS13 has a protective role after ischemic stroke. In this study, we show that VWF deficiency or VWF heterozygosity in mice reduces infarct volume by two-fold after focal cerebral ischemia compared to wild-type (WT) in the middle cerebral artery occlusion (MCAO) stroke model. Furthermore, infusion of recombinant human VWF in WT mice not only accelerates thrombosis in the ferric-chloride injured artery model, but also increases infarct volume compared to vehicle-treated controls. These findings suggest an essential role of VWF in modulating infarction after stroke. We also show that ADAMTS13 deficiency in mice results in approximately 20% larger infarcts after cerebral ischemia compared to WT. The larger infarcts observed in ADAMTS13 deficient mice were due to VWF because mice deficient in both ADAMTS13 and VWF had infarct sizes similar to VWF deficient mice. Importantly, infusion of r-human ADAMTS13 immediately before reperfusion (two hour after occlusion) significantly reduced infarct volume (106.2 ± 9.7 mm3 vs 75.8 ± 6.9 mm3, P&lt;0.05). Of note, we observed that ADAMTS13 protein was induced in the ischemic penumbra region of brain after ischemic stroke. Our findings reveal an important role for VWF in modulating infarct volume after ischemic stroke. In addition, recombinant-ADAMTS13 could become a new therapeutic agent for stroke therapy.

scholarly journals Therapeutic Effects of Systemic Administration of the Novel RANKL-Modified Peptide, MHP1, for Ischemic Stroke in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Munehisa Shimamura ◽  
Hironori Nakagami ◽  
Hideo Shimizu ◽  
Kouji Wakayama ◽  
Tomohiro Kawano ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Brain Parenchyma ◽  
Neurological Deficits ◽  
Therapeutic Effects ◽  
Inhibitory Effects ◽  
Continuous Administration ◽  
Anti Inflammatory ◽  
Rank Signaling ◽  
Continuous Injection

Microglial healing peptide 1, “MHP1”, is a newly developed synthetic peptide composed of the DE and a part of the EF loop of the receptor activator of nuclear factor-кB (NFκB) ligand (RANKL). Our previous report demonstrated that MHP1 significantly inhibits Toll-like receptor (TLR) 2- and 4-induced inflammation in microglia/macrophages through RANK signaling without osteoclast activation. However, its inhibitory effects on ischemic stroke when administered intravenously have not been clarified. First, we examined whether MHP1 could penetrate the brain parenchyma. Intravenous injection of FITC-conjugated MHP1 demonstrated that MHP1 could cross the blood-brain-barrier in peri-infarct regions, but not in intact regions. Because MHP1 in the parenchyma was reduced at 60 minutes after injection, we speculated that continuous injection was necessary to achieve the therapeutic effects. To check the possible deactivation of MHP1 by continuous injection, the anti-inflammatory effects were checked in MG6 cells after incubation in 37°C for 24 hours. Although the inhibitory effects for IL6 and TNFα were reduced compared to nonincubated MHP1, its anti-inflammatory efficacy remained, indicating that continuous administration with pump was possible. The single and successive continuous administration of MHP1 starting from 4 or 6 hours after cerebral ischemia successfully reduced infarct volume and prevented the exacerbation of neurological deficits with reduced activation of microglia/macrophages and inflammatory cytokines. Different from recombinant RANKL, MHP1 did not activate osteoclasts in the paralytic arm. Although further modification of MHP1 is necessary for stabilization, the MHP1 could be a novel agent for the treatment ischemic stroke.

scholarly journals Neuroprotective and Anti-Inflammatory Effect of Pterostilbene Against Cerebral Ischemia/Reperfusion Injury via Suppression of COX-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjun Yan ◽  
Dongqing Ren ◽  
Xiaoxue Feng ◽  
Jinwen Huang ◽  
Dabin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Inflammatory Cytokines ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Polymorphonuclear Leucocyte ◽  
The Body ◽  
Cox 2 ◽  
Anti Inflammatory

Background: The incidence of cerebral ischemia disease leading cause of death in human population worldwide. Treatment of cerebral ischemia remains a clinical challenge for researchers and mechanisms of cerebral ischemia remain unknown. During the cerebral ischemia, inflammatory reaction and oxidative stress plays an important role. The current investigation scrutinized the neuroprotective and anti-inflammatory role of pterostilbene against cerebral ischemia in middle cerebral artery occlusion (MCAO) rodent model and explore the underlying mechanism.Methods: The rats were divided into following groups viz., normal, sham, MCAO and MCAO + pterostilbene (25 mg/kg) group, respectively. The groups received the oral administration of pterostilbene for 30 days followed by MCAO induction. The neurological score, brain water content, infarct volume and Evan blue leakage were estimated. Hepatic, renal, heart, inflammatory cytokines and inflammatory mediators were estimated.Results: Pterostilbene treatment significantly (p &lt; 0.001) improved the body weight and suppressed the glucose level and brain weight. Pterostilbene significantly (p &lt; 0.001) reduced the hepatic, renal and heart parameters. Pterostilbene significantly (p &lt; 0.001) decreased the level of glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and decreased the level of malonaldehyde (MDA), 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Pterostilbene significantly (p &lt; 0.001) inflammatory cytokines and inflammatory parameters such as cyclooxygenase-2 (COX-2), inducible nitric oxidase synthase (iNOS) and prostaglandin (PGE2). Pterostilbene significantly (p &lt; 0.001) down-regulated the level of metalloproteinases (MMP) such as MMP-2 and MMP-9. Pterostilbene suppressed the cellular swelling, cellular disintegration, macrophage infiltration, monocyte infiltration and polymorphonuclear leucocyte degranulation in the brain.Conclusion: In conclusion, Pterostilbene exhibited the neuroprotective effect against cerebral ischemia in rats via anti-inflammatory mechanism.

scholarly journals Tetrandrine alleviates cerebral ischemia/reperfusion injury by suppressing NLRP3 inflammasome activation via Sirt-1

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9042
Author(s):  
Jun Wang ◽  
Ming Guo ◽  
Ruojia Ma ◽  
Maolin Wu ◽  
Yamei Zhang
Keyword(s):  
Cerebral Ischemia ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sirtuin 1 ◽  
Neurological Deficits ◽  
Inflammasome Activation ◽  
Cerebral Ischemia Reperfusion ◽  
Nlrp3 Inflammasome Activation

Background & Aims Tetrandrine (Tet) has been reported to have anti-inflammatory effects and protect from the ischemic strokes. The NLRP3 inflammasome plays a key role in cerebral ischemia/reperfusion (I/R)-induced inflammatory lesions. However, the molecular mechanisms of Tet related to the progression of cerebral ischemia are still unclear. Therefore, the aim of this study was to investigate the possible effects of Tet on cerebral ischemia and the related mechanisms involved in NLRP3 inflammasome. Methods C57BL/6J mice used as a cerebral I/R injury model underwent middle cerebral artery occlusion (MCAO) for 2 h following reperfusion for 24 h. Tet (30 mg/kg/day, i.p.) was administered for seven days and 30 min before and after MCAO. Their brain tissues were evaluated for NLRP3 inflammasome and Sirtuin-1 (Sirt-1) expression. An intracerebroventricular injection of Sirt-1 siRNA was administered to assess the activation of the NLRP3 inflammasome. Results Tet significantly reduced the neurological deficits, infarction volume, and cerebral water content in MCAO mice. Moreover, it inhibited I/R-induced over expression of NLRP3, cleaved caspase-1, interleukin (IL)-1β, IL-18, and Sirt-1. Sirt-1 knockdown with siRNA greatly blocked the Tet-induced reduction of neurological severity score and infarct volume, and reversed the inhibition of NLRP3 inflammasome activation. Conclusion Our results demonstrate that Tet has benefits for cerebral I/R injury, which are partially related to the suppression of NLRP3 inflammasome activation via upregulating Sirt-1.

scholarly journals Electroacupuncture Pretreatment Elicits Tolerance to Cerebral Ischemia/Reperfusion through Inhibition of the GluN2B/m-Calpain/p38 MAPK Proapoptotic Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Bao-yu Zhang ◽  
Guan-ran Wang ◽  
Wen-hua Ning ◽  
Jian Liu ◽  
Sha Yang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
P38 Mapk ◽  
Cellular Localization ◽  
Mapk Pathway ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Inhibition Mechanism ◽  
Tunel Staining ◽  
Model Preparation

Background. As one of the first steps in the pathology of cerebral ischemia, glutamate-induced excitotoxicity progresses too fast to be the target of postischemic intervention. However, ischemic preconditioning including electroacupuncture (EA) might elicit cerebral ischemic tolerance through ameliorating excitotoxicity. Objective. To investigate whether EA pretreatment based on TCM theory could elicit cerebral tolerance against ischemia/reperfusion (I/R) injury, and explore its potential excitotoxicity inhibition mechanism from regulating proapoptotic pathway of the NMDA subtype of glutamate receptor (GluN2B). Methods. The experimental procedure included 5 consecutive days of pretreatment stage and the subsequent modeling stage for one day. All rats were evenly randomized into three groups: sham MCAO/R, MCAO/R, and EA+MCAO/R. During pretreatment procedure, only rats in the EA+MCAO/R group received EA intervention on GV20, SP6, and PC6 once a day for 5 days. Model preparation for MCAO/R or sham MCAO/R started 2 hours after the last pretreatment. 24 hours after model preparation, the Garcia neurobehavioral scoring criteria was used for the evaluation of neurological deficits, TTC for the measurement of infarct volume, TUNEL staining for determination of neural cell apoptosis at hippocampal CA1 area, and WB and double immunofluorescence staining for expression and the cellular localization of GluN2B and m-calpain and p38 MAPK. Results. This EA pretreatment regime could improve neurofunction, decrease cerebral infarction volume, and reduce neuronal apoptosis 24 hours after cerebral I/R injury. And EA pretreatment might inhibit the excessive activation of GluN2B receptor, the GluN2B downstream proapoptotic mediator m-calpain, and the phosphorylation of its transcription factor p38 MAPK in the hippocampal neurons after cerebral I/R injury. Conclusion. The EA regime might induce tolerance against I/R injury partially through the regulation of the proapoptotic GluN2B/m-calpain/p38 MAPK pathway of glutamate.

scholarly journals Pien-Tze-Huang attenuates neuroinflammation in cerebral ischemia-reperfusion injury in rats partially through the TLR4/NF-κB/MAPK pathway

2021 ◽  
Author(s):  
Xiao-qin Zhang ◽  
Qing Zhang ◽  
Li-li Huang ◽  
Ming-zhen Liu ◽  
Zai-xing Cheng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion ◽  
Protein Expressions ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Pien Tze Huang ◽  
Anti Inflammatory

Abstract Background Pien-Tze-Huang (PTH), one of the most famous traditional Chinese medicines in China, is traditionally applied to treat various inflammation-related diseases including stroke. However, literature regarding the anti-inflammatory effects and possible mechanisms of PTH in ischemic stroke is unavailable. This study intended to investigate the anti-inflammatory effects of PTH against cerebral ischemia-reperfusion injury and clarify its potential molecular mechanisms. Methods Cerebral ischemia-reperfusion injury was induced through transient left transient middle cerebral artery occlusion (MCAO) in male rats receiving oral pretreatment with PTH (180 mg/kg) for 4 days. TLR4 antagonist TAK-242 (3 mg/kg) was injected intraperitoneally at 1.5 h after MCAO. Magnetic resonance imaging, hematoxylin–eosin staining, RT-PCR, western blot, and immunofluorescence methods were used to studied the effect and mechanism of PTH against ischemic stroke. Results PTH treatment reduced cerebral infarct volume, improved neurological function, and ameliorated brain histopathological damage in MCAO rats. In addition, it markedly suppressed a variety of inflammatory responses as evidenced by the reduced mRNA levels of IL-1β, IL-6, TNF-α and MCP-1; the inhibition of microglia and astrocyte activations; and the decreased protein expressions of iNOS and COX-2 in injured brains. Moreover, PTH down-regulated the protein expressions of TLR4, MyD88, and TRAF6; reduced the expression and NF-κB; and lowered the protein expressions of p-ERK1/2, p-JNK, and p-p38. Similar effects were observed in the TAK-242 treated group. However, TAK-242 did not significantly reinforce the anti-inflammatory effects of PTH. Conclusion PTH could attenuate neuroinflammation, improve neurological function, and alleviate brain injury in MCAO rats, and its potential mechanisms are partly connected to inhibition of neuroinflammation involving the TLR4/NF-κB/MAPK signaling pathway.

Abstract 137: The Effect Of Mitophagy During Transient Ischemic Brain In Rats

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Qiang Li ◽  
Ting Zhang ◽  
Jixian Wang ◽  
Yongting Wang ◽  
Guo-Yuan Yang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Atp Synthesis ◽  
Beclin 1 ◽  
Neurological Deficits ◽  
Ischemic Brain ◽  
Pre Treatment ◽  
The Impact

Background and Purpose: Mitochondria provides energy to maintain normal cell functioning. Mitophagy is one of mitochondria functions, which can clear out injured mitochondria, ensure stability of mitochondria and promote cell survival in hostile environment. However, if mitophagy occurs during cerebral ischemia is unknown. The present study explored dynamic mitophagy, the effect of promoting mitophagy, and the molecular mechanisms of mitophagy during cerebral ischemia/reperfusion. Methods: Adult male SD rats underwent 2h middle cerebral artery occlusion (MCAO) followed by 6 to 72h reperfusion. Dynamic changes of mitophagy were determined by LC3 immunostaining, Western blot analysis, and transmission electron microscope. To study the impact of mitophagy, we injected rapamycin, a mitophagy stimulator, into the left ventricle in rats underwent transient MCAO. To evaluate the effect of mitophagy, neuronal death and neurological deficits were determined. To explore the effect of mitophagy on mitochondria function, the number of mitochondria, the levels of MDA, ATP, and JC-1 were examined. To study the mechanism of mitophagy, mitochondrial Beclin-1 and p62 expression were also determined. Results: We demonstrated that autophagy was mainly detected in mitochondria in the peri-focal area of ischemic cortex after ischemia/reperfusion. Mitophagy was increased at 6h (p<0.05), peaked at 24h (p<0.05), gradually reduced at 48h (p<0.05), and returned to normal at 72h of transient MCAO. Pre-treatment with rapamycin greatly enhanced mitophagy, reduced infarct volume, and improved neurological outcomes compared to the control (p<0.05). We found that the number of mitochondria and mtDNA copy, mitochondria ATP synthesis level, and JC-1 were increased (p<0.05), and MDA was reduced in rapamycin treated rats (p<0.05). We further demonstrated that rapamycin pre-treatment enhanced mitochondrial Beclin-1and p62 in mitochondria. Conclusion: We demonstrated ischemia could induce mitophagy in brain cells. Rapamycin attenuated ischemic brain injury, which was via stimulating mitophagy that can reduce oxidative stress and improve mitochondria function. The mechanism of rapamycin promoting mitophagy was through increasing Beclin-1 and p62 expression.

scholarly journals Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage

2018 ◽  
Vol 125 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Chun Li ◽  
Hong Sun ◽  
Guodong Xu ◽  
Kimberly D. McCarter ◽  
Jiyu Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Ischemic Brain Damage ◽  
Mitochondrial Oxidative Stress ◽  
Ischemic Brain

Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo-treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg·kg−1·day−1) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg·kg−1·day−1ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation.NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products.

scholarly journals Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yanhua Qin ◽  
Weiming Hu ◽  
Yang Yang ◽  
Zhiying Hu ◽  
Weiyun Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Tunel Staining ◽  
Cox 2

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

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