scholarly journals Characterization of a novel model of global forebrain ischaemia–reperfusion injury in mice and comparison with focal ischaemic and haemorrhagic stroke

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Natasha Ting Lee ◽  
Carly Selan ◽  
Joanne S. J. Chia ◽  
Sharelle A. Sturgeon ◽  
David K. Wright ◽  
...  
Keyword(s):  
Blood Flow ◽  
Haemorrhagic Stroke ◽  
Artery Occlusion ◽  
Ischaemia Reperfusion Injury ◽  
Artery Ligation ◽  
Ischaemic Injury ◽  
Ischaemia Reperfusion ◽  
Inflammatory Chemokines ◽  
Apoptotic Activity ◽  
Global Brain Ischaemia

Abstract Stroke is caused by obstructed blood flow (ischaemia) or unrestricted bleeding in the brain (haemorrhage). Global brain ischaemia occurs after restricted cerebral blood flow e.g. during cardiac arrest. Following ischaemic injury, restoration of blood flow causes ischaemia–reperfusion (I/R) injury which worsens outcome. Secondary injury mechanisms after any stroke are similar, and encompass inflammation, endothelial dysfunction, blood–brain barrier (BBB) damage and apoptosis. We developed a new model of transient global forebrain I/R injury (dual carotid artery ligation; DCAL) and compared the manifestations of this injury with those in a conventional I/R injury model (middle-cerebral artery occlusion; MCAo) and with intracerebral haemorrhage (ICH; collagenase model). MRI revealed that DCAL produced smaller bilateral lesions predominantly localised to the striatum, whereas MCAo produced larger focal corticostriatal lesions. After global forebrain ischaemia mice had worse overall neurological scores, although quantitative locomotor assessment showed MCAo and ICH had significantly worsened mobility. BBB breakdown was highest in the DCAL model while apoptotic activity was highest after ICH. VCAM-1 upregulation was specific to ischaemic models only. Differential transcriptional upregulation of pro-inflammatory chemokines and cytokines and TLRs was seen in the three models. Our findings offer a unique insight into the similarities and differences in how biological processes are regulated after different types of stroke. They also establish a platform for analysis of therapies such as endothelial protective and anti-inflammatory agents that can be applied to all types of stroke.

scholarly journals The mitochondria-targeting peptide elamipretide diminishes circulating HtrA2 in ST-segment elevation myocardial infarction

2017 ◽  
Vol 8 (8) ◽  
pp. 695-702 ◽  
Author(s):  
Marcus Hortmann ◽  
Samuel Robinson ◽  
Moritz Mohr ◽  
Maximillian Mauler ◽  
Daniela Stallmann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Serum Level ◽  
Reperfusion Injury ◽  
Myocardial Damage ◽  
Artery Occlusion ◽  
Ischaemia Reperfusion Injury ◽  
St Segment Elevation ◽  
Ischaemia Reperfusion ◽  
Targeting Peptide ◽  
Mitochondria Targeting

Background: The extent of myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) depends on both the time to reperfusion as well as injury induced by ischaemia–reperfusion resulting in a cascade of cellular and humoral reactions. As a consequence of ischaemia–reperfusion in the heart, the high-temperature requirement serine peptidase 2 (HtrA2) is translocated from the mitochondria to the cytosol, whereupon it induces protease activity-dependent apoptosis mediated via caspases. Myocardial damage induced by reperfusion cannot be monitored due to a current lack in specific biomarkers. We examined the serum level of HtrA2 as a potentially novel biomarker for mitochondrial-induced cardiomyocyte apoptosis. Methods: After informed consent, peripheral blood was obtained from patients ( n=19) with first-time acute anterior STEMI after percutaneous coronary intervention. Within this group, 10 of the patients received the mitochondria-targeting peptide elamipretide (phase 2a clinical study EMBRACE (NCT01572909)). Blood was also obtained from a control group of healthy donors ( n=16). The serum level of HtrA2 was measured by an enzyme-linked immunosorbent assay (ELISA). In a murine model of myocardial ischaemia–reperfusion injury, HtrA2 was determined in plasma by ELISA after left anterior descending artery occlusion. Results: HtrA2 median was significantly increased in patients with STEMI compared to healthy controls 392.4 (240.7–502.8) pg/mL vs. 1805.5 (981.3–2220.1) pg/mL ( P⩽0.05). Elamipretide significantly reduced the HtrA2 median serum level after myocardial infarction 1805.5 (981.3–2220.1) pg/mL vs. 496.5 (379.4–703.8) pg/mL ( P⩽0.05). Left anterior descending artery occlusion in mice significantly increased HtrA2 mean in plasma (117.4 fg/ml±SEM 28.1 vs. 525.2 fg/ml±SEM 96; P⩽0.05). Conclusion: Compared to healthy controls, we found significantly increased serum levels of HtrA2 in patients with STEMI. The result was validated in a murine model of myocardial ischaemia–reperfusion injury. In humans the increased serum level was significantly reduced by the mitochondria-targeting peptide elamipretide. In conclusion, HtrA2 is detectable in serum of patients with STEMI and might present a novel biomarker for mitochondrial-induced cardiomyocyte apoptosis. Consequently, HtrA2 may also show promise as a biomarker for the identification of ischaemia–reperfusion injury. However, this must be validated in a lager clinical trial.

Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury

2011 ◽  
Vol 121 (6) ◽  
pp. 257-266 ◽  
Author(s):  
Mahmoud Abu-Amara ◽  
Shi Yu Yang ◽  
Alberto Quaglia ◽  
Peter Rowley ◽  
Achala De Mel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Reperfusion Injury ◽  
Protective Effects ◽  
Ischaemic Preconditioning ◽  
Ischaemia Reperfusion Injury ◽  
Hepatic Microcirculation ◽  
Ischaemia Reperfusion ◽  
Liver Transaminases ◽  
Remote Ischaemic Preconditioning

NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.

scholarly journals Ischaemia-reperfusion injury in central retinal artery occlusion

2013 ◽  
Vol 2013 (oct21 1) ◽  
pp. bcr2013201415-bcr2013201415 ◽  
Author(s):  
S. Saxena ◽  
N. Mishra ◽  
C. H. Meyer ◽  
L. Akduman
Keyword(s):  
Reperfusion Injury ◽  
Central Retinal Artery Occlusion ◽  
Retinal Artery Occlusion ◽  
Artery Occlusion ◽  
Central Retinal Artery ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Retinal Artery

scholarly journals Electroacupuncture Ameliorates Cognitive Impairment through Inhibition of Ca2+-Mediated Neurotoxicity in a Rat Model of Cerebral Ischaemia–reperfusion Injury

2018 ◽  
Vol 36 (6) ◽  
pp. 401-407 ◽  
Author(s):  
Yun Zhang ◽  
Xiang Mao ◽  
Ruhui Lin ◽  
Zuanfang Li ◽  
Jing Lin
Keyword(s):  
Cognitive Impairment ◽  
Rat Model ◽  
Cerebral Ischaemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Ischaemia Reperfusion Injury ◽  
Tetrazolium Chloride ◽  
Ischaemia Reperfusion ◽  
Intracellular Ca

Background The hippocampus is vulnerable to severe damage after cerebral ischaemia–reperfusion (I/R) injury. This study aimed to explore the effect of electroacupuncture (EA) on cognitive impairment and its relationship with Ca2+neurotoxicity in a rat model of I/R injury induced by middle cerebral artery occlusion (MCAO). Methods 60 adult male Sprague-Dawley rats were randomly divided into three groups: control (sham surgery) group, untreated MCAO group and EA-treated MCAO+EA group. Rats in the MCAO and MCAO+EA groups underwent modelling of poststroke cognitive impairment by MCAO surgery. EA was performed for 30 min daily at GV20 and GV24 (1–20 Hz) for 1 week. The Morris water maze experiment was used to assess cognitive function. 2,3,5-triphenyl tetrazolium chloride staining was used to measure infarct volume. The intracellular Ca2+content in the Cornu Ammonis (CA)1 area of the hippocampus was assessed by laser confocal scanning microscopy. ELISA was performed to evaluate the concentration of glutamate (Glu) in the hippocampus, and the protein expression of two Glu receptors (N-methyl-D-aspartic acid receptor (NMDAR) 2A and NMDAR2B) were analysed by Western blotting. Results Compared with the untreated MCAO group, EA effectively ameliorated cognitive impairment (P=0.01) and shrunk the infarct volume (P=0.032). The content of intracellular Ca2+, Glu and NMDAR2B in the hippocampus was significantly raised by MCAO (P=0.031-0.043), while EA abrogated these effects. NMDAR2A was decreased by MCAO (P=0.015) but increased by EA (P=0.033). Conclusions EA had a beneficial effect on cognitive repair after cerebral I/R, and its mechanism of action likely involves a reduction of Ca2+influx via inhibition of Glu neurotoxicity and downregulation of NMDAR2B expression.

scholarly journals Vascular anatomy defines sites of indomethacin induced jejunal ulceration along the mesenteric margin

Gut ◽  
1997 ◽  
Vol 41 (6) ◽  
pp. 763-770 ◽  
Author(s):  
A Anthony ◽  
R E Pounder ◽  
A P Dhillon ◽  
A J Wakefield
Keyword(s):  
Reperfusion Injury ◽  
Vascular Anatomy ◽  
Mucosal Injury ◽  
Rat Jejunum ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemic Injury ◽  
Ischaemia Reperfusion ◽  
Vasa Recta ◽  
Dose Study ◽  
The Relationship

Background—Indomethacin induces ulceration in the rat jejunum with sparing of the ileum. The ulcers localise between vasa recta along the mesenteric margin of the bowel, observations that have not been fully explained.Aim—To examine the relationship between the localisation of experimental ulcers and the vascular anatomy of the rat small intestine.Methods—The normal vascular anatomy of the rat jejunum and ileum was studied and compared using arterial carbon ink perfusion. The anatomical localisation of early and advanced lesions induced by indomethacin was examined with particular reference to the vasculature. Mucosal injury induced by feeding vessel ligation for 24 hours or brief ischaemia-reperfusion injury was examined. The existence of anatomically sensitive sites to indomethacin was tested in a two dose study.Results—In the rat jejunum, poorly vascularised sites along the mesenteric margin were highly susceptible to indomethacin induced injury, such sites being absent from the ileum. Villous contraction was a feature of both early indomethacin injury and ischaemia-reperfusion injury in the rat jejunum. Twenty four hour ligation of jejunal vasa brevia selectively induced ischaemic injury along the mesenteric margin. Two doses of indomethacin to rats did not induce greater injury than a single dose.Conclusions—Results support the hypothesis that the rat jejunum possesses vascularly compromised sites along the mesenteric margin that are susceptible to indomethacin induced injury. Indomethacin may cause ischaemia-reperfusion injury selectively at these sites.

Electroacupuncture Ameliorates Cognitive Impairment and Regulates the Expression of Apoptosis-Related Genes Bcl-2 and Bax in rats with cerebral ischaemia-reperfusion injury

2015 ◽  
Vol 33 (6) ◽  
pp. 478-484 ◽  
Author(s):  
Fang Liu ◽  
Yi-Jing Jiang ◽  
Hong-Jia Zhao ◽  
Li-Qun Yao ◽  
Li-Dian Chen
Keyword(s):  
Cognitive Impairment ◽  
Cerebral Ischaemia ◽  
Artery Occlusion ◽  
Control Group ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Ischaemia Reperfusion Injury ◽  
Functional Rehabilitation ◽  
Ischaemia Reperfusion ◽  
Cerebral Artery Occlusion

Background Post-stroke cognitive impairment seriously affects the quality of life and functional rehabilitation of patients with stroke. Objective To examine the effects of electroacupuncture (EA) at GV20 and GV24 on cognitive impairment and apoptosis including expression of apoptosis-related genes Bcl-2 and Bax in a rat model of cerebral ischaemia-reperfusion (IR) induced by middle cerebral artery occlusion (MCAO). Methods Thirty-five Sprague-Dawley rats were allocated to a sham operation control group (SC group, n=10) or underwent surgery and MCAO (n=25). Postoperatively the latter group was randomly subdivided into EA or untreated (IR) groups. Cognitive impairment was assessed using the Morris water maze (MWM). Apoptosis was examined by detection of Bcl-2 and Bax expression in the cerebral cortex. Results The EA group had significantly decreased neurological deficit scores compared to the IR group (p<0.05). In the MWM test, significant differences in escape latency and route were observed between the EA and IR groups (p<0.05). Rats in the EA group performed better in the probe trial than those in the IR group (p<0.05). EA treatment markedly reduced the number of TUNEL-positive cells compared to the IR group (20.13±4.30% vs 38.40±3.38%; p<0.001). Reverse transcription-polymerase chain reaction (RT-PCR) results showed the Bcl-2/Bax ratio was significantly increased in the EA group compared to the IR group (1.61±0.19 vs 0.50±0.05, p<0.01). Conclusions These findings suggest that EA ameliorates cognitive impairment of rats with IR injury by modulating Bcl-2 and Bax expression.

Ischaemia-reperfusion injury in the critically ill

2016 ◽  
Author(s):  
Mitchell P. Fink
Keyword(s):  
Solid Organ Transplantation ◽  
Myocardial Damage ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Solid Organ ◽  
Therapeutic Approaches ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Clinical Conditions ◽  
Ros Scavengers

Ischaemia/reperfusion (I/R) injury contributes to the pathogenesis of many common clinical conditions, including stroke, myocardial damage after percutaneous intervention for acute coronary artery occlusion, primary graft dysfunction after solid organ transplantation. The mechanisms that are responsible for I/R injury remain incompletely understood, but damage caused by reactive oxygen species (ROS) and reactive nitrogen species clearly is important. A number of therapeutic approaches, such as administration of ROS scavengers, are effective in animal models of I/R injury, but for the most part, translation of these findings into strategies that can clearly benefit patients has yet to be achieved.

Pyrrolidine dithiocarbamate protects the small bowel from warm ischaemia/reperfusion injury of the intestine: the role of haem oxygenase

2006 ◽  
Vol 111 (6) ◽  
pp. 373-380 ◽  
Author(s):  
Ismail H. Mallick ◽  
Marc C. Winslet ◽  
Alexander M. Seifalian
Keyword(s):  
Reperfusion Injury ◽  
Redox Status ◽  
Artery Occlusion ◽  
Zinc Protoporphyrin ◽  
Pyrrolidine Dithiocarbamate ◽  
Sprague Dawley ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Group I ◽  
Haem Oxygenase

IR (ischaemia/reperfusion) injury of the intestine occurs commonly during abdominal surgery. We have previously shown that PDTC (pyrrolidine dithiocarbamate), an HO-1 (haem oxygenase-1) donor, improves intestinal microvascular perfusion. In the present study, we have investigated the effects of PDTC on the intestinal microcirculation following IR (ischaemia/reperfusion) injury of the intestine. Male Sprague–Dawley rats (n=72) were randomly assigned to four groups (n=18/group): (i) sham-operated group, who underwent laparotomy without induction of IR of the intestine; (ii) IR group, who were subjected to 30 min of superior mesenteric artery occlusion and 2 h of reperfusion; (iii) PDTC+IR group, who received PDTC prior to IR; and (iv) ZnPP group, who received the HO-1 inhibitor ZnPP (zinc protoporphyrin) followed by procedures as in group (iii). The ileum was evaluated for changes in tissue cytochrome c oxidase redox status, RBC (red blood cell) dynamics and leucocyte–endothelial interactions. The expression of HO-1 in the ileal tissue was examined at the end of the reperfusion. PDTC significantly improved the intestinal tissue oxygenation, mucosal perfusion index and RBC velocity compared with the IR and ZnPP groups. PDTC also decreased the leucocyte–endothelial interactions (P<0.05 compared with the IR and ZnPP groups). PDTC induced the expression of HO-1, whereas ZnPP abolished this effect.

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