scholarly journals Perioperative Dexmedetomidine attenuates brain ischemia reperfusion injury possibly via up-regulation of astrocyte Connexin 43

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaoyang Zheng ◽  
Xiaoying Cai ◽  
Fang Ye ◽  
Ying Li ◽  
Qin Wang ◽  
...  
Keyword(s):  
Brain Ischemia ◽  
Connexin 43 ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Brain Lesions ◽  
Neurological Injury ◽  
Inflammatory Factors ◽  
Tnf Α ◽  
Gsk 3Β ◽  
Cerebral Arterial Occlusion

Abstract Background Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them. Methods Adult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation. Results Dexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia (P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine (P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43. Conclusions Perioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.

Postnatal shifts in ischemic tolerance and cell survival signaling in murine myocardium

2013 ◽  
Vol 305 (10) ◽  
pp. R1171-R1181 ◽  
Author(s):  
Norman Y. Liaw ◽  
Louise See Hoe ◽  
Freya L. Sheeran ◽  
Jason N. Peart ◽  
John P. Headrick ◽  
...  
Keyword(s):  
Cell Survival ◽  
Connexin 43 ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
High Expression ◽  
Hsp27 Phosphorylation ◽  
Myocardial Stress ◽  
Survival Signaling ◽  
Gsk 3Β

The immature heart is known to be resistant to ischemia-reperfusion (I/R) injury; however, key proteins engaged in phospho-dependent signaling pathways crucial to cell survival are not yet defined. Our goal was to determine the postnatal changes in myocardial tolerance to I/R, including baseline expression of key proteins governing I/R tolerance and their phosphorylation during I/R. Hearts from male C57Bl/6 mice (neonates, 2, 4, 8, and 12 wk of age, n = 6/group) were assayed for survival signaling/effectors [Akt, p38MAPK, glycogen synthase kinase-3β (GSK-3β), heat shock protein 27 (HSP27), connexin-43, hypoxia-inducible factor-1α (HIF-1α), and caveolin-3] and regulators of apoptosis (Bax and Bcl-2) and autophagy (LC3B, Parkin, and Beclin1). The effect of I/R on ventricular function was measured in isolated perfused hearts from immature (4 wk) and adult (12 wk) mice. The neonatal myocardium exhibits a large pool of inactive Akt; high phospho-activation of p38MAPK, HSP27 and connexin-43; phospho-inhibition of GSK-3β; and high expression of caveolin-3, HIF-1α, LC3B, Beclin1, Bax, and Bcl-2. Immature hearts sustained less dysfunction and infarction following I/R than adults. Emergence of I/R intolerance in adult vs. immature hearts was associated with complex proteomic changes: decreased expression of Akt, Bax, and Bcl-2; increased GSK-3β, connexin-43, HIF-1α, LC3B, and Bax:Bcl-2; enhanced postischemic HIF-1α, caveolin-3, Bax, and Bcl-2; and greater postischemic GSK-3β and HSP27 phosphorylation. Neonatal myocardial stress resistance reflects high expression of prosurvival and autophagy proteins and apoptotic regulators. Notably, there is high phosphorylation of GSK-3β, p38MAPK, and HSP27 and low phosphorylation of Akt (high Akt “reserve”). Subsequent maturation-related reductions in I/R tolerance are associated with reductions in Akt, Bcl-2, LC3B, and Beclin1, despite increased expression and reduced phospho-inhibition of GSK-3β.

scholarly journals Post-treatment curcumin reduced ischemia–reperfusion-induced pulmonary injury via the Notch2/Hes-1 pathway

2019 ◽  
Vol 48 (4) ◽  
pp. 030006051989243
Author(s):  
HaiZou bo ◽  
XiaoSun feng
Keyword(s):  
Lung Injury ◽  
Mrna Expression ◽  
Ischemia Reperfusion ◽  
Limb Ischemia ◽  
Post Treatment ◽  
Inflammatory Factors ◽  
Pulmonary Injury ◽  
Pathological Changes ◽  
Sprague Dawley ◽  
Tnf Α

Objective To investigate the influence of curcumin on the Notch2/Hes-1 pathway after pulmonary injury induction via limb ischemia–reperfusion (I/R). Methods Adult male Sprague–Dawley rats were randomly divided into four groups (n = 30 each): sham, I/R, curcumin post-treatment (I/R+Cur), and inhibitor (I/R+DAPT). Hind-limb ischemia was induced for 4 hours, followed by reperfusion for 4 hours. After ischemia, curcumin (200 mg/kg) or DAPT (0.5 µm) was injected intraperitoneally in the I/R+Cur or I/R+DAPT group, respectively. PaO2 was examined after 4 hours of reperfusion. Pathological changes in the lung and the apoptotic index (AI) were examined. Lung malondialdehyde (MDA), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β levels, the wet/dry (W/D) ratio, semi-quantitative score of lung injury (SSLI), and Notch2 protein and Hes-1 mRNA expression were also examined. Results In the I/R group, inflammatory changes were observed, AI increased, and MDA, SSLI, W/D, TNF-α, IL-1β, Notch2, and Hes1-mRNA expression increased, while PaO2 decreased compared with the Sham group. Pathological changes in the I/R+Cur group were reversed. All indexes in the I/R+DAPT and I/R+Cur group were similar. Conclusion Curcumin post-treatment reduced I/R-induced lung injury in rats. Its mechanism may be related to the inhibition of Notch2/Hes-1 signaling pathway and the release of inflammatory factors.

scholarly journals The neuroprotective effect of pretreatment with carbon dots from Crinis Carbonisatus (carbonized human hair) against cerebral ischemia reperfusion injury

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Zhang ◽  
Suna Wang ◽  
Fang Lu ◽  
Meiling Zhang ◽  
Hui Kong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Carbon Dots ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Tnf Α

Abstract Background Cerebral infarction and cerebral hemorrhage, also known as “stroke”, is one of the leading cause of death. At present, there is no real specific medicine for stroke. Crinis Carbonisatus (named Xue-yu-tan in Chinese), produced from carbonized hair of healthy human, and has been widely applied to relieve pain and treat epilepsy, stroke and other diseases in China for thousands of years. Results In this work, a new species of carbon dots derived from Crinis Carbonisatus (CrCi-CDs) were separated and identified. And the neuroprotective effect of carbon dots from CrCi were evaluated using the middle cerebral artery occlusion (MCAO) model. Neurological deficit score and infarction volume was assessed, evans blue content of ischemic hemispheres was measured, the concentrations of inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) in the cortex were measured, and the levels of neurotransmitters in the brain were determined. Preconditioning of CrCi-CDs significantly reduced ischemic lesion volume and blood–brain-barrier (BBB) permeability, improved neurologic deficits, decreased the level of TNF-α and IL-6 in MCAO rats, inhibited excitatory neurotransmitters aspartate (Asp) and glutamate (Glu), and increased the level of 5-hydroxytryptamine (5-HT). The RNA-Sequencing results reveal that further potential mechanisms behind the activities may be related to the anti-inflammation effects and inhibition of neuroexcitatory toxicity. Conclusion CrCi-CDs performs neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms may correlate with its anti-inflammatory action, which suggested that CrCi-CDs have potential value in clinical therapy on the acute apoplexy cases in combination with thrombolytic drugs. Graphic abstract

scholarly journals TNF-α Induces Neutrophil Apoptosis Delay and Promotes Intestinal Ischemia-Reperfusion-Induced Lung Injury through Activating JNK/FoxO3a Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Daili Chen ◽  
Chaojin Chen ◽  
Xue Xiao ◽  
Ziyan Huang ◽  
Xiaolei Huang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Causative Factors ◽  
Tnf Α ◽  
Intestinal Ischemia Reperfusion ◽  
Injury Status

Background. Intestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury. Methods. A mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor-α (TNF-α) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured in vitro and then stimulated by TNF-α to mimic in vivo inflammatory stimuli; this TNF-α stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated in vivo by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor. Results. IIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF-α plasma level showing the most pronounced increase. Inhibition of TNF-α led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. In vitro knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF-α-induced PMN apoptosis. Further in vivo experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury. Conclusion. TNF-α activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.

scholarly journals Postconditioning with Isoflurane Reduced Ischemia-induced Brain Injury in Rats

2008 ◽  
Vol 108 (6) ◽  
pp. 1055-1062 ◽  
Author(s):  
Jeong Jin Lee ◽  
Liaoliao Li ◽  
Hae-Hyuk Jung ◽  
Zhiyi Zuo
Keyword(s):  
Potassium Channel ◽  
Brain Ischemia ◽  
Adult Male ◽  
Channel Blocker ◽  
Brain Slices ◽  
Arterial Occlusion ◽  
Sprague Dawley ◽  
Potassium Channel Blocker ◽  
Sprague Dawley Rats ◽  
Cerebral Arterial Occlusion

Background Preexposure of brain to isoflurane, a commonly used anesthetic, induces ischemic tolerance. This phenomenon is called isoflurane preconditioning. However, it is not known whether isoflurane application after ischemia provides neuroprotection. Methods Corticostriatal slices (400 microm) freshly prepared from adult male Sprague-Dawley rats were subjected to a 15-min oxygen-glucose deprivation (OGD; to simulate ischemia in vitro). Isoflurane was applied after OGD. Brain slices were harvested 2 h after OGD for measuring 2,3,5-triphenyltetrazolium chloride (TTC) conversion to quantify cell injury. Adult male Sprague-Dawley rats were also subjected to middle cerebral arterial occlusion for 90 min and then treated with or without 2% isoflurane for 60 min started at the onset of reperfusion. The infarct volumes, neurologic deficit scores, and performance on rotarod were evaluated at 24 h after the onset of reperfusion. Results Isoflurane applied immediately after the 15-min OGD for 30 min dose-dependently reversed the OGD-induced decrease of TTC conversion. The TTC conversion was 34 +/- 16% and 58 +/- 28% of the control, respectively, for OGD alone and OGD plus 2% isoflurane (P &lt; 0.05, n = 12). Application of 2% isoflurane for 30 min started at 10 min after the OGD also reduced the OGD-decreased TTC conversion. The presence of 0.3 microm glibenclamide, a general adenosine 5'-triphosphate-sensitive potassium channel blocker, or 500 microm 5-hydroxydecanoic acid, a mitochondrial adenosine 5'-triphosphate-sensitive potassium channel blocker, during the application of 2% isoflurane abolished the isoflurane preservation of TTC conversion. Application of isoflurane during reperfusion also improved neurologic outcome after brain ischemia. Conclusions The results suggest that isoflurane administrated after OGD or brain ischemia provides neuroprotection. Mitochondrial adenosine 5'-triphosphate-sensitive potassium channels may be involved in this protection.

ADAMTS13 Gene Deletion Aggravates Ischemic Brain Damage

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 260-260 ◽  
Author(s):  
Kenji Nishio ◽  
Masayuki Fujioka ◽  
Kazuhide Hayakawa ◽  
Kenichi Mishima ◽  
Michihiro Fujiwara ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Neurological Deficits ◽  
Doppler Flowmetry ◽  
Adamts13 Deficiency ◽  
Cerebral Arterial Occlusion ◽  
The Brain

Abstract Background: The proteolytic activity of human ADAMTS13 regulates the size of von Willebrand factor (VWF) multimers, controlling excessive platelet aggregation and preventing microvascular thrombus formation. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP) and patients with TTP often have neurological deficits such as stupor or coma. Therefore, ADAMTS13 appears necessary for vascular homeostasis in the brain and may also influence the response to brain injury during ischemic stroke. Method and Result: We investigated the role of ADAMTS13 in a mouse middle cerebral arterial occlusion (MCAO) model of ischemia-reperfusion injury in the brain. We compared 24 wild type mice (WT) and 24 ADAMTS13 gene deleted mice (KO), which are healthy and fertile. All mice were males 6–8 weeks of age. Investigators were blinded to the genotype until all analyses were finished. We applied MCAO for 30 minutes followed by 23.5 hours of reperfusion. The cerebral blood flow (CBF) around the cortex of the ischemic region was measured by laser Doppler flowmetry for 60 minutes after MCAO. In both WT and KO mice, the CBF decreased to less than 20% of baseline during MCAO and returned to normal immediately after reperfusion. However, during the subsequent 30 min the CBF decreased to 34.6±5.8% of baseline for KO mice compared to 83.2±6.8% of baseline for WT mice (P &lt; 0.01) and remained significantly decreased at 24 hours, suggesting that ADAMTS13 deficiency promotes thrombosis after reperfusion injury. The infarction volumes of the brain were determined from the area not stained by 2,3,5,-triphenyltetrazolium chloride (TTC) 24 hours after MCAO. KO mice had significantly increased volume of brain infarction compared with WT (31.0±6.5mm3 vs 11.4±1.9 mm3, P &lt; 0.01). The degree of post-ischemic inflammation was estimated by Western blotting of plasma HMGB1 (high-mobility group box1) 24 hours after MCAO. Plasma HMGB1 was increased to 34.4 ± 5.3 ng/ml in KO mice, compared to 19.6 ± 3.5 ng/ml in WT mice (P &lt; 0.05). The KO and WT mice did not differ during the MCAO procedure in body temperature, survival (80% vs 85%) at 24 hours, prothrombin time, arterial pH, pO2 or pCO2. Conclusion: ADAMTS13 deficiency aggravates the extent of persistent brain ischemia, infarct volume and inflammatory response after brief MCAO. Therefore, ADAMTS13 plays a neuroprotective role against ischemia-reperfusion injury.

scholarly journals Inhibition of Tumor Necrosis Factor and Amelioration of Brain Infarction in Mice

1997 ◽  
Vol 17 (2) ◽  
pp. 229-232 ◽  
Author(s):  
Hiroshi Nawashiro ◽  
David Martin ◽  
John M. Hallenbeck
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Brain Infarction ◽  
Arterial Occlusion ◽  
Type I ◽  
Tnf Α ◽  
Cerebral Arterial Occlusion ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF- α) is expressed in the ischemic brain; however, its precise role is not fully understood. We studied the effect of the dimeric form of the type I soluble TNF receptor linked to polyethylene glycol (TNFbp) on focal cerebral ischemia in mice using a permanent middle cerebral arterial occlusion (MCAO) model. TNFbp was applied topically, intravenously, or intraperitoneally. TNFbp binds and inhibits TNF- α. The volume of cortical ischemic lesions was measured by means of 2,3,5-triphenyltetrazolium chloride 24 h after MCAO. TNFbp produced a significant reduction in the cortical infarct volume of vehicle-treated animals ( p < 0.001). The reduction in the volume of brain damage was 26% in animals that received 3 mg/kg of TNFbp topically. Further analysis of TNF- α inhibition following acute brain ischemia is indicated.

Abstract P603: Lifetime Increase In Cerebral Angiotensin-(1-7) Induces Neuroprotection In A Model Of Brain Ischemia And Reperfusion

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Lucas M Kangussu ◽  
Ana F Almeida-Santos ◽  
Michael Bader ◽  
Andre R Massensini ◽  
Robson A Santos ◽  
...  
Keyword(s):  
Brain Ischemia ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Global Cerebral Ischemia ◽  
Transgenic Rat ◽  
Blue Dye ◽  
Ischemia And Reperfusion ◽  
Sprague Dawley ◽  
Neurological Score ◽  
Tnf Α

Recent studies showed that angiotensin-(1-7) [Ang-(1-7)] has cerebroprotective actions in ischemic and hemorrhagic stroke. Here we tested the hypothesis that transgenic rat (TGR-7371), which overexpress Ang-(1-7) in the brain, would exhibit neuroprotection in a model of brain ischemia/reperfusion by bilateral common carotid arteries occlusion (BCCAo). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed 7 days after transient (25 min) BCCAo in TGR-7371 and Sprague-Dawley (SD) rats. The integrity of the blood-brain barrier (BBB) was assessed by the degree of extravasation of Evans blue dye (EB) intravenously injected and expressed as μg/100 mg of tissue. Cytokine levels were quantified in the whole brain through Elisa assay and expressed as pg/100 mg of tissue. Neurological deficits, such as ptosis palpebral, walking in circles, and/or ataxia, were observed in both SD-BCCAo and TGR-BCCAo, contrasting to sham-operated groups. However, TGR-BCCAo showed a significant lower neurological score and latency in BAT when compared with SD-BCCAo. SD-BCCAo showed greater extravasation of EB (13.5 ± 2; n=4) than sham group (2.4 ± 0.07; n=4). TGR-BCCAo had a significant reduced amount of EB (8 ± 1.5; n=5), indicating attenuation in loss of integrity of the BBB. As expected, levels of pro-inflammatory cytokines were increased in SD-BCCAo (IL-1β: 225 ± 16, IL-6: 290 ± 24, TNF-α: 404 ± 39) when compared to SD control rats (IL-1β: 24 ± 1, IL-6: 24 ± 3, TNF-α: 50 ± 4). Interestingly, TGR-BCCAo presented lower levels of cytokines (IL-1β: 125 ± 15; IL-6: 205 ± 27; TNF-α: 286 ± 6) when compared to SD-BCCAo. Levels of IL-10 were higher in SD-BCCAo than in SD control (112 ± 5 vs 29 ± 5) and even higher in TGR-BCCAo (172 ± 27). The present study shows that lifetime increase in cerebral expression of Ang-(1-7) induces neuroprotection in experimental global cerebral ischemia and reperfusion.

scholarly journals Lung injury in brain ischemia/reperfusion is exacerbated by mechanical ventilation with moderate tidal volume in rats

2020 ◽  
Vol 319 (2) ◽  
pp. R133-R141
Author(s):  
Maryam Naseh ◽  
Amirreza Dehghanian ◽  
Sara Keshtgar ◽  
Farzaneh Ketabchi
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Brain Ischemia ◽  
Sham Group ◽  
Ischemia Reperfusion ◽  
Arterial Blood ◽  
Pulmonary Capillary ◽  
Partial Pressures ◽  
Tnf Α

Ischemic stroke is one of the most frequent causes of injury in the central nervous system which may lead to multiorgan dysfunction, including in the lung. The aim of this study was to investigate whether brain ischemia/reperfusion with or without mechanical ventilation leads to lung injury. Male Sprague-Dawley rats were assigned to four groups: Sham, 1-h brain ischemia (MCAO)/24-h reperfusion (I/R), mechanical ventilation with moderate tidal volume (MTV), and I/R+MTV. The pulmonary capillary permeability ( Kfc) was measured in the isolated perfused lung. Mean arterial blood pressure (MAP), heart rate (HR), blood-gas variables, histopathological parameters, lung glutathione peroxidase, and TNF-α were measured. Kfc in the I/R, MTV, and I/R+MTV groups were higher than that in the Sham group. In the I/R, MTV, and I/R+MTV groups, arterial partial pressures of oxygen and the arterial partial pressure of oxygen/fraction of inspired oxygen ratios were lower, whereas arterial partial pressures of carbon dioxide were higher than those in the Sham group. The histopathological score in the I/R group was more than that in the Sham group, and in the MTV and I/R+MTV groups were higher than those in the Sham and I/R groups. Furthermore, there were stepwise rises in TNF-α in the I/R, MTV, and I/R+MTV groups, respectively. There was no significant difference in MAP between groups. However, HR in the MTV group was higher than that in the Sham group. Brain ischemia/reperfusion leads to pulmonary capillary endothelial damage and the impairment of gas exchange in the alveolar-capillary barrier, which is exacerbated by mechanical ventilation with moderate tidal volume partially linked to inflammatory reactions.

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