scholarly journals Inhibition of Brain Swelling after Ischemia-Reperfusion byβ-Adrenergic Antagonists: Correlation with Increased K+and Decreased Ca2+Concentrations in Extracellular Fluid

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Dan Song ◽  
Junnan Xu ◽  
Ting Du ◽  
Enzhi Yan ◽  
Leif Hertz ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Extracellular Fluid ◽  
Artery Occlusion ◽  
Cell Swelling ◽  
Cultured Astrocytes ◽  
High K ◽  
Ionic Changes ◽  
Adrenergic Antagonists ◽  
Cerebral Artery Occlusion ◽  
Adrenergic Activation

Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and byβ1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+concentration and by theβ-adrenergic agonist isoproterenol. Larger K+increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specificallyβ1-adrenergic pathways, indicating failure of K+-mediated, but notβ1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+concentration occurs in ischemia. Ca2+omission abolished K+uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, makingβ1-adrenergic activation the only stimulus and its inhibition effective against edema.

MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

2002 ◽  
Vol 283 (3) ◽  
pp. H1005-H1011 ◽  
Author(s):  
Katsuyoshi Shimizu ◽  
Zsombor Lacza ◽  
Nishadi Rajapakse ◽  
Takashi Horiguchi ◽  
James Snipes ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion Injury ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sham Treatment ◽  
Cerebral Artery Occlusion

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% ( n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% ( n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels ( n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Becca Ward ◽  
Mohammed Abdelsaid ◽  
Tianzheng Yu ◽  
Yisang Yoon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Proton Channel ◽  
Ros Generation ◽  
Vascular Integrity ◽  
Voltage Gated ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

scholarly journals The role of PI3K-mediated AMPA receptor changes in post-conditioning of propofol in brain protection

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Chenxu Wang ◽  
Ying Wei ◽  
Yuan Yuan ◽  
Yonghao Yu ◽  
Keliang Xie ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sham Operation ◽  
Short Term ◽  
Selective Antagonist ◽  
Cerebral Artery Occlusion

Abstract Background We aimed to study the role of amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) glutamate receptor 2 (GluR2) subunit trafficking, and activity changes in short-term neuroprotection provided by propofol post-conditioning. We also aimed to determine the role of phosphoinositide-3-kinase (PI3K) in the regulation of these processes. Methods Rats underwent 1 h of focal cerebral ischemia followed by 23 h of reperfusion were randomly divided into 6 groups (n = 36 per group): sham- operation (S), ischemia–reperfusion (IR), propofol (P group, propofol 20 mg/kg/h at the onset of reperfusion for 2 h after 60 min of occlusion), and LY294002 (PI3K non-selective antagonist) + sham (L + S, LY294002 of 1.5 mg/kg was infused 30 min before sham operation), LY294002+ ischemia–reperfusion (L + IR, LY294002 of 1.5 mg/kg was infused 30 min before middle cerebral artery occlusion), LY294002 + IR + propofol (L + P, LY294002 of 1.5 mg/kg was infused 30 min before middle cerebral artery occlusion and propofol 20 mg/kg/h at the onset of reperfusion for 2 h after 60 min of occlusion). Results Compared with group IR, rats in group P had significant lower neurologic defect scores and infarct volume. Additionally, consistent with enhanced expression of PI3K-AMPAR GluR2 subunit complex substances in ipsilateral hippocampus, GluR2 subunits showed increased levels in both the plasma and postsynaptic membranes of neurons, while pGluR2 expression was reduced in group P. Furthermore, LY294002, the PI3K non-selective antagonist, blocked those effects. Conclusion These observations demonstrated that propofol post-conditioning revealed acute neuroprotective role against transient MCAO in rats. The short-term neuroprotective effect was contributed by enhanced GluR2 subunits trafficking to membrane and postsynaptic membranes of neurons, as well as down-regulated the expression of pGluR2 in damaged hippocampus. Finally, the above-mentioned protective mechanism might be contributed by increased combination of PI3K to AMPAR GluR2 subunit, thus maintained the expression and activation of AMPAR GluR2 in the ipsilateral hippocampus.

scholarly journals Effects of Shaoyao-Gancao Decoction on Infarcted Cerebral Cortical Neurons: Suppression of the Inflammatory Response following Cerebral Ischemia-Reperfusion in a Rat Model

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Ying Zhang ◽  
Xinling Jia ◽  
Jian Yang ◽  
Qing Li ◽  
Guofeng Yan ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Tissue ◽  
Cortical Neurons ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Artery Occlusion ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Cortical Neurons ◽  
Staining Methods ◽  
Cerebral Artery Occlusion

The mechanisms by which Shaoyao-Gancao decoction (SGD) inhibits the production of inflammatory cytokines in serum and brain tissue after cerebral ischemia-reperfusion (CI-RP) in rats were investigated. A right middle cerebral artery occlusion was used to induce CI-RP after which the rats were divided into model (n=39), SGD (n=28), clopidogrel (n=25) and sham operated (n=34) groups. The Bederson scale was used to evaluate changes in behavioral indices. The levels of IL-1β, TNF-α, MCP-1, IL-10, RANTES, VEGF, and TGF-β1 in the serum and infarcted brain tissues were measured. Nissl body and immunohistochemical staining methods were used to detect biochemical changes in neurons, microglial cells, and astrocytes. Serum levels of VEGF, TNF-α, MCP-1, IL-1β, and IL-10 increased significantly 24 h after CI-RP. In brain tissue, levels of TNF-αand IL-1βsignificantly increased 24 h after CI-RP, whereas levels of TGF-β1 and MCP-1 were significantly higher 96 h after CI-RP (P<0.05). SGD or clopidogrel after CI-RP reduced TNF-αand IL-1βlevels in brain tissue and serum levels of MCP-1, IL-1β, and IL-10. SGD increased the number of NeuN-positive cells in infarcted brain tissue and reduced the number of IBA1-positive and GFAP-positive cells. The efficacy of SGD was significantly higher than that of clopidogrel.

scholarly journals Preparation, Characterization, Pharmacokinetics and Biodistribution of Baicalin-Loaded Liposome on Cerebral Ischemia-Reperfusion after i.v. Administration in Rats

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1747 ◽  
Author(s):  
Nan Li ◽  
Lingling Feng ◽  
Yujun Tan ◽  
Yan Xiang ◽  
Ruoqi Zhang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Zeta Potential ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

The dry root of Scutellaria baicalensis, has traditionally been applied in the treatment of cerebral ischemia in Chinese clinics. Baicalin (BA) is considered the key ingredient in it for the brain protection effects. The bioavailability of BA is very low because of its poor lipid and water solubility, which limits the therapeutic effects and clinical application. The aim of the present study was to develop a novel BA-loaded liposome (BA-LP) formulation to improve the drug lipophilicity and further to enhance the drug-concentration in the brain tissues. This study is also designed to investigate the pharmacokinetics of BA in the pathological conditions of stroke and evaluate the pharmacokinetic differences of BA caused by stroke after intravenous administration with BA and BA-LP. In this study, the novel BA-LP prepared in early stage were characterized by morphology, size, zeta potential, encapsulation rate and the in vitro release. The pharmacokinetics and biodistribution of BA and BA-LP were investigated by intravenous administration in rats with middle cerebral artery occlusion (MCAO) model and normal group respectively. BA-LP had a mean particle size of 160–190 nm, zeta potential of −5.7 mV, and encapsulation efficiency of 42 ± 1%. The BA-LP showed a sustained-release behavior, the in vitro drug-release kinetic model of BA-LP fit well with the biphasic dynamic model equation: Q = 1 − (60.12e0.56t − 59.08e0.0014t). Pharmacokinetic behavior in MCAO rats is not consistent with that of normal rats. The middle cerebral artery occlusion rats got higher Cmax and AUC0–t, which were about 1.5–2 times to normal rats both in BA and liposome groups. In addition, it got especially higher distribution in brain, while BA were not detected in brain tissues on normal rats. The Cmax and AUC0–t values were significantly greater with liposome than BA on both normal and MCAO rats. The tissue distribution behavior was significantly altered in the case of liposome administrated in comparison with BA, which the concentrations in the heart, liver, spleen, lungs and brain were all increased after administrated liposome, but decreased in kidneys. The TI values showed that the target of liposome was improved especially to heart, spleen and brain, and the brain’s target was higher in striatum and cerebellum. In conclusion, BA-LP might be a potential drug delivery system to improve the therapeutic efficacy of BA. In addition, these results also suggest that the pathological damages of ischemia-reperfusion have a significant impact on the pharmacokinetic traits of BA.

scholarly journals Hemorrhagic Transformation and Microvascular Integrity during Focal Cerebral Ischemia/Reperfusion

1996 ◽  
Vol 16 (6) ◽  
pp. 1373-1378 ◽  
Author(s):  
Gerhard F. Hamann ◽  
Yasushi Okada ◽  
Gregory J. del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Time Dependent ◽  
Adolescent Male ◽  
Blood Components ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Artery Occlusion

Hemorrhagic transformation after cerebral ischemia is a well known clinical concern. The frequency of intact basal lamina (BL), identified by laminin antigen, in hemorrhagic and nonhemorrhagic zones after middle cerebral artery occlusion (MCA:O) and 3-h MCA:O with reperfusion in adolescent male baboons was assessed. Parenchymal hemoglobin was not detected prior to 24-h reperfusion. A significant decrease in the density of laminin (BL) in hemorrhagic zones (6.2 ± 2.4) compared with nonhemorrhagic ischemic zones (10.5 ± 2.4) (p < 0.05) and nonischemic basal ganglia (17.0 ± 2.7) (p < 0.01) was observed. Time-dependent changes in BL integrity appear linked to the extravasation of blood components.

scholarly journals Endothelin Levels Increase in Rat Focal and Global Ischemia

1994 ◽  
Vol 14 (2) ◽  
pp. 337-342 ◽  
Author(s):  
F. C. Barone ◽  
M. Y.-T. Globus ◽  
W. J. Price ◽  
R. F. White ◽  
B. L. Storer ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Vascular Function ◽  
Tissue Injury ◽  
Extracellular Fluid ◽  
Artery Occlusion ◽  
Global Ischemia ◽  
Vessel Occlusion ◽  
Cerebral Artery Occlusion

Endothelin-1, a peptide exhibiting extremely potent cerebral vasoactive properties, is elevated in the cerebrospinal fluid after hemorrhagic stroke and implicated in cerebral vasospasm. The purpose of this study was to determine changes in endothelin in ischemic rat brain by assaying endothelin tissue and extracellular levels. Immunoreactive endothelin levels in ischemic brain tissue following permanent or transient focal ischemia produced by middle cerebral artery occlusion was determined. In addition, endothelin levels were assayed in striatal extracellular fluid collected by microdialysis before, during, and after global ischemia produced by two-vessel occlusion combined with hypotension. Twenty-four hours after the onset of permanent middle cerebral artery occlusion, the ischemic cortex level (0.58 ± 0.27 fmol/mg protein) of immunoreactive endothelin was significantly (p < 0.05) increased, by 100%, over that in the nonischemic cortex (0.29 ± 0.13 fmol/mg protein). Transient artery occlusion for 80 min with reperfusion for 24 h also resulted in a similar significant (p < 0.05) increase, 78%, in immunoreactive endothelin in the ischemic zone. Global forebrain ischemia significantly (p < 0.05) increased the level of immunoreactive endothelin collected in striatal microdialysis perfusate, from a basal level of 14.6 ± 6.7 to 26.5 ± 7.7 and 26.2 ± 7.4 amol/μl (i.e. 82 and 79%). These changes reflect the relative picomolar extracellular concentration increases during ischemia and following reperfusion, respectively. This is the first demonstration of elevated levels of endothelin in focal ischemic tissue and in the extracellular fluid in global ischemia and suggests a role of the peptide in ischemic and postischemic derangements of cerebral vascular function and tissue injury.

scholarly journals The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke

2016 ◽  
Vol 36 (12) ◽  
pp. 2146-2161 ◽  
Author(s):  
Yi-Je Chen ◽  
Hai M Nguyen ◽  
Izumi Maezawa ◽  
Eva M Grössinger ◽  
April L Garing ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Adult Brain ◽  
Activated Microglia ◽  
Pharmacological Target ◽  
Cerebral Artery Occlusion

Activated microglia/macrophages significantly contribute to the secondary inflammatory damage in ischemic stroke. Cultured neonatal microglia express the K+ channels Kv1.3 and KCa3.1, both of which have been reported to be involved in microglia-mediated neuronal killing, oxidative burst and cytokine production. However, it is questionable whether neonatal cultures accurately reflect the K+ channel expression of activated microglia in the adult brain. We here subjected mice to middle cerebral artery occlusion with eight days of reperfusion and patch-clamped acutely isolated microglia/macrophages. Microglia from the infarcted area exhibited higher densities of K+ currents with the biophysical and pharmacological properties of Kv1.3, KCa3.1 and Kir2.1 than microglia from non-infarcted control brains. Similarly, immunohistochemistry on human infarcts showed strong Kv1.3 and KCa3.1 immunoreactivity on activated microglia/macrophages. We next investigated the effect of genetic deletion and pharmacological blockade of KCa3.1 in reversible middle cerebral artery occlusion. KCa3.1 −/− mice and wild-type mice treated with the KCa3.1 blocker TRAM-34 exhibited significantly smaller infarct areas on day-8 after middle cerebral artery occlusion and improved neurological deficit. Both manipulations reduced microglia/macrophage activation and brain cytokine levels. Our findings suggest KCa3.1 as a pharmacological target for ischemic stroke. Of potential, clinical relevance is that KCa3.1 blockade is still effective when initiated 12 h after the insult.

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