Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke

2006 ◽  
Vol 291 (5) ◽  
pp. H2210-H2215 ◽  
Author(s):  
Hua Hong ◽  
Jin-Sheng Zeng ◽  
David L. Kreulen ◽  
David I. Kaufman ◽  
Alex F. Chen
Keyword(s):  
Ischemic Stroke ◽  
Nadph Oxidase ◽  
Cerebral Infarction ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Small Gtpase ◽  
Sprague Dawley ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Core ◽  
Transient Focal Ischemia

Statins have recently been shown to exert neuronal protection in ischemic stroke. Reactive oxygen species, specifically superoxide formed during the early phase of reperfusion, augment neuronal injury. NADPH oxidase is a key enzyme for superoxide production. The present study tested the hypothesis that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia. Transient focal ischemia was created in halothane-anesthetized adult male Sprague-Dawley rats (250–300 g) by middle cerebral artery occlusion (MCAO). Atorvastatin (Lipitor, 10 mg/kg sc) was administered three times before MCAO. Infarct volume was measured by triphenyltetrazolium chloride staining. NADPH oxidase enzymatic activity and superoxide levels were quantified in the ischemic core and penumbral regions by lucigenin (5 μM)-enhanced chemiluminescence. Expression of NADPH oxidase membrane subunit gp91phox and membrane-translocated subunit p47phox and small GTPase Rac-1 was analyzed by Western blot. NADPH oxidase activity and superoxide levels increased after reperfusion and peaked within 2 h of reperfusion in the penumbra, but not in the ischemic core, in MCAO rats. Atorvastatin pretreatment prevented these increases, blunted expression of membrane subunit gp91phox, and prevented translocation of cytoplasmic subunit p47phox to the membrane in the penumbra 2 h after reperfusion. Consequently, cerebral infarct volume was significantly reduced in atorvastatin-treated compared with nontreated MCAO rats 24 h after reperfusion. These results indicate that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia.

Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia

2000 ◽  
Vol 92 (4) ◽  
pp. 646-651 ◽  
Author(s):  
Ramin Rak ◽  
Daniel L. Chao ◽  
Ryszard M. Pluta ◽  
James B. Mitchell ◽  
Edward H. Oldfield ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Rat Model ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Triphenyltetrazolium Chloride ◽  
Content Type ◽  
Physiological Variables ◽  
Transient Focal Ischemia ◽  
Fine Print

Object. The use of thrombolytic agents in the treatment of stroke has yielded surprisingly modest success, possibly because of reperfusion injury mediated by reactive oxygen species (ROS). Therefore, scavenging ROS may be of therapeutic value in the treatment of stroke. Nitroxides are low-weight superoxide dismutase mimics, which allows them to act as cell-permeable antioxidants. In this study the nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (Tempol) is investigated to determine its ability to reduce reperfusion injury.Methods. Male Sprague—Dawley rats weighing between 280 g and 350 g underwent middle cerebral artery occlusion with an intraluminal suture for 60 minutes. Regional cerebral blood flow, blood pressure, cerebral temperature, and rectal temperature were monitored during the procedure. After reperfusion, the animals were randomized to groups receiving blinded intravenous administration of either Tempol (10 mg/kg; eight animals) or vehicle (eight animals) over the first 20 minutes of reperfusion (Study I). In a second study to determine dose dependency, animals were randomized to groups receiving Tempol (20 mg/kg; eight animals), low-dose Tempol (5 mg/kg; eight animals), or vehicle (eight animals; Study II). The rats were killed after 4 hours of reperfusion, and brain sections were stained with 2,3,5 triphenyltetrazolium chloride. Infarct volumes were measured using digital imaging.Animals receiving Tempol had significantly reduced infarct volumes at doses of 20 mg/kg and 10 mg/kg compared with controls (49.01 ± 18.22% reduction [p = 0.003] and 47.47 ± 34.57 [p = 0.02], respectively). No significant differences in the physiological variables measured were observed between groups.Conclusions. Tempol provides significant neuroprotection after reperfusion in a rat model of transient focal ischemia. These results support the importance of ROS in reperfusion injury and encourage further study of this molecule as a therapeutic agent following thrombolysis.

scholarly journals Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

2010 ◽  
Vol 31 (4) ◽  
pp. 1107-1118 ◽  
Author(s):  
Slavianka G Moyanova ◽  
Federica Mastroiacovo ◽  
Lidia V Kortenska ◽  
Rumiana G Mitreva ◽  
Erminia Fardone ◽  
...  
Keyword(s):  
Brain Damage ◽  
Metabotropic Glutamate Receptors ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Protective Role ◽  
Ischemic Brain Damage ◽  
Systemic Injection ◽  
Ischemic Brain ◽  
Metabotropic Glutamate ◽  
Transient Focal Ischemia

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

scholarly journals Non-Invasive Multimodality Imaging Directly Shows TRPM4 Inhibition Ameliorates Stroke Reperfusion Injury

2018 ◽  
Vol 10 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Bo Chen ◽  
Gandi Ng ◽  
Yahui Gao ◽  
See Wee Low ◽  
Edwin Sandanaraj ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Transient Receptor Potential ◽  
Multimodality Imaging ◽  
Infarct Volume ◽  
Triphenyltetrazolium Chloride ◽  
In Vivo Evaluation ◽  
Transient Receptor Potential Melastatin ◽  
Imaging Results ◽  
Trpm4 Channel

Abstract The transient receptor potential melastatin 4 (TRPM4) channel has been suggested to play a key role in the treatment of ischemic stroke. However, in vivo evaluation of TRPM4 channel, in particular by direct channel suppression, is lacking. In this study, we used multimodal imaging to assess edema formation and quantify the amount of metabolically functional brain salvaged after a rat model of stroke reperfusion. TRPM4 upregulation in endothelium emerges as early as 2 h post-stroke induction. Expression of TRPM4 channel was suppressed directly in vivo by treatment with siRNA; scrambled siRNA was used as a control. T2-weighted MRI suggests that TRPM4 inhibition successfully reduces edema by 30% and concomitantly salvages functionally active brain, measured by 18F-FDG-PET. These in vivo imaging results correlate well with post-mortem 2,3,5-triphenyltetrazolium chloride (TTC) staining which exhibits a 34.9% reduction in infarct volume after siRNA treatment. Furthermore, in a permanent stroke model, large areas of brain tissue displayed both edema and significant reductions in metabolic activity which was not shown in transient models with or without TRPM4 inhibition, indicating that tissue salvaged by TRPM4 inhibition during stroke reperfusion may survive. Evans Blue extravasation and hemoglobin quantification in the ipsilateral hemisphere were greatly reduced, suggesting that TRPM4 inhibition can improve BBB integrity after ischemic stroke reperfusion. Our results support the use of TRPM4 blocker for early stroke reperfusion.

Abstract 16251: Neuroprotection by Near-infrared Light in a Rat Stroke Model

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Aqeela Afzal ◽  
Janis T Eells ◽  
Michele Salzman ◽  
Matthias Riess
Keyword(s):  
Carotid Artery ◽  
Near Infrared ◽  
Apoptotic Cell ◽  
Infarct Volume ◽  
Infrared Light ◽  
Sprague Dawley ◽  
Triphenyltetrazolium Chloride ◽  
Locomotor Function ◽  
Post Stroke ◽  
Intravenous Tissue Plasminogen Activator

Introduction: Intravenous tissue Plasminogen Activator (tPA) is the only FDA approved pharmacological therapy for stroke. However, tPA can only be administered within 4.5 hours post stroke, and intracerebral hemorrhage remains a serious complication, severely limiting the use of tPA. Photobiomodulation (PBM) stimulates healing and repair of injuries by lowering swelling and inflammation. Targeting mitochondria, PBM results in modulation of reactive oxygen species, increased ATP production, activation of transcriptional factors, increased nitric oxide release and prevention of apoptotic cell death. Studies using ~809 nm light-emitting diodes (LED) have reported mixed results in animals and human clinical trials. Hypothesis: The use of 670 nm LED PBM rescues locomotor function in a rat model of ischemic stroke. Methods: A heat blunted nylon monofilament suture was introduced into the left common carotid artery and fed through the internal carotid artery into the middle cerebral artery of anesthetized male Sprague Dawley rats. Occlusion was maintained for 60 min and reperfusion achieved by removal of the filament. A 670 nm LED was used directly on top of the skull. One 90 sec treatment with a hand-held WARP10 device (Quantum Devices, Barneveld, WI, USA) delivered a power density of 50 mW/cm2 and a dose of 4 J/cm2. The light was administered at reperfusion, 2 hrs post and 24 hrs post reperfusion. Behavior was recorded in a Phenotyper cage pre and 24 hrs post stroke and analyzed using specialized software. Rats were euthanized 24 hrs post stroke, and their brains removed for infarct volume assessment by triphenyltetrazolium chloride staining. Statistics: ANOVA with Newman-Keuls post hoc test. Data are mean ± SEM, significance accepted at p < 0.05. Results: Rats treated with 670 nm LED PBM had significantly reduced infarct volumes compared to stroke alone (64±16% vs 83±14%). In addition, LED-treated rats showed better recovery of locomotor function: distance moved (sham control 3133±291, stroke 704±254, stroke+LED 3693±1953 cm). Conclusions: Our data suggest a potential neuroprotective role of 670 nm LED PBM in a rat experimental model of stroke.

scholarly journals Modulation by Nitric Oxide of Cerebral Neutrophil Accumulation after Transient Focal Ischemia in Rats

2000 ◽  
Vol 20 (5) ◽  
pp. 812-819 ◽  
Author(s):  
Sophie Batteur-Parmentier ◽  
Isabelle Margaill ◽  
Michel Plotkine
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Focal Ischemia ◽  
Left Middle Cerebral Artery ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Transient Focal Ischemia

A beneficial role of nitric oxide (NO) after cerebral ischemia has been previously attributed to its vascular effects. Recent data indicate a regulatory role for NO in initial leukocyte-endothelial interactions in the cerebral microcirculation under basal and ischemic conditions. In this study, the authors tested the hypothesis that endogenous NO production during and/or after transient focal cerebral ischemia can also be neuroprotective by limiting the process of neutrophil infiltration and its deleterious consequences. Male Sprague-Dawley rats were subjected to 2 hours occlusion of the left middle cerebral artery and the left common carotid artery. The effect of NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, intraperitoneally), an NO synthase inhibitor, was examined at 48 hours after ischemia on both infarct size and myeloperoxidase activity, an index of neutrophil infiltration. L-NAME given 5 minutes after the onset of ischemia increased the cortical infarct volume by 34% and increased cortical myeloperoxidase activity by 60%, whereas administration of L-NAME at 1, 7, and 22 hours of reperfusion had no effect. Such exacerbations of infarction and myeloperoxidase activity produced when L-NAME was given 5 minutes after the onset of ischemia were not observed in rats rendered neutropenic by vinblastine. These results suggest that after transient focal ischemia, early NO production exerts a neuroprotective effect by modulating neutrophil infiltration.

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