scholarly journals Cilostazol Ameliorates Warfarin-Induced Hemorrhagic Transformation After Cerebral Ischemia in Mice

Stroke ◽  
2013 ◽  
Vol 44 (10) ◽  
pp. 2862-2868 ◽  
Author(s):  
Akira Kitashoji ◽  
Yusuke Egashira ◽  
Keisuke Mishiro ◽  
Yukiya Suzuki ◽  
Hideki Ito ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Survival Rate ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Vascular Endothelial ◽  
Cerebral Artery Occlusion

Background and Purpose— Although long-term treatment with the oral anticoagulant warfarin is widely used to prevent cardioembolic ischemic stroke, it has been reported that warfarin can exacerbate hemorrhagic transformation (HT) after cerebral ischemia. We investigated whether cilostazol, a phosphodiesterase-III inhibitor, suppressed the warfarin-induced HT after cerebral ischemia in mice. Methods— Male ddY mice were treated with oral warfarin before 3-hour middle cerebral artery occlusion followed by 21-hour reperfusion to induce HT. The duration of warfarin pretreatment was determined by measurement of prothrombin time-international normalized ratio value. Cilostazol or vehicle was administered by intraperitoneal injection immediately after reperfusion. The infarct volume, brain swelling, and brain hemoglobin content were evaluated at 24 hours after middle cerebral artery occlusion. We also evaluated the survival rate of each treated group for 7 days after surgery. To investigate the mechanism underlying cilostazol’s effects, the proteins involved in vascular endothelial integrity were investigated using Western blotting. Results— HT volume was exacerbated by warfarin treatment, and cilostazol (3 mg/kg, IP) suppressed this exacerbation (sham, mean±SD, 29.2±13.4 mg/dL; vehicle, 33.3±11.9 mg/dL; warfarin, 379.4±428.9 mg/dL; warfarin+cilostazol 1 mg/kg, 167.5±114.2 mg/dL; warfarin+cilostazol 3 mg/kg, 116.9±152.3 mg/dL). Furthermore, cilostazol improved survival rate and upregulated the expression of tight junction proteins and vascular endothelial cadherin. Conclusions— Cilostazol reduced the warfarin-related risk of HT after ischemia by protecting the vascular endothelial cells. This result suggested that cilostazol administration in patients with acute ischemic stroke might reduce HT.

scholarly journals Progesterone Enhances Functional Recovery after Middle Cerebral Artery Occlusion in Male Mice

2004 ◽  
Vol 24 (7) ◽  
pp. 805-813 ◽  
Author(s):  
Claire L. Gibson ◽  
Sean P. Murphy
Keyword(s):  
Survival Rate ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Water Maze ◽  
Artery Occlusion ◽  
Motor Ability ◽  
Male Mice ◽  
Cerebral Artery Occlusion

Sex differences have been observed in the outcome after ischemia that are believed to be attributable to sex steroid hormones. The present study investigated the possible benefits of progesterone administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received progesterone (8 mg/kg, intraperitoneally) or vehicle (dimethyl sulfoxide) 1, 6, and 24 hours after MCAO. The lesion volume at 48 hours after MCAO was significantly reduced ( P < 0.05) in progesterone-treated mice compared with vehicle-treated mice. All other mice underwent tests of well being (survival rate and body weight recovery), motor ability (grid test and rotarod), and cognitive ability (water maze) for up to 21 days. MCAO significantly worsened outcome in all of these tests compared with shams. Progesterone treatment was beneficial in that compared with vehicle, it significantly improved survival rate, weight recovery, and motor ability. This improvement was most apparent during water maze testing, where progesterone-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate beneficial effects of progesterone administration after cerebral ischemia and illustrate the need to further investigate the mechanisms of progesterone action.

Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alexander Akhmedov ◽  
Remo D Spescha ◽  
Francesco Paneni ◽  
Giovani G Camici ◽  
Thomas F Luescher
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Oxidized Ldl ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

scholarly journals A Novel Model for Encephalomyosynangiosis Surgery after Middle Cerebral Artery Occlusion-Induced Stroke in Mice

2021 ◽  
Author(s):  
Mitch Paro ◽  
Daylin Gamiotea Turro ◽  
Leslie Blumenfeld ◽  
Ketan R Bulsara ◽  
Rajkumar Verma
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Artery Occlusion ◽  
Novel Treatment ◽  
Graft Tissue ◽  
Cerebral Artery Occlusion

Background and Purpose: No effective treatment is available for most patients who suffer ischemic stroke. Development of novel treatment options is imperative. The brain attempts to self-heal after ischemic stroke via various mechanism mediated by restored blood circulation in affected region of brain but this process is limited by inadequate angiogenesis or neoangiogenesis. Encephalomyosynangiosis (EMS) is a neurosurgical procedure that achieves angiogenesis with low morbidity in patients with moyamoya disease, reducing risk of stroke. However, EMS, surgery has never been studied as an therapeutic option after ischemic stroke. Here we described a novel procedure and feasibility data for EMS after ischemic stroke in mice. Methods: A 60 mins of middle cerebral artery occlusion (MCAo) was used to induce ischemic stroke in mice. After 3-4 hours of MCAo onset/sham, EMS was performed. Mortality of EMS, MCAo and. MCAo+EMS mice was recorded up to 21 days after surgery. Graft tissue viability was measured using a nicotinamide adenine dinucleotide reduced tetrazolium reductase assay. Results: EMS surgery after ischemic stroke does not increase mortality compared to stroke alone. Graft muscle tissue remained viable 21 days after surgery. Conclusions: This novel protocol is effective and well-tolerated, may serve as novel platform for new angiogenesis and thus recovery after ischemic stroke. If successful in mice, EMS can a very feasible and novel treatment option for ischemic stroke in humans.

Abstract TP106: Automated Assessment of Behavioral Function After Experimental Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Terrance Chiang ◽  
Sean Harvey ◽  
Arjun V Pendharkar ◽  
Michelle Y Cheng ◽  
Gary K Steinberg
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Motor Deficit ◽  
Motor Deficits ◽  
Stroke Models ◽  
Cerebral Artery Occlusion ◽  
Significant Motor

Introduction: Manual scoring of behavior tests is commonly used for assessing motor deficits after stroke, however, it is labor intensive and subject to bias. These limitations lead to inconsistent assessment between research groups and non-reproducible data. In this study, we investigated the feasibility of an automated motor deficit assessment system, Erasmus ladder, in two ischemic stroke models. Methods: Distal middle cerebral artery occlusion (dMCAO n=10) or transient middle cerebral artery occlusion (tMCAO 30 minutes, n=15) were performed on male C57BL6J mice (11-13 weeks) to generate cortical ischemic stroke, with. Naïve mice (n=10) were used as controls. Immunohistochemistry was performed on brains collected at post-stroke day (PD) 30 to assess for infarct size (MAP2) and inflammation (CD68). Mice without infarct in both cortex and striatum were excluded from the study. Behavior was assessed using Erasmus ladder at pre-stroke baseline (4 unperturbed and 4 perturbed sessions) and on PD 7, 14, 21, and 28 (all perturbed sessions). Results: Erasmus ladder detected significant motor deficits in the tMCAO model, specifically in the pre- and post- perturbed times as well as several key step types (HH long). Analyses in the tMCAO model reveal changes in various step patterns and their capability to react to the perturbation (obstacle). These significant motor deficits after tMCAO were detectable until PD28. We also observed a sustained decline in the use of affected limb compared to unaffected limb until PD28. While this trend is also present in dMCAO model, motor deficits were detected in the dMCAO only at early timepoints (PD7) and the difference subsided by PD28. Conclusion: We have assessed the data collected by Erasmus ladder on mice that underwent two commonly used stroke models (tMCAO and dMCAO). Our data showed that Erasmus ladder can detect long term motor deficit including reduced use of affected limb, step pattern, and motor reaction to obstacle. This automated instrument is effective in detecting motor deficits in the tMCAO model and thus, can be used to evaluate treatments for enhancing recovery after stroke.

Melatonin and calpeptin synergistically protect against post-reperfusion injury in a rat middle cerebral artery occlusion stroke model

2021 ◽  
Vol 4 (4) ◽  
pp. 592-612
Author(s):  
Ye Feng ◽  
Qian Xu ◽  
Raymond Tak Fai Cheung
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Reperfusion Injury ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neurological Deficit ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Stroke Model ◽  
Cerebral Artery Occlusion

Cerebral ischemia induces oxidative injury and increases the intracellular calcium ion concentration to activate several calcium-dependent proteases such as calpains. Calpain activation leads to various necrotic and apoptotic processes. Calpeptin is a potent, cell-permeable calpain inhibitor. As a strong antioxidant and free radical scavenger, melatonin shows beneficial effect in rodent models of focal cerebral ischemia when given prior to ischemia or reperfusion. This study was focused on the neuroprotective effects of melatonin and/or calpeptin given after onset of reperfusion. For this purpose, right-sided middle cerebral artery occlusion (MCAO) for 90 minutes followed by 24 or 72 hours of reperfusion was performed in male Sprague Dawley rats, then, melatonin 50 or 150 µg/kg, calpeptin 10, 15 or 50 µg/kg or a combination of melatonin 50 µg/kg plus calpeptin 15 or 50 µg/kg were injected via an intracerebroventricular route at 15 minutes after onset of reperfusion. Melatonin or calpeptin tended to reduce the relative infarct volume and significantly decreased the neurological deficit at 24 hours. The combination achieved a greater protection than each of them alone. Melatonin, calpeptin or the combination all decreased Fluoro-Jade B (FJB)+ degenerative neurons and cleaved/total caspase-3 ratio at 24 hours. These treatments did not significantly impact the density of surviving neurons and ED-1+ macrophage/activated microglia. At the 72-hour-reperfusion, melatonin or the combination decreased the relative infarct volume and neurological deficit. Nevertheless, only the combination reduced FJB+ degenerating neurons at 72 hours. In conclusion, a combination of melatonin and calpeptin exerted synergistic protection against post-reperfusion injury in a rat MCAO stroke model.

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