Brain infarct volume after permanent focal ischemia is not dependent on Nox2 expression

Object. The authors have previously shown that tamoxifen is effective in protecting brain tissue from ischemic injury in a rat model of reversible focal ischemia. In this study the authors tested whether similar protective effects are found in a rat model of permanent focal ischemia (permanent middle cerebral artery [MCA] occlusion). Methods. Tamoxifen (20 mg/kg) was given either before or at 1, 3, or 6 hours after permanent MCA occlusion in rats, with sustaining doses given every 12 hours thereafter. The median infarct volume measured after 72 hours was 113 mm3 for the vehicle (dimethyl sulfoxide) groups, compared with 31 mm3 for pretreatment, and 14, 27, and 98 mm3 for treatment beginning at 1, 3, and 6 hours, respectively, after permanent MCA occlusion. The infarct reductions in the pretreated and 1- and 3-hour post—MCA occlusion treatment groups were statistically significant (p < 0.05). At 3 hours after permanent MCA occlusion, tamoxifen also significantly reduced the infarct size at a lower dose of 5 mg/kg but not at 1 mg/kg; the same sustaining doses of 5 and 1 mg/kg were given every 12 hours. Conclusions. Tamoxifen is as effective in a permanent model of focal ischemia as it is in the reversible model, and the therapeutic window of 3 hours after initiation of ischemia is identical. This effectiveness is likely due to several properties of the drug, including its known ability to cross the blood—brain barrier. Because tamoxifen has been administered safely in humans for treatment of gliomas at similarly high doses to those used in this study, it may be clinically useful as a treatment for ischemic stroke.

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Neurofilament Proteolysis after Focal Ischemia; When Do Cells Die after Experimental Stroke?

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199906000-00008 ◽

1999 ◽

Vol 19 (6) ◽

pp. 652-660 ◽

Cited By ~ 41

Author(s):

Jaroslaw Aronowski ◽

Ki-Hyun Cho ◽

Roger Strong ◽

James C. Grotta

Keyword(s):

Time Course ◽

Infarct Volume ◽

Focal Ischemia ◽

Cellular Damage ◽

Experimental Stroke ◽

Infarct Core ◽

Similar Time ◽

The Core ◽

Tetrazolium Staining ◽

Previous Demonstration

To determine the occurrence and time-course of presumably irreversible subcellular damage after moderate focal ischemia, rats were subjected to 1, 3, 6, 9, or 24 hours of permanent unilateral middle cerebral and common carotid occlusion or 3 hours of reversible occlusion followed by 3, 6, or 21 hours of reperfusion. The topography and the extent of damage were analyzed with tetrazolium staining and immunoblot using an antibody capable of detecting breakdown of neurofilament. Neurofilament proteolysis began after 3 hours in the infarct core but was still incomplete in penumbral regions up to 9 hours. Similarly, tetrazolium-staining abnormalities were observed in the core of 50% of animals after 3 hours of ischemia. At 6 hours of permanent ischemia, infarct volume was maximal, and further prolongation of occlusion to 9 or 24 hours did not increase abnormal tetrazolium staining. In contrast to permanent ischemia and in agreement with the authors' previous demonstration of “reperfusion injury” in this model, prolongation of reperfusion from 3 hours to 6 and 21 hours after 3 hours of reversible occlusion gradually augmented infarct volume by 203% and 324%, respectively. Neurofilament proteolysis initiated approximately 3 hours after ischemia was quantitatively greatest in the core and extended during reperfusion to incorporate penumbra with a similar time course to that of tetrazolium abnormalities. These data demonstrate that, at least as measured by neurofilament breakdown and mitochondrial failure, extensive cellular damage is not present in penumbral regions for up to 9 hours, suggesting the potential for rescuing these regions by appropriate and timely neuroprotective strategies.

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Zingiber officinaleMitigates Brain Damage and Improves Memory Impairment in Focal Cerebral Ischemic Rat

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/429505 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 35

Author(s):

Jintanaporn Wattanathorn ◽

Jinatta Jittiwat ◽

Terdthai Tongun ◽

Supaporn Muchimapura ◽

Kornkanok Ingkaninan

Keyword(s):

Cognitive Function ◽

Cerebral Ischemia ◽

Brain Damage ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Morris Water Maze Test ◽

Brain Infarct ◽

Ginger Rhizome ◽

The Brain

Cerebral ischemia is known to produce brain damage and related behavioral deficits including memory. Recently, accumulating lines of evidence showed that dietary enrichment with nutritional antioxidants could reduce brain damage and improve cognitive function. In this study, possible protective effect ofZingiber officinale, a medicinal plant reputed for neuroprotective effect against oxidative stress-related brain damage, on brain damage and memory deficit induced by focal cerebral ischemia was elucidated. Male adult Wistar rats were administrated an alcoholic extract of ginger rhizome orally 14 days before and 21 days after the permanent occlusion of right middle cerebral artery (MCAO). Cognitive function assessment was performed at 7, 14, and 21 days after MCAO using the Morris water maze test. The brain infarct volume and density of neurons in hippocampus were also determined. Furthermore, the level of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in cerebral cortex, striatum, and hippocampus was also quantified at the end of experiment. The results showed that cognitive function and neurons density in hippocampus of rats receiving ginger rhizome extract were improved while the brain infarct volume was decreased. The cognitive enhancing effect and neuroprotective effect occurred partly via the antioxidant activity of the extract. In conclusion, our study demonstrated the beneficial effect of ginger rhizome to protect against focal cerebral ischemia.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.201 ◽

2010 ◽

Vol 31 (4) ◽

pp. 1107-1118 ◽

Cited By ~ 24

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.

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Oxymatrine protects rat brains against permanent focal ischemia and downregulates NF-κB expression

Brain Research ◽

10.1016/j.brainres.2009.02.069 ◽

2009 ◽

Vol 1268 ◽

pp. 174-180 ◽

Cited By ~ 68

Author(s):

Ying Liu ◽

Xiang-jian Zhang ◽

Chen-hui Yang ◽

Hong-guang Fan

Keyword(s):

Focal Ischemia ◽

Permanent Focal Ischemia

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Prolonged Mild Hypothermia Therapy Protects the Brain Against Permanent Focal Ischemia

Stroke ◽

10.1161/01.str.32.1.232 ◽

2001 ◽

Vol 32 (1) ◽

pp. 232-239 ◽

Cited By ~ 80

Author(s):

H. Yanamoto ◽

I. Nagata ◽

Y. Niitsu ◽

Z. Zhang ◽

J.-H. Xue ◽

...

Keyword(s):

Mild Hypothermia ◽

Focal Ischemia ◽

The Brain ◽

Permanent Focal Ischemia

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The Effect of ONO-2506 on Permanent Focal Ischemia in Rats

Maturation Phenomenon in Cerebral Ischemia III ◽

10.1007/978-3-642-58602-6_38 ◽

1999 ◽

pp. 315-315

Author(s):

T. Asano ◽

T. Matsui ◽

E. Mori ◽

A. Tamura ◽

N. Tateishi ◽

...

Keyword(s):

Focal Ischemia ◽

Permanent Focal Ischemia

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Abstract WMP44: Functional Recovery Following a Combination of Thrombin Inhibitor Argatroban and Tissue Plasminogen Activator (tPA) in Thromboembolic Stroke in Nonhuman Primates

Stroke ◽

10.1161/str.48.suppl_1.wmp44 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Junko Suzuki ◽

Yoshitaka Itani ◽

Shinya Ogawa ◽

Kazunori Yamanaka ◽

Ikuo Hayashi ◽

...

Keyword(s):

Acute Stroke ◽

Plasminogen Activator ◽

Functional Recovery ◽

Nonhuman Primates ◽

Infarct Volume ◽

Thrombin Inhibitor ◽

Thromboembolic Stroke ◽

Brain Infarct ◽

Occlusion Time ◽

Tissue Plasminogen

Introduction: Early treatment following an acute stroke with the thrombolytic tissue plasminogen activator (tPA) increases functional recovery. Complications of tPA treatment include hemorrhaging and narrow therapeutic time window. Thus, better treatments for acute stroke are needed. While a number of novel treatments for acute ischemic stroke have been derived from preclinical rodent stroke models, to date, none have succeeded in clinical studies. Nonhuman primates are phylogenetically closer to humans than rodents, which could narrow the current translational shortfall between preclinical and clinical findings. The goal of the current study was to test the effect of a combination of argatroban, a thrombin inhibitor, and tPA on functional recovery and brain infarction size following thromboembolic ischemia in nonhuman primates. Methods: Autologous blood clots were injected into the internal carotid artery of cynomolgus macaques to induced a thromboembolic stroke. Either tPA (0.9 mg/kg; n = 8) or vehicle (n = 8) was intravenously infused for one hour an hour following the induction of ischemia. In a third group, after completion of tPA infusion, argatroban (0.6 mg/kg; n= 7) was intravenously infused for 22 hours. Doppler ultrasound recorded middle cerebral artery (MCA) blood flow for six hours following induction of stroke. In addition, brain infarct volume (TTC staining) and functional assessment (Neurologic Deficit Score; NDS) were determined 24 hours after ischemia. Results: Compared to vehicle treatment, tPA treatment significantly decreased MCA occlusion time, brain infarct volume and NDS. Treatment with the combination of argatroban and tPA decreased occlusion time, brain infarct volume and NDS similar to tPA treatment alone. Conclusion: The current study suggests that the addition of argatroban could enhance recanalization rates observed with tPA treatment alone. However, in contrast to previous findings in rats, the combination of argatroban and tPA does not appear to further enhance tissue or functional recovery from a thromboembolic stroke compared to tPA treatment alone.

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