scholarly journals The Two Pathophysiologies of Focal Brain Ischemia: Implications for Translational Stroke Research

2012 ◽  
Vol 32 (7) ◽  
pp. 1310-1316 ◽  
Author(s):  
Konstantin-Alexander Hossmann
Keyword(s):  
Vascular Occlusion ◽  
Maximum Size ◽  
Focal Ischemia ◽  
Therapeutic Window ◽  
Stroke Research ◽  
Naturally Occurring ◽  
Free Interval ◽  
Postischemic Recirculation ◽  
Primary Core ◽  
Focal Brain Ischemia

Brain injury after focal ischemia evolves along two basically different pathophysiologies, depending on the severity of the primary flow reduction and the dynamics of postischemic recirculation. In permanent and gradually reversed focal ischemia as after thromboembolic occlusion, primary core injury is irreversible but the expansion of the core into the penumbra can be alleviated by hemodynamic and molecular interventions. Such alleviation can only be achieved within 3 hours after the onset of ischemia because untreated core injury expands to near maximum size during this interval. In promptly reversed transient ischemia as after mechanical vascular occlusion, primary core injury may recover but a secondary delayed injury evolves after a free interval of as long as 6 to 12 hours. This injury can be alleviated throughout the free interval but the longer window is without clinical relevance because transient mechanical vascular occlusion is not a model of naturally occurring stroke. As this difference is widely ignored in stroke research, most clinical trials have been designed with a far too long therapeutic window, which explains their failure. Transient mechanical vascular occlusion models should, therefore, be eliminated from the repertoire of preclinical stroke research.

scholarly journals Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction

2019 ◽  
Vol 20 (3) ◽  
pp. 544 ◽  
Author(s):  
Nicola Potere ◽  
Marco Del Buono ◽  
Giampaolo Niccoli ◽  
Filippo Crea ◽  
Stefano Toldo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Ischemia Reperfusion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Therapeutic Window ◽  
Naturally Occurring ◽  
Survival Pathways ◽  
Density Lipoprotein Receptor ◽  
Reperfusion Injury Salvage Kinase

Cardioprotection refers to a strategy aimed at enhancing survival pathways in the injured yet salvageable myocardium following ischemia-reperfusion. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can be targeted following reperfusion, to induce a cardioprotective signaling through the activation of the reperfusion injury salvage kinase (RISK) pathway. The data from preclinical studies with non-selective and selective LRP1 agonists are promising, showing a large therapeutic window for intervention to reduce infarct size after ischemia-reperfusion. A pilot clinical trial with plasma derived α1-antitrypsin (AAT), a naturally occurring LRP1 agonist, supports the translational value of LRP1 as a novel therapeutic target for cardioprotection. A phase I study with a selective LRP1 agonist has been completed showing no toxicity. These findings may open the way to early phase clinical studies with pharmacologic LRP1 activation in patients with acute myocardial infarction (AMI).

scholarly journals Dose Effect Evaluation and Therapeutic Window of the Neuro-EPO Nasal Application for the Treatment of the Focal Ischemia Model in the Mongolian Gerbil

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Iliana Sosa Teste ◽  
Yuneidys Mengana Tamos ◽  
Yamila Rodríguez Cruz ◽  
Adriana Muñoz Cernada ◽  
Janette Cruz Rodríguez ◽  
...  
Keyword(s):  
Brain Ischemia ◽  
Mongolian Gerbil ◽  
Neuroprotective Effect ◽  
Developed Countries ◽  
Focal Ischemia ◽  
Exploratory Activity ◽  
Dose Effect ◽  
Therapeutic Window ◽  
Average Dose ◽  
Thalamic Nuclei

Cerebrovascular disease is the third leading cause of death and the leading cause of disability in Cuba and in several developed countries. A possible neuroprotective agent is the rHu-EPO, whose effects have been demonstrated in models of brain ischemia. The Neuro-EPO is a derivative of the rHu-EPO that avoids the stimulation of erythropoiesis. The aim of this study was to determine the Neuro-EPO delivery into the central nervous system (CNS) to exert a neuroprotective effect in cerebral ischemia model of the Mongolian gerbil. The Neuro-EPO in a rate of 249.4 UI every 8 hours for 4 days showed 25% higher viability efficacy (), improving neurological score and behavior of the spontaneous exploratory activity, the preservation of CA3 areas of the hippocampus, the cortex, and thalamic nuclei in the focal ischemia model of the Mongolian gerbil. In summary, this study, the average dose-used Neuro-EPO (249.4 UI/10 μL/every 8 hours for 4 days), proved to be valid indicators of viability, neurological status, and spontaneous exploratory activity, being significantly lower than that reported for the systemically use of the rHu-EPO as a neuroprotectant. Indeed, up to 12 h after brain ischemia is very positive Neuro-EPO administration by the nasal route as a candidate for neuroprotection.

scholarly journals Targeting Histone Deacetylases as a Multifaceted Approach to Treat the Diverse Outcomes of Stroke

Stroke ◽  
2009 ◽  
Vol 40 (8) ◽  
pp. 2899-2905 ◽  
Author(s):  
Brett Langley ◽  
Camille Brochier ◽  
Mark A. Rivieccio
Keyword(s):  
Protein Function ◽  
Histone Deacetylases ◽  
Cell Loss ◽  
Focal Ischemia ◽  
Therapeutic Window ◽  
Low Molecular Weight ◽  
Hdac Inhibition ◽  
Preclinical Models ◽  
Multifaceted Approach ◽  
Tissue Plasminogen

Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair. Several converging lines of inquiry suggest that histone deacetylase (HDAC) inhibition could be a strategy to achieve these goals. Here, we review evidence that targeting HDACs with low-molecular-weight inhibitors significantly decreases neuronal injury and improves functional outcome in multiple preclinical models of focal ischemia. These salutary effects emanate, in part, from modifications of chromatin and nonchromatin proteins that enhance adaptive gene expression or adaptive protein function. Together, the findings suggest that HDAC inhibition is a strategy capable of targeting diverse pathophysiologies of stroke with a wide therapeutic window.

Experimental models of focal and multifocal cerebral ischemia: a review

2018 ◽  
Vol 29 (6) ◽  
pp. 661-674 ◽  
Author(s):  
Kristy L. Meadows
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Treatment Options ◽  
Experimental Models ◽  
Preclinical Research ◽  
Stroke Research ◽  
Naturally Occurring ◽  
Tissue Plasminogen ◽  
Stroke Models

AbstractRodent and rabbit stroke models have been instrumental in our current understanding of stroke pathophysiology; however, translational failure is a significant problem in preclinical ischemic stroke research today. There are a number of different focal cerebral ischemia models that vary in their utility, pathophysiology of causing disease, and their response to treatments. Unfortunately, despite active preclinical research using these models, treatment options for ischemic stroke have not significantly advanced since the food and drug administration approval of tissue plasminogen activator in 1996. This review aims to summarize current stroke therapies, the preclinical experimental models used to help develop stroke therapies, as well as their advantages and limitations. In addition, this review discusses the potential for naturally occurring canine ischemic stroke models to compliment current preclinical models and to help bridge the translational gap between small mammal models and human clinical trials.

scholarly journals Pixel-by-Pixel Spatiotemporal Progression of Focal Ischemia Derived Using Quantitative Perfusion and Diffusion Imaging

2003 ◽  
Vol 23 (12) ◽  
pp. 1479-1488 ◽  
Author(s):  
Qiang Shen ◽  
Xiangjun Meng ◽  
Marc Fisher ◽  
Christopher H. Sotak ◽  
Timothy Q. Duong
Keyword(s):  
Diffusion Imaging ◽  
Focal Ischemia ◽  
Therapeutic Window ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Quantitative Perfusion ◽  
Apparent Diffusion ◽  
Permanent Occlusion ◽  
Time Invariant ◽  
And Diffusion

Pixel-by-pixel spatiotemporal progression of focal ischemia (permanent occlusion) in rats was investigated using quantitative perfusion and diffusion magnetic resonance imaging every 30 minutes for 3 hours. The normal left-hemisphere apparent diffusion coefficient (ADC) was 0.76 ± 0.03 × 10−3 mm2/s and CBF was 0.7 ± 0.3 mL · g−1 · min−1 (mean ± SD, n = 5). The ADC and CBF viability thresholds yielding the lesion volumes (LV) at 3 hours that best approximated the 2,3,5-triphenyltetrazolium chloride (TTC) infarct volumes (200 ± 30 mm2) at 24 hours were 0.53 ± 0.02 × 10−3 mm2/s (30% ± 2% reduction) and 0.30 ± 0.09 mL · g−1 · min−1 (57% ±11% reduction), respectively. Temporal evolution of the ADC- and CBF-defined LV showed a significant “perfusion-diffusion mismatch” up to 2 hours ( P < 0.05, n = 11), a potential therapeutic window. Based on the viability thresholds, three pixel clusters were identified on the CBF-ADC scatterplots: (1) a “normal” cluster with normal CBF and ADC, (2) an “ischemic core” cluster with markedly reduced CBF and ADC, and (3) a “mismatch” cluster with reduced CBF but slightly reduced ADC. These clusters were color-coded and mapped onto the image and CBF-ADC spaces. Lesions grew peripheral and medial to the initial ADC abnormality. In contrast to the CBF distribution, the ADC distribution in the ischemic hemisphere was bimodal; the relatively time-invariant bimodal-ADC minima were 0.57 ± 0.02 × 10−3 mm2/s (corresponding CBF 0.35 ± 0.04 mL · g−1 · min−1), surprisingly similar to the TTC-derived thresholds. Together, these results illustrate an analysis approach to systemically track the pixel-by-pixel spatiotemporal progression of acute ischemic brain injury.

Neuroprotective activity of tamoxifen in permanent focal ischemia

2003 ◽  
Vol 99 (1) ◽  
pp. 138-142 ◽  
Author(s):  
Harold K. Kimelberg ◽  
Yiqiang Jin ◽  
Carol Charniga ◽  
Paul J. Feustel
Keyword(s):  
Rat Model ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Protective Effects ◽  
Content Type ◽  
Mca Occlusion ◽  
Fine Print ◽  
Permanent Focal Ischemia

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.

scholarly journals Stroke Pentagon: Stroke Management Approach in Resource Poor Settings

2020 ◽  
Vol 13 (1) ◽  
pp. 57
Author(s):  
Chukwuemeka O. EZE
Keyword(s):  
Developing Countries ◽  
Vascular Occlusion ◽  
Stroke Care ◽  
Sudden Onset ◽  
Management Approach ◽  
Stroke Management ◽  
Focal Neurological Deficit ◽  
Case Presentation ◽  
Stroke Research ◽  
Cerebral Vascular Occlusion

Stroke is a neurological condition that is characterized by sudden onset focal neurological deficit due to spontaneous cerebral vascular occlusion or rupture. It is a neurological emergency and its prevalence is very high, especially in developing countries where it assumes an epidemic proportion. It is globally the second most common cause of death after ischaemic heart disease. The poor indices in developing countries are multifactorial and related to late case presentation, ignorance, poverty, and unavailability of comprehensive and well-coordinated stroke care. There is a need to identify the available and cheap stroke management steps in the developing countries and strengthen the system to maximize the benefits in reduction of the morbidity and mortality of stroke. It is against this background that we identified Stroke prevention, acute stroke management, Stroke rehabilitation, Stroke research, and Stroke support as five pillars (stroke pentagon) in stroke management in developing countries. There is a need to sensitize the stakeholders in stroke management as highlighted in the stroke pentagon to assume more responsibility. Moreover, there is the need to have a more coordinated and concerted stroke management approach which will involve all the identified five pillars to ensure improved stroke indices in the developing countries.

scholarly journals Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia

2019 ◽  
Vol 40 (6) ◽  
pp. 1274-1289 ◽  
Author(s):  
Ana I Oliveira-Ferreira ◽  
Sebastian Major ◽  
Ingo Przesdzing ◽  
Eun-Jeung Kang ◽  
Jens P Dreier
Keyword(s):  
Blood Flow ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Brain Ischemia ◽  
Regional Blood Flow ◽  
Focal Ischemia ◽  
Cell Counting ◽  
High Susceptibility ◽  
Endothelin 1 ◽  
Focal Brain Ischemia

Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.

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