scholarly journals Effect of glibenclamide on the prevention of secondary brain injury following ischemic stroke in humans

2014 ◽  
Vol 36 (1) ◽  
pp. E11 ◽  
Author(s):  
Arjun Khanna ◽  
Brian P. Walcott ◽  
Kristopher T. Kahle ◽  
J. Marc Simard
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Edema ◽  
Vasogenic Edema ◽  
Ion Homeostasis ◽  
Secondary Brain Injury ◽  
Protective Effects ◽  
Cation Conductance ◽  
Integral Role ◽  
Prospective Phase ◽  
Molecular Pathophysiology

Cerebral edema and hemorrhagic conversion are common, potentially devastating complications of ischemic stroke and are associated with high rates of mortality and poor functional outcomes. Recent work exploring the molecular pathophysiology of the neurogliovascular unit in ischemic stroke suggests that deranged cellular ion homeostasis due to altered function and regulation of ion pumps, channels, and secondary active transporters plays an integral role in the development of cytotoxic and vasogenic edema and hemorrhagic conversion. Among these proteins involved in ion homeostasis, the ischemia-induced, nonselective cation conductance formed by the SUR1-TRPM4 protein complex appears to play a prominent role and is potently inhibited by glibenclamide, an FDA-approved drug commonly used in patients with Type 2 diabetes. Several robust preclinical studies have demonstrated the efficacy of glibenclamide blockade of SUR1-TRPM4 activity in reducing edema and hemorrhagic conversion in rodent models of ischemic stroke, prompting the study of the potential protective effects of glibenclamide in humans in an ongoing prospective phase II clinical trial. Preliminary data suggest glibenclamide significantly reduces cerebral edema and lowers the rate of hemorrhagic conversion following ischemic stroke, suggesting the potential use of glibenclamide to improve outcomes in humans.

scholarly journals Potential Therapies for Cerebral Edema After Ischemic Stroke: A Mini Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Yi Yao ◽  
Yonggang Zhang ◽  
Xiaoyang Liao ◽  
Rong Yang ◽  
Yi Lei ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Cerebral Edema ◽  
Animal Studies ◽  
Vasogenic Edema ◽  
Therapeutic Agents ◽  
Research Progress ◽  
Cytotoxic Edema ◽  
Causes Of Mortality ◽  
Three Stages

Stroke is the leading cause of global mortality and disability. Cerebral edema and intracranial hypertension are common complications of cerebral infarction and the major causes of mortality. The formation of cerebral edema includes three stages (cytotoxic edema, ionic edema, and vasogenic edema), which involve multiple proteins and ion channels. A range of therapeutic agents that successfully target cerebral edema have been developed in animal studies, some of which have been assessed in clinical trials. Herein, we review the mechanisms of cerebral edema and the research progress of anti-edema therapies for use after ischemic stroke.

scholarly journals Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

2021 ◽  
Vol 22 (11) ◽  
pp. 5679
Author(s):  
Michel J. A. M. van Putten ◽  
Christoph Fahlke ◽  
Karl W. Kafitz ◽  
Jeannette Hofmeijer ◽  
Christine R. Rose
Keyword(s):  
Ischemic Stroke ◽  
Brain Damage ◽  
Cerebral Edema ◽  
Ion Homeostasis ◽  
Energy Depletion ◽  
Brain Functioning ◽  
Tripartite Synapse ◽  
Chronic Disability ◽  
Cellular Volume ◽  
Monovalent Ions

Ischemic stroke is a leading cause of mortality and chronic disability. Either recovery or progression towards irreversible failure of neurons and astrocytes occurs within minutes to days, depending on remaining perfusion levels. Initial damage arises from energy depletion resulting in a failure to maintain homeostasis and ion gradients between extra- and intracellular spaces. Astrocytes play a key role in these processes and are thus central players in the dynamics towards recovery or progression of stroke-induced brain damage. Here, we present a synopsis of the pivotal functions of astrocytes at the tripartite synapse, which form the basis of physiological brain functioning. We summarize the evidence of astrocytic failure and its consequences under ischemic conditions. Special emphasis is put on the homeostasis and stroke-induced dysregulation of the major monovalent ions, namely Na+, K+, H+, and Cl-, and their involvement in maintenance of cellular volume and generation of cerebral edema.

scholarly journals BIIB093 (intravenous glibenclamide) for the prevention of severe cerebral edema

2021 ◽  
Vol 12 ◽  
pp. 80
Author(s):  
Daniel W. Griepp ◽  
Jason Lee ◽  
Christina M. Moawad ◽  
Cyrus Davati ◽  
Juliana Runnels ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Cerebral Edema ◽  
Transient Receptor Potential ◽  
Small Sample Size ◽  
Vasogenic Edema ◽  
Receptor Potential ◽  
Outcome Data ◽  
Small Sample ◽  
Sulfonylurea Receptor

Background: Vasogenic edema in the setting of acute ischemic stroke can be attributed to the opening of transient receptor potential 4 channels, which are expressed in the setting of injury and regulated by sulfonylurea receptor 1 (SUR1) proteins. Glibenclamide, also known as glyburide, RP-1127, Cirara, and BIIB093, is a second-generation sulfonylurea that binds SUR1 at potassium channels and may significantly reduce cerebral edema following stroke, as evidenced by recent clinical trials. This review provides a comprehensive analysis of clinical considerations of glibenclamide use and current patient outcomes when administered in the setting of acute ischemic stroke to reduce severe edema. Methods: National databases (MEDLINE, EMBASE, Cochrane, and Google scholar databases) were searched to identify studies that reported on the clinical outcomes of glibenclamide administered immediately following acute ischemic stroke. Results: The pharmacological mechanism of glibenclamide was reviewed in depth as well as the known indications and contraindications to receiving treatment. Eight studies were identified as having meaningful clinical outcome data, finding statistically significant differences in glibenclamide treatment groups ranging from matrix metalloproteinase-9 serum levels, midline shift, modified Rankin Scores, National Institute of Health Stroke Score, and mortality endpoints. Conclusion: Studies analyzing the GAMES-Pilot and GAMES-PR trials suggest that glibenclamide has a moderate, however, measurable effect on intermediate biomarkers and clinical endpoints. Meaningful conclusions are limited by the small sample size of patients studied.

Cerebrolysin and Aquaporin 4 Inhibition Improve Pathological and Motor Recovery after Ischemic Stroke

2018 ◽  
Vol 17 (4) ◽  
pp. 299-308 ◽  
Author(s):  
Bogdan Catalin ◽  
Otilia-Constantina Rogoveanu ◽  
Ionica Pirici ◽  
Tudor Adrian Balseanu ◽  
Adina Stan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Vasogenic Edema ◽  
Artery Occlusion ◽  
Aquaporin 4 ◽  
Hypertonic Solution ◽  
Water Metabolism ◽  
Scar Region ◽  
Function Preservation ◽  
Neurotropic Factor ◽  
Cerebral Artery Occlusion

Background: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative. Objective: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke. Methods: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed. Results: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals. Conclusion: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region.

scholarly journals Acute Ischemic Stroke: A Review of Imaging, Patient Selection, and Management in the Endovascular Era. Part II: Patient Selection, Endovascular Thrombectomy, and Postprocedure Management

2018 ◽  
Vol 02 (03) ◽  
pp. 169-183
Author(s):  
Sharath Kumar G G ◽  
Chinmay Nagesh
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Patient Selection ◽  
Secondary Brain Injury ◽  
Selection Methods ◽  
Vessel Occlusion ◽  
Endovascular Thrombectomy ◽  
Advantages And Disadvantages ◽  
Imaging Patient ◽  
Selection Of

AbstractAppropriate patient selection and expedient recanalization are the mainstay of modern management of acute ischemic stroke (AIS). Only a minority of patients (7–15%) of patients are eligible for endovascular therapy. Patient selection may be time based or perfusion based. Central to both paradigms is the selection of a patient with a small core, a significant penumbra that can be differentiated from areas of oligemia. A brief review of patient selection methods is presented. Endovascular thrombectomy techniques using stentrievers or aspiration catheters have now become the treatment of choice for AIS with large vessel occlusion. A range of devices, each with its own advantages and disadvantages, are available in the market for the neurointerventionist to choose. Techniques vary between devices and between operators, but standardization and protocolization are important within each center. Complications must be anticipated to be avoided. Once reperfusion is achieved, outcomes must be safeguarded with competent postprocedure management to prevent secondary brain injury. These aspects are reviewed in this article.

Protective effects of the angiotensin II AT2 receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach

2018 ◽  
Vol 132 (5) ◽  
pp. 581-593 ◽  
Author(s):  
Douglas M. Bennion ◽  
Chad H. Jones ◽  
Alex N. Dang ◽  
Jacob Isenberg ◽  
Justin T. Graham ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Angiotensin Ii ◽  
Receptor Agonist ◽  
At2 Receptor ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Receptor Agonists ◽  
Compound 21 ◽  
Neuroprotective Actions

Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor (AT2 receptor) agonists in ischemic stroke have been previously demonstrated in multiple studies. However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular (ICV) and systemic administration, are unsuitable for translation into humans; in the latter case because AT2 receptor agonists are blood–brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the BBB and deliver the selective AT2 receptor agonist Compound 21 (C21) to naïve rats or rats that had undergone endothelin 1 (ET-1)-induced ischemic stroke. The results obtained from the present study indicated that C21 applied N2B entered the cerebral cortex and striatum within 30 min in amounts that are therapeutically relevant (8.4–9 nM), regardless of whether BBB was intact or disintegrated. C21 was first applied N2B at 1.5 h after stroke indeed provided neuroprotection, as evidenced by a highly significant, 57% reduction in cerebral infarct size and significant improvements in Bederson and Garcia neurological scores. N2B-administered C21 did not affect blood pressure or heart rate. Thus, these data provide proof-of-principle for the idea that N2B application of an AT2 receptor agonist can exert neuroprotective actions when administered following ischemic stroke. Since N2B delivery of other agents has been shown to be effective in certain human central nervous system diseases, the N2B application of AT2 receptor agonists may become a viable mode of delivering these neuroprotective agents for human ischemic stroke patients.

scholarly journals Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

1999 ◽  
Vol 19 (9) ◽  
pp. 1020-1028 ◽  
Author(s):  
Yvan Gasche ◽  
Miki Fujimura ◽  
Yuiko Morita-Fujimura ◽  
Jean-Christophe Copin ◽  
Makoto Kawase ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Vasogenic Edema ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Brain Barrier ◽  
Critical Event ◽  
Secondary Brain Injury ◽  
Blood Brain ◽  
Bbb Permeability

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

scholarly journals Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Jing Yu ◽  
Wen-na Wang ◽  
Nathanael Matei ◽  
Xue Li ◽  
Jin-wei Pang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Brain Infarction ◽  
Neutrophil Infiltration ◽  
Artery Occlusion ◽  
Receptor Protein ◽  
Related Factor ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Interacting Protein

Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.

Sign in / Sign up

Export Citation Format

Share Document