Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain

See related article, pages 1751–1758. Since the ischemic penumbra was discovered and since a therapeutic window for acute ischemic stroke has been postulated, stroke experts are looking for safe and effective drugs to treat as many acute ischemic stroke patients as possible. Maturation of ischemic damage is a complex process, triggered by hypoperfusion at critical levels and spontaneously evolving toward cell death. It is a self-perpetuating process in which some critical steps (such as ion pumps failure and iNOS production) maintain and enhance the process.1 Reperfusion may reverse the ischemic cascade but, at the same time, induces a further damage. The risk/benefit ratio of reperfusion depends on the amount of penumbral salvageable tissue, that is “individual” and only partially predictable.2,3 Spontaneous reperfusion may occur, and symptoms may reverse, partially or totally, but the percentages of spontaneous reperfusion so far reported account for approximately the 24% of all stroke cases.4 A review of published articles about cerebral angiography in stroke reported that the percentage of spontaneous reperfusion …

Event Abstract Back to Event Effectiveness of NA-1, a PSD95 inhibitor, in a non-human primate model of embolic stroke Douglas J. Cook1*, L. Teves1 and Michael Tymianski1 1 Toronto Western Hospital Research Institute, Canada Introduction: NA-1 is an inhibitor of the interactions of NMDA glutamate receptors with the submembrane scaffolding protein PSD-95. Treatment with NA-1 decreases stroke volume and improves functional recovery in rodent models of stroke. NA-1 is being evaluated in an ongoing Phase II human clinical trial of its efficacy in reducing the burden of embolic strokes incurred during endovascular aneurysm repair (ENACT trial; clincialtrials.gov NCT00728182). To test whether NA-1 is neuroprotective in embolic strokes in a gyrencephalic non-human primate species we undertook a randomized, blinded, crossover trial of NA-1 vs placebo in a paradigm that simulates the ENACT trial. Methods: Ten adolescent cynomolgus macaques(2.25-4.0 kg) underwent transfemoral, right intracarotid injection of twenty 100um polystyrene spheres followed by treatment with placebo(saline) or NA-1 infused intravenously 1 hour following the embolic procedure. MRI T2 and diffusion weighted imaging(7 Tesla, Bruker Biospin) was obtained at 4, 24 hours and 4 weeks post-stroke. Raw counts and volumetric measurement of diffusion lesions were collected. Primate Stroke Scale scoring was obtained serially for 2 weeks following recovery. Following a 4-week washout period each animal was crossed over to the other treatment group and the procedure was repeated. Results: There were no differences in physiologic parameters between groups. The strokes did not cause gross motor deficits. Animals treated with NA-1 exhibited markedly reduced stroke numbers and volume as compared with placebo-treated animals with the greatest difference observed in the cortex (Figure 1). There was no carry-over effect noted with a 4-week washout. Conclusion: NA-1 significantly reduced embolic stroke number and volume in gyrencephalic non-human primates. This result supports the ENACT paradigm, and the notion that NA-1 should be tested for efficacy in reducing the burden of procedurally-induced strokes in patients. Conference: B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Cook DJ, Teves L and Tymianski M (2009). Effectiveness of NA-1, a PSD95 inhibitor, in a non-human primate model of embolic stroke. Front. Neurosci. Conference Abstract: B.R.A.I.N. platform in Physiology poster day 2009. doi: 10.3389/conf.neuro.03.2009.17.009 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 16 Dec 2009; Published Online: 16 Dec 2009. * Correspondence: Douglas J Cook, Toronto Western Hospital Research Institute, Toronto, Canada, dj.cook@me.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Douglas J Cook L. Teves Michael Tymianski Google Douglas J Cook L. Teves Michael Tymianski Google Scholar Douglas J Cook L. Teves Michael Tymianski PubMed Douglas J Cook L. Teves Michael Tymianski Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Stroke is the third leading cause of death and a leading cause of adult disability in the United States.1 From a global perspective, stroke is also a leading cause of death and disability. The past 20 years have seen significant improvements in stroke prevention, yet each year, >700 000 people have a new or recurrent stroke.2,3 The medical and societal costs of stroke exceed $62 billion in the United States alone.4 Any intervention that could reverse or limit the effects of a stroke would have dramatic medical, societal, and public health benefits. This section will focus on treatment of acute ischemic stroke, which accounts for 80% to 85% of all strokes. Other recent publications have focused on therapies for intracerebral hemorrhage. Acute interventions to reduce the effects of an ischemic stroke can be organized into several main approaches: (1) reperfusion strategies (lytics, endovascular/mechanical); (2) neuroprotection; and (3) restoration, regeneration, and rehabilitation. ### Medical Therapies Thrombolytic therapies for acute ischemic stroke have been used or under study for 30 to 40 years, yet only recently has an agent been approved by the US Food and Drug Administration (FDA) and included in the treatment guidelines. Intravenous recombinant tissue plasminogen activator (rtPA) is the only FDA-approved medical therapy proven to reduce the effects of an ischemic stroke.5,6 Its main mechanism of action is to lyse a clot that is occluding a cerebral vessel, thereby reperfusing distal ischemic brain tissue and preventing or limiting the area of cell death and tissue necrosis. The efficacy of intravenous rtPA was proven in the pivotal National Institute of Neurological Disorders and Stroke (NINDS) rtPA study, which showed improved outcomes for patients treated within 3 hours of stroke onset.7 The NINDS tissue plasminogen activator (tPA) trial had an efficacy end point that was equivalent to the …

MRI evaluation of BBB disruption after adjuvant AcSDKP treatment of stroke with tPA in rat

Recent MRI advances in experimental stroke.

The development of additional effective therapies for acute ischemic stroke remains a challenging but critical endeavor. Intravenous recombinant tissue plasminogen activator (rtPA) initiated within 3 hours of stroke onset remains the only approved and validated therapy for acute ischemic stroke, and regulatory approval has expanded recently. Many other therapies have been evaluated, and these trials have either been inconclusive or negative.1 These acute stroke trials do provide valuable information concerning how to implement future trials and some glimmers of hope about existing data. Some of the lessons learned from prior acute stroke trials that will help to guide future trials are outlined below. The two fundamental approaches to the development of acute stroke therapy remain reperfusion and neuroprotection. This short review will focus on the current status of both approaches and how they might be combined, hopefully in the near future. Negative acute stroke treatment trials may be explained by the following: 1. The agents evaluated in clinical trials may not have been adequately tested in preclinical studies to provide robust confirmation of efficacy in appropriate animal models. 2. Side effects precluded adequate drug assessment or did not allow use of adequate drug concentrations. 3. Because of macro-occlusions and, perhaps, micro-occlusions, the drug did not penetrate into or beyond the penumbral tissue in adequate concentrations. 4. Trials included patients not appropriate for the purported mechanism of action of the drug being tested. 5. Patients were included too late after stoke onset to allow for adequate assessment of the drug’s efficacy, and imaging studies were not done to identify patients with appropriate tissue for treatment. 6. Trials have been inadequately powered to detect modest treatment effects. 7. Trials included too many patients with mild or very severe deficits in whom treatment effects are likely difficult to assess with currently used outcome measures. 8. The single primary outcome measure …

Stroke continues to be a significant cause of morbidity and mortality in the United States. Approximately 700 000 Americans have a new or recurrent stroke each year, and stroke remains the third leading cause of death in the United States when considered independently from other cardiovascular diseases. Stroke also remains a leading cause of serious, long-term disability in the United States.1 Major advances have been made during the past several decades in stroke prevention, treatment, and rehabilitation. Despite successes in delivering effective new therapies, significant obstacles remain in ensuring that scientific advances are consistently translated into clinical practice. In many instances, these obstacles can be related to a fragmentation of stroke-related care caused by inadequate integration of the various facilities, agencies, and professionals that should closely collaborate in providing stroke care. There is increased emphasis on improving the components of stroke care, including recommendations from the Brain Attack Coalition for primary stroke centers and a formal process provided through the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) for the certification of primary stroke centers.2–4 It is critically important to look carefully at how the distinct components can be better integrated into systems of stroke care. The American Stroke Association (ASA), a division of the American Heart Association (AHA), is dedicated to improving stroke prevention, treatment, and rehabilitation through research, education, advocacy, and the development and application of scientifically based standards and guidelines. The ASA convened a multidisciplinary group, the Task Force on the Development of Stroke Systems, to describe the current fragmentation of stroke care, to define the key components of a stroke system, and to recommend methods for encouraging the implementation of stroke systems. The term “stroke system” is used in this article to avoid the corporate and financial connotations associated with the words “network” and …

In the acutely infarcted brain, cytokines are released into cerebrospinal fluid and blood. Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, among others, may play a role in the acute increases in plasma adrenocorticotropic hormone, cortisol, epinephrine, norepinephrine, and vasopressin.1–6 Increases in cytokines and hormones may in turn induce changes in other variables. When recorded on admission in acute stroke patients, many variables have been found to be associated with poor outcome in acute stroke. Body temperature7 is one such variable, blood glucose another,8–18 and C-reactive protein (CRP)19–22 and white blood cell count (WBC)20,23 serum cortisol and ferritin24 are further examples. Elevated plasma and cerebrospinal fluid levels of glutamate, glycine,25 ferritin,26 and IL-627 were also associated with deteriorating stroke. It seems plausible that these variables generally are unaffected at stroke onset and then increase in the early hours after onset, depending on the severity of the stroke. We found this to be the case with temperature,28 which in a large series of patients was normal when measured within 2 hours of stroke onset, but which rose at 4 to 6 hours after stroke onset in patients with severe neurological deficits. At 8 to 10 hours after stroke onset, elevated temperature was associated with poor outcome. This association arose several hours after onset of severe stroke. Thus, the initial severity of the stroke …

615-P: Associations between Food Addiction and Brain Tissue Integrity in Persons with Type 2 Diabetes Mellitus

Introduction: Recent evidence remains inconclusive about the impact of atrial fibrillation (AF) on prognosis after intravenous thrombolysis and/or intra-arterial (IA) acute stroke treatment (AIS). Hypothesis: AF (either first episode or chronic) adversely affects stroke outcomes in patients undergoing IA treatment for AIS. Methods: We analyzed data from the 434 subjects in the IA treatment arm of Interventional Management of Stroke (IMS) III trial. The trial included AIS patients who were eligible for IV rtPA infusion within three hours after stroke onset. The subjects that were randomized to the IA treatment arm later received a protocol approved endovascular treatment. Demographics, vascular risk factors, and outcome measures were compared between patients with and without atrial fibrillation. The main outcomes considered were early neurological deterioration and hemorrhagic complications, excellent (mRS: scores of 0-2) functional outcome at 3 months, and good quality of life (EQ-5D index 0.5-1.0) at one year from randomization. Adjusted logistic regression analysis was performed to compare these outcomes. Results: Of the 434 patients who were studied (mean ± SD age, 66.3 ± 12.3 years, with 50.2% of patients being men), 153 had AF either chronic or diagnosed at baseline EKG and 281 had no AF. The patients with AF were significantly older (age 71.2±8.2 vs. 63.6±13.3 years), had more severe strokes (NIHSS>=20) at baseline assessment (40.5% vs. 24.9%). The subjects with AF had higher adjusted odds of early neurological deterioration (OR 1.3, 95%CI 0.6-1.9, p=0.81), symptomatic intracranial hemorrhage (OR 1.7; 95% CI 0.7-3.8; p=0.27), and subarachnoid hemorrhage (OR 1.4; 95% CI 0.7-2.7; p=0.31). The subjects with AF had lower odds of having good functional outcome 3 months after randomization (OR 0.8; 95% CI 0.4-1.1; p=0.06). The two groups did not differ in their adjusted odds of symptomatic ICH, parenchymal hematomas, 90 days mortality, and quality of life after one year. Conclusions: In the patients undergoing IA treatment for AIS, AF may adversely impact early recovery in neurological function and long-term functional outcomes but not the rates of hemorrhagic complications, mortality, or good quality of life.

BackgroundThe efficacy and safety of endovascular thrombectomy (EVT) >6 hours from acute ischemic stroke (AIS) onset for patients selected without computed tomography (CT) perfusion or magnetic resonance imaging is undetermined in routine clinical practice.MethodsIn this single‐center study, we identified consecutive late‐presenting patients with AIS who were eligible for EVT on the basis of noncontrast CT/CT angiography (without CT perfusion or magnetic resonance imaging) using an Alberta Stroke Program Early CT Score of ≥6, >6 hours from stroke onset, between January 2018 and March 2022. During the study period, EVT capacity limitations meant EVT‐eligible patients presenting out of regular working hours, consistently received best medical management (BMM). Functional outcomes (modified Rankin Scale at 90 days), symptomatic intracranial hemorrhage, and mortality at 90 days were compared between patients receiving EVT or BMM following multivariable adjustment for age, sex, baseline stroke severity, Alberta Stroke Program Early CT Score, onset‐to‐neuroimaging time, intravenous thrombolysis, and clot location.ResultsAmong 4802 patients with AIS, 150 patients (3.1%) presenting beyond 6 hours of onset were eligible for EVT: 74 (49%) treated with EVT and 76 (51%) with BMM. Compared with the BMM group, patients treated with EVT had significantly improved functional outcome (modified Rankin Scale) (adjusted common odds ratio, 2.23 [95% CI, 1.18–4.22]; P=0.013), and higher rates of functional independence (modified Rankin Scale ≤2; 39.2.% versus 9.2%; adjusted odds ratio, =4.73 [95% CI, 1.64–13.63]; P=0.004). No significant difference was observed between the EVT and BMM groups in the symptomatic intracranial hemorrhage (5.4% versus 2.6%; P=0.94) or mortality (20.2% versus 47.3%; P=0.16) rates, respectively.ConclusionIn routine clinical practice, of the 3.1% of patients in our AIS population presenting after 6 hours from stroke onset who were deemed eligible for EVT by noncontrast CT/CT angiography alone, those treated with EVT achieved significantly improved functional outcome, compared with patients treated with BMM only. No significant differences were noted between the 2 groups with respect to symptomatic intracranial hemorrhage and mortality. While confirmatory randomized trials are awaited, these findings suggest that EVT is effective and safe when performed in patients with AIS selected without CT perfusion or magnetic resonance imaging >6 hours from stroke onset.

EMBO Reports (2019) e48380 Invasive autopsy has been crucial to determine the cause of death—as part of a criminal investigation or for public health purposes—but the vivisection of the corpse often meets resistance from relatives or certain religious or ethnic groups. To address religious objections or feelings that invasive autopsy violates the dignity of the deceased, pathologists have been using non‐invasive scanning techniques, originally developed for medical diagnosis, either as alternatives to, or to complement traditional autopsies. The use of computer tomography and magnetic resonance imaging in places where they are readily available not only appeals to relatives who object to vivisection but it also provides additional information or helps to confirm conclusions about the cause of death. > … the rate of autopsy has been declining […], partly out of growing opposition to what is often considered unnecessary mutilation of the bodies of loved ones. Autopsy has a long history dating back to at least 3,000 years BC in ancient Egypt. Julius Caesar was subjected to an official autopsy in 44 BC after his murder in the Roman senate. In the modern era, autopsies are routinely used to determine causes of death, especially when people die unexpectedly or under suspicious circumstances. Yet, the rate of autopsy has been declining in almost every developed country and many developing ones, partly out of growing opposition to what is often considered unnecessary mutilation of the bodies of loved ones. For example, autopsies were performed on 40–60% of all people who died in hospital in the United States before 1970, but that rate has now fallen to below 5% [1]. This comes at a time when autopsies for reasons other than establishing cause of death have become increasingly valuable: to evaluate the extent of human disease in patients and the effectiveness of …

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

Background: Ischemic stroke is a leading cause of long-term neurological disability worldwide. Within minutes of its onset, blood flow to the brain’s ischemic core drops dramatically, resulting in irreversible damage and eventual neuronal death in the affected area. Currently, effective clinical therapies to reduce brain injury caused by ischemic stroke are still limited. Catalpol, a bioactive compound extracted from the traditional Chinese medicine herb Rehmannia glutinosa , has shown neuroprotective effects in various neurological disorders. Emerging evidence suggests that catalpol exerts therapeutic benefits in ischemic stroke; however, its effect on neuronal apoptosis following cerebral ischemia (CI) and the underlying pharmacological mechanisms remain incompletely understood. Objective: This study aimed to gain deeper insights into the effects of catalpol on neuronal apoptosis following ischemic stroke. Materials and Methods: To evaluate the effects of catalpol both in vivo and in vitro , a rat model of middle cerebral artery occlusion/reperfusion and an oxygen–glucose deprivation/reperfusion (OGD/R) cell model were established. Behavioral assessments were performed to determine the impact of catalpol on neurological function in ischemic rats. In addition, cerebral infarction size, brain index, cerebral blood flow, and histological analyses, including 2,3,5-triphenyltetrazolium chloride and hematoxylin-eosin staining, were used to assess the therapeutic potential of catalpol. Neuronal apoptosis in ischemic rats was evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The protective effects of catalpol against OGD/R-induced injury in SH-SY5Y cells were assessed using cell counting kit-8 and lactate dehydrogenase assays. Hoechst 33342 and TUNEL staining were also employed to examine apoptosis in OGD/R-exposed neurons following catalpol treatment. Furthermore, immunofluorescence staining and Western blot analysis were conducted to detect the expression of key signaling proteins. Results: In vivo , catalpol alleviated neurological deficits and improved both neurological function and brain tissue integrity in ischemic rats. It enhanced neuronal morphology and reduced apoptosis following CI. In vitro , catalpol protected against OGD/R-induced cellular injury. Findings from both animal and cell-based experiments confirmed that catalpol mitigates oxidative stress damage and inflammation while inhibiting neuronal apoptosis after CI. These neuroprotective effects are likely mediated through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3 beta (GSK3β)/β-catenin signaling pathway. Conclusions: The present study suggests that catalpol protects neurons and inhibits apoptosis by activating the PI3K/Akt/GSK3β/β-catenin signaling cascade, highlighting its potential as a therapeutic intervention for ischemic stroke.

Optimal Imaging at the Primary Stroke Center.