Cerebroprotection for Acute Ischemic Stroke: Looking Ahead

Stroke ◽  
2021 ◽  
Author(s):  
Patrick D. Lyden
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Activated Protein C ◽  
Functional Impairments ◽  
Stroke Treatment ◽  
Target Drug ◽  
Single Target ◽  
Novel Approaches

We search for ischemic stroke treatment knowing we have failed—intensely and often—to translate mechanistic knowledge into treatments that alleviate our patients’ functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection—either as an adjunct to recanalization or as stand-alone treatment—will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC (activated protein C). Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Before clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor comorbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.

Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke

2018 ◽  
Vol 17 (5) ◽  
pp. 338-347 ◽  
Author(s):  
Shan Wang ◽  
Fei Ma ◽  
Longjian Huang ◽  
Yong Zhang ◽  
Yuchen Peng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Complex Disease ◽  
Time Window ◽  
Recombinant Tissue Plasminogen Activator ◽  
Research Progress ◽  
Apium Graveolens ◽  
Synthetic Compound ◽  
Stroke Treatment ◽  
Single Target ◽  
Anti Oxidant

Background and Objective: Stroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.

scholarly journals Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 767
Author(s):  
Courtney Davis ◽  
Sean I. Savitz ◽  
Nikunj Satani
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Culture Conditions ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Inflammatory Molecules ◽  
The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

Current Perspectives Regarding Stem Cell-based Therapy for Ischemic Stroke

2018 ◽  
Vol 24 (28) ◽  
pp. 3332-3340 ◽  
Author(s):  
Kyeong-Ah Kwak ◽  
Ho-Beom Kwon ◽  
Joo Won Lee ◽  
Young-Seok Park
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Ischemic Stroke ◽  
Time Window ◽  
Experimental Studies ◽  
Cell Type ◽  
Stroke Treatment ◽  
Cell Based Therapy ◽  
Regenerative Approach ◽  
Therapeutic Time Window

Stroke is a leading cause of death and disability worldwide. Conventional treatment has a limitation of very narrow therapeutic time window and its devastating nature necessitate a novel regenerative approach. Transplanted stem cells resulted in functional recovery through multiple mechanisms including neuroprotection, neurogenesis, angiogenesis, immunomodulation, and anti-inflammatory effects. Despite the promising features shown in experimental studies, results from clinical trials are inconclusive from the perspective of efficacy. The present review presents a synopsis of stem cell research on ischemic stroke treatment according to cell type. Clinical trials to the present are briefly summarized. Finally, the hurdles and issues to be solved are discussed for clinical application.

Recent Advances in Multi-target Anti-Alzheimer Disease Compounds (2013 Up to the Present)

2019 ◽  
Vol 26 (30) ◽  
pp. 5684-5710 ◽  
Author(s):  
Ning Wang ◽  
Panpan Qiu ◽  
Wei Cui ◽  
Xiaojun Yan ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Chemical Structures ◽  
Target Drug ◽  
Single Target ◽  
Approved Drugs ◽  
Multiple Drugs ◽  
Fda Approved Drugs ◽  
Ad Therapy

: Since the last century, when scientists proposed the lock-and-key model, the discovery of drugs has focused on the development of drugs acting on single target. However, single-target drug therapies are not effective to complex diseases with multi-factorial pathogenesis. Moreover, the combination of single-target drugs readily causes drug resistance and side effects. In recent years, multi-target drugs have increasingly been represented among FDA-approved drugs. Alzheimer’s Disease (AD) is a complex and multi-factorial disease for which the precise molecular mechanisms are still not fully understood. In recent years, rational multi-target drug design methods, which combine the pharmacophores of multiple drugs, have been increasingly applied in the development of anti-AD drugs. In this review, we give a brief description of the pathogenesis of AD and provide detailed discussions about the recent development of chemical structures of anti-AD agents (2013 up to present) that have multiple targets, such as amyloid-β peptide, Tau protein, cholinesterases, monoamine oxidase, β-site amyloid-precursor protein-cleaving enzyme 1, free radicals, metal ions (Fe2+, Cu2+, Zn2+) and so on. In this paper, we also added some novel targets or possible pathogenesis which have been reported in recent years for AD therapy. We hope that these findings may provide new perspectives for the pharmacological treatment of AD.

scholarly journals Top Priorities for Cerebroprotective Studies: A Paradigm Shift

Stroke ◽  
2021 ◽  
Author(s):  
Patrick Lyden ◽  
Alastair Buchan ◽  
Johannes Boltze ◽  
Marc Fisher ◽  
Keyword(s):  
Ischemic Stroke ◽  
Brain Tissue ◽  
Imaging Techniques ◽  
Neurovascular Unit ◽  
Clinical Trial Design ◽  
Clinical Work ◽  
Brain Regions ◽  
Tissue Imaging ◽  
Health Concern ◽  
Stroke Treatment

Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although “time is still brain,” tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.

scholarly journals Xiaoxuming Decoction: A Traditional Herbal Recipe for Stroke With Emerging Therapeutic Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Zhang ◽  
Yue Wang ◽  
Aiwen Chen ◽  
Xinwei Huang ◽  
Qianyu Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Alternative Therapy ◽  
Acute Stage ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
Endovascular Thrombectomy ◽  
Therapeutic Mechanisms ◽  
New Perspective

Xiaoxuming decoction (XXMD) has been traditionally used to manage stroke though debates on its clinical efficacy were present in the history. Till nowadays, it is still one of the most commonly used herbal recipes for stroke. One of the reasons is that a decent proportion of ischemic stroke patients still have residue symptoms even after thrombolysis with rt-PA or endovascular thrombectomy. Numerous clinical studies have shown that XXMD is an effective alternative therapy not only at the acute stage, but also at the chronic sequelae stage of ischemic stroke. Modern techniques have isolated groups of compounds from XXMD which have shown therapeutic effects, such as dilating blood vessels, inhibiting thrombosis, suppressing oxidative stress, attenuating nitric oxide induced damage, protecting the blood brain barrier and the neurovascular unit. However, which of the active compounds is responsible for its therapeutic effects is still unknown. Emerging studies have screened and tested these active compounds aiming to find individual compounds that can be used as drugs to treat stroke. The present study summarized both clinical evidence of XXMD in managing stroke and experimental evidence on its molecular mechanisms that have been reported recently using advanced techniques. A new perspective has also been discussed with an aim to provide new targets that can be used for screening active compounds from XXMD.

Abstract W MP7: Predictors and Implications of Capacity to Provide Informed Consent for Acute Ischemic Stroke Treatment Trials

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Hari Kishan R Indupuru ◽  
Loren Shen ◽  
Amber N Jacobs ◽  
Chunyan Cai ◽  
James C Grotta ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Informed Consent ◽  
Acute Ischemic Stroke ◽  
Stroke Patients ◽  
Stroke Treatment ◽  
Capacity To Consent ◽  
Decision Making Capacity ◽  
The Right ◽  
Study Designs

Background and objectives: Enrollment into AIS trials has always been limited by the ability of the patient to give informed consent or the availability of a Legally Authorized Representative (LAR) in decision making capacity on behalf of the patient. In this analysis we try to identify the factors contributing to an acute ischemic stroke (AIS) patient’s inability to give informed consent. We hypothesized that clinical features and demographics would differ between those patients with and without capacity to consent. Methods: This analysis includes patients who enrolled into the coordinating center of the prospective, randomized ARTSS-2 clinical trial (Argatroban + TPA for acute ischemic stroke) and also screen failures due to inability to consent. Data is collected prospectively in the study screening log. The data collected included age, gender, race, NIHSS, lesion location, ER arrival time and mode of consent (self-consent, LAR-consent and unable to consent). Results: Between 12/11 and 06/13, a total of 33 acute ischemic stroke patients received IV-tPA and were eligible for the ARTSS-2 study. While 19 were enrolled, 14/33 (42.4%) were otherwise eligible, but not enrolled due to inability to self-consent and no LAR present. Patients not enrolled due to lack of capacity to consent and without LAR present tended to have higher median NIHSS scores and greater proportions of drowsiness and aphasia compared to the other groups (see table). Conclusion: Approximately 2 in 5 AIS patients are not eligible for AIS clinical trials based solely on their lack of capacity for informed consent. It is remains ethically imperative that current clinical trials as well as future study designs address this disregarded group of patients who deserve the right to be able to participate in research. Addressing this group of patients through exception from informed consent (EFIC) will both extend research to all stroke patients, but also greatly enhance AIS research.

scholarly journals Repair Mechanisms of the Neurovascular Unit after Ischemic Stroke with a Focus on VEGF

2021 ◽  
Vol 22 (16) ◽  
pp. 8543
Author(s):  
Sunhong Moon ◽  
Mi-Sook Chang ◽  
Seong-Ho Koh ◽  
Yoon Kyung Choi
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Neural Stem Cells ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Neurovascular Unit ◽  
Regeneration Ability ◽  
Therapeutic Effects ◽  
Related Factors

The functional neural circuits are partially repaired after an ischemic stroke in the central nervous system (CNS). In the CNS, neurovascular units, including neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes maintain homeostasis; however, these cellular networks are damaged after an ischemic stroke. The present review discusses the repair potential of stem cells (i.e., mesenchymal stem cells, endothelial precursor cells, and neural stem cells) and gaseous molecules (i.e., nitric oxide and carbon monoxide) with respect to neuroprotection in the acute phase and regeneration in the late phase after an ischemic stroke. Commonly shared molecular mechanisms in the neurovascular unit are associated with the vascular endothelial growth factor (VEGF) and its related factors. Stem cells and gaseous molecules may exert therapeutic effects by diminishing VEGF-mediated vascular leakage and facilitating VEGF-mediated regenerative capacity. This review presents an in-depth discussion of the regeneration ability by which endogenous neural stem cells and endothelial cells produce neurons and vessels capable of replacing injured neurons and vessels in the CNS.

scholarly journals Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic Versus Acute Administration to Protect Heart, Brain, and Spinal Cord

2020 ◽  
Vol 40 (1) ◽  
pp. 161-187 ◽  
Author(s):  
Hylde Zirpoli ◽  
Chuchun L. Chang ◽  
Yvon A. Carpentier ◽  
Adina T. Michael-Titus ◽  
Vadim S. Ten ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Clinical Trials ◽  
Fatty Acid ◽  
Acute Treatment ◽  
Molecular Mechanisms ◽  
Acute Administration ◽  
Omega 3 ◽  
Omega 3 Fatty Acid ◽  
Novel Approaches ◽  
Brain And Spinal Cord

This article reviews novel approaches for omega-3 fatty acid (FA) therapeutics and the linked molecular mechanisms in cardiovascular and central nervous system (CNS) diseases. In vitro and in vivo research studies indicate that omega-3 FAs affect synergic mechanisms that include modulation of cell membrane fluidity, regulation of intracellular signaling pathways, and production of bioactive mediators. We compare how chronic and acute treatments with omega-3 FAs differentially trigger pathways of protection in heart, brain, and spinal cord injuries. We also summarize recent omega-3 FA randomized clinical trials and meta-analyses and discuss possible reasons for controversial results, with suggestions on improving the study design for future clinical trials. Acute treatment with omega-3 FAs offers a novel approach for preserving cardiac and neurological functions, and the combinations of acute treatment with chronic administration of omega-3 FAs might represent an additional therapeutic strategy for ameliorating adverse cardiovascular and CNS outcomes.

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