Hypothermic neuroprotection against acute ischemic stroke: The 2019 update.
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ABSTRACT:
SUBMITTER: Wu L
PROVIDER: S-EPMC7026854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Stroke is the second most common cause of global death following coronary artery disease. Time is crucial in managing stroke to reduce the rapidly progressing insult of the ischemic penumbra and the serious neurologic deficits that might follow it. Strokes are mainly either hemorrhagic or ischemic, with ischemic being the most common of all types of strokes. Thrombolytic therapy with recombinant tissue plasminogen activator and endovascular thrombectomy are the main types of management of acute ischemic stroke (AIS). In addition, there is a vital need for neuroprotection in the setting of AIS. Neuroprotective agents are important to investigate as they may reduce mortality, lessen disability, and improve quality of life after AIS. In our review, we will discuss the main types of management and the different modalities of neuroprotection, their mechanisms of action, and evidence of their effectiveness after ischemic stroke.
| S-EPMC9195142 | biostudies-literature
Project description:Excessive and unresolved neuroinflammation is part of the pathological cascade in brain injuries such as acute ischemia, as well as neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease. Particularly, timely resolution of inflammation is critical for the recovery and repair after brain injury. The nuclear factor-κB (NF-κB) signaling plays a central role in neuroinflammation through transcriptional induction of proinflammatory genes. Here, we report that TRIM9, a brain-specific member of the TRIpartite motif (TRIM) family with ubiquitin E3 ligase activity, is upregulated in the peri-infarct cortical areas of mouse brain upon ischemic stroke, and governs the resolution of NF-κB-mediated neuroinflammation. Mechanistically, neuronal TRIM9 sequestered β-TrCP, a component of the Skp-Cullin-F-box (SCF) E3 ligase complex, from ubiquitinating IκBα, thereby mitigating NF-κB-dependent inflammatory responses including production of proinflammatory mediators and infiltration of immune cells. Consequently, Trim9 deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological and neurological outcomes. Systemic administration of recombinant adeno-associated virus (AAV)-PHP.B, allowing brain-wide enriched TRIM9 expression, effectively resolved neuroinflammation and alleviated neuronal death in aging mice. This reveals that TRIM9 is essential for fine tuning of NF-κB-dependent neuroinflammation, and TRIM9-potentiation based therapy may offer a new approach for the treatment of stroke and inflammation-related neurological disorders.
2018-12-31 | GSE114652 | GEO
Project description:Acute ischemic stroke is a major cause of morbidity and mortality in developed countries. Intravenous thrombolysis with tissue plasminogen activator (tPA) within 4.5 hours of symptoms onset significantly improves clinical outcomes in patients with acute ischemic stroke. This narrow window for treatment leads to a small proportion of eligible patients to be treated. Intravenous or intra-arterial trials, combined intravenous/intra-arterial trials, and newer devices to mechanically remove the clot from intracranial arteries have been investigated or are currently being explored to increase patient eligibility and to improve arterial recanalization and clinical outcome. New retrievable stent-based devices offer higher revascularization rates with shorter time to recanalization and are now generally preferred to first generation thrombectomy devices such as Merci Retriever or Penumbra System. These devices have been shown to be effective for opening up occluded vessels in the brain but its efficacy for improving outcomes in patients with acute stroke has not yet been demonstrated in a randomized clinical trial. We summarize the results of the major systemic thrombolytic trials and the latest trials employing different endovascular approaches to ischemic stroke.
| S-EPMC4101197 | biostudies-literature
Project description:Background and purpose: A major gap in the field of ischemic preconditioning (IPC) is whether or not long-lasting neuroprotection can be achieved. Moreover, the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain. To fill these gaps, we tested the hypothesis that IPC exerts long-lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses, nuclear factor erythroid 2-related factor 2 (Nrf2). We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood-brain barrier-permeable Nrf2 activator, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-trifluoethyl amide (CDDO-TFEA).Methods: IPC was induced by transient middle cerebral artery occlusion (MCAO) for 12 min, and ischemic stroke was generated by MCAO for 60 min in wild-type (WT) or Nrf2 knockout (KO) mice. Sensorimotor function, learning/memory skills, and brain tissue loss were measured up to 35 days after stroke. Primary rodent cortical neurons from wildtype (WT) and Nrf2 KO mice were subjected to lethal oxygen-glucose deprivation (OGD) or a brief OGD episode as a preconditioning (PC) stimulus before OGD. Cell viability/death, lipid electrophile generation, and Nrf2 activation were measured. CDDO-TFEA or its vehicle was administered in vivo for three consecutive days before MCAO. Tissue loss and neurological tests were performed 35 days after stroke.Results: IPC significantly reduced sensorimotor deficits, post-stroke cognitive impairments, and brain tissue loss, 35 days after MCAO in WT mice. These enduring protective effects of IPC were inhibited in Nrf2 KO mice. In neuronal cultures, PC also endowed primary neurons with ischemic tolerance against OGD-induced cell death, an effect that was abolished by loss of Nrf2 expression in KO neurons. PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway. The mechanism underlying IPC may be translatable, as exogenous administration of the Nrf2 activator CDDO-TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO.Conclusions: IPC provides long-lasting neuroprotection against ischemic brain injury and post-stroke cognitive dysfunction. Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury.
| S-EPMC6953417 | biostudies-literature
Project description:Endovascular recanalization therapy (ERT) has been a standard of care for patients with acute ischemic stroke due to large artery occlusion (LAO) within 6 hours after onset, since five landmark ERT trials conducted by 2015 demonstrated its clinical benefit. Recently, two randomized clinical trials demonstrated that ERT, even in the late time window of up to 16 hours or 24 hours after last known normal time, improved the outcome of patients who had a target mismatch, defined as either clinical-core mismatch or perfusion-core mismatch, which prompted the update of national guidelines in several countries. Accordingly, to provide evidence-based and up-to-date recommendations for ERT in patients with acute LAO in Korea, the Clinical Practice Guidelines Committee of the Korean Stroke Society decided to revise the previous Korean Clinical Practice Guidelines of Stroke for ERT. For this update, the members of the writing group were appointed by the Korean Stroke Society and the Korean Society of Interventional Neuroradiology. After thoroughly reviewing the updated evidence from two recent trials and relevant literature, the writing members revised recommendations, for which formal consensus was achieved by convening an expert panel composed of 45 experts from the participating academic societies. The current guidelines are intended to help healthcare providers, patients, and their caregivers make well-informed decisions and to improve the quality of care regarding ERT. The ultimate decision for ERT in a particular patient must be made in light of circumstances specific to that patient.
| S-EPMC6736502 | biostudies-literature
Project description:Endovascular recanalization therapy (ERT) has been a standard of care for patients with acute ischemic stroke due to large artery occlusion (LAO) within 6 hours after onset, since five landmark ERT trials conducted by 2015 demonstrated its clinical benefit. Recently, two randomized clinical trials demonstrated that ERT, even in the late time window of up to 16 hours or 24 hours after last known normal time, improved the outcome of patients who had a target mismatch, defined as either clinical-core mismatch or perfusion-core mismatch, which prompted the update of national guidelines in several countries. Accordingly, to provide evidence-based and up-to-date recommendations for ERT in patients with acute LAO in Korea, the Clinical Practice Guidelines Committee of the Korean Stroke Society decided to revise the previous Korean Clinical Practice Guidelines of Stroke for ERT. For this update, the members of the writing group were appointed by the Korean Stroke Society and the Korean Society of Interventional Neuroradiology. After thoroughly reviewing the updated evidence from two recent trials and relevant literature, the writing members revised recommendations, for which formal consensus was achieved by convening an expert panel composed of 45 experts from the participating academic societies. The current guidelines are intended to help healthcare providers, patients, and their caregivers make well-informed decisions and to improve the quality of care regarding ERT. The ultimate decision for ERT in a particular patient must be made in light of circumstances specific to that patient.
| S-EPMC6549067 | biostudies-literature
Project description:While several large pivotal clinical trials recently revealed a substantial benefit of endovascular thrombectomy for acute ischemic stroke (AIS) caused by large-vessel occlusion, many patients still experience mediocre prognosis. Enlargement of the ischemic core, failed revascularization, incomplete reperfusion, distal embolization, and secondary reperfusion injury substantially impact the salvaging of brain tissue and the functional outcomes of AIS. Here, we propose novel concept of "Multiphase Adjuvant Neuroprotection" as a new paradigm that may help guide our search for adjunctive treatments to be used together with thrombectomy. The premise of multiphase adjuvant neuroprotection is based on the diverse and potentially nonoverlapping pathophysiologic mechanisms that are triggered before, during, and after thrombectomy therapies. Before thrombectomy, strategies should focus on preventing the growth of the ischemic core; during thrombectomy, improving recanalization while reducing distal embolization and maximizing reperfusion are of significant importance; after reperfusion, strategies should focus on seeking targets to reduce secondary reperfusion injury. The concept of multiphase adjuvant neuroprotection, wherein different strategies are employed throughout the various phases of clinical care, might provide a paradigm to minimize the final infarct size and improve functional outcome in AIS patients treated with thrombectomy. With the success of thrombectomy in selected AIS patients, there is now an opportunity to revisit stroke neuroprotection. Notably, if the underlying mechanisms of these neuroprotective strategies are identified, their role in the distinct phases will provide further avenues to improve patient outcomes of AIS.
| S-EPMC7045534 | biostudies-literature
Project description:Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.
| S-EPMC6561179 | biostudies-literature
Project description:Nonarteritic central retinal artery occlusion (NA-CRAO) is a variant of acute ischemic stroke (AIS) and is a cause of sudden severe loss of vision. There are guidelines by the American Heart Association and the American Stroke Association for the care of CRAO patients. This review explores the basis of retinal neuroprotection for CRAO and its potential for improving the outcome of NA-CRAO. Recently, there have been significant advances in research into the use of neuroprotection to treat retinal diseases, including retinal detachment, age-related macular degeneration, and inherited retinal diseases. Also, neuroprotective research in AIS has been extensive, and newer drugs tested, including Uric acid, Nerinetide, and Otaplimastat, with promising results. Progress in cerebral neuroprotection after AIS offers hope for retinal neuroprotection after CRAO; and a possibility of extrapolating research findings from AIS into CRAO. Combining neuroprotection and thrombolysis can extend the therapeutic window for NA-CRAO treatment and potentially improve outcomes. Experimented neuroprotection for CRAO includes Angiopoietin (Comp Ang1), KUS 121, Gene therapy (XIAP), and hypothermia. Efforts in the field of neuroprotection for NA-CRAO should focus on better imaging to delineate the penumbra after an acute episode of NA-CRAO (using a combination of high-definition optical coherence angiography and electrophysiology). Also, research should explore details of pathophysiologic mechanisms involved in NA-CRAO, allowing for further neuroprotective intervention, and closing the gap between preclinical and clinical neuroprotection.
| S-EPMC10239763 | biostudies-literature
Project description:Ischemic stroke is a common disease with high morbidity and mortality. Remote ischemic preconditioning (RIPC) can stimulate endogenous protection mechanisms by inducing ischemic tolerance to reduce subsequent damage caused by severe or fatal ischemia to non-ischemic organs. This study was designed to assess the therapeutic properties of RIPC in ischemic stroke and to elucidate their underlying mechanisms. Neurobehavioral function was evaluated with the modified neurological severity score (mNSS) test and gait analysis. PET/CT was used to detect the ischemic volume and level of glucose metabolism. The protein levels of cytochrome c oxidase-IV (COX-IV) and heat shock protein 60 (HSP60) were tested by Western blotting. TUNEL and immunofluorescence staining were used to analyze apoptosis and to observe the nuclear translocation and colocalization of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in apoptotic cells. Transmission electron microscopy (TEM) was used to detect mitochondrial-derived vesicle (MDV) production and to assess mitochondrial ultrastructure. The experimental results showed that RIPC exerted significant neuroprotective effects, as indicated by improvements in neurological dysfunction, reductions in ischemic volume, increases in glucose metabolism, inhibition of apoptosis, decreased nuclear translocation of AIF and EndoG from mitochondria and improved MDV formation. In conclusion, RIPC alleviates ischemia/reperfusion injury after ischemic stroke by inhibiting apoptosis via the endogenous mitochondrial pathway.
| S-EPMC7093414 | biostudies-literature