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Background: Oenothera rosea L'Her Ex. Aiton, presenting antioxidant and anti-inflammatory activities, is traditionally used to treat bruises and headaches and as a healing agent. This study aimed to investigate whether its organic fraction (EAOr) has neuroprotective properties against neuroinflammation in the context of ischemia/reperfusion. Methods: The chemical composition of EAOr was determined using HPLC techniques, and its neuroprotective activities were evaluated in a common carotid-artery ligation model for the induction of ischemia/reperfusion (I/R). The animals were supplemented with EAOR for 15 days. On the last day, the animals were rested for one hour, following which the common carotid-artery ligation procedure was performed to induce I/R. The neurological deficit was evaluated at 24 h after I/R using Bederson's scale, and the relative expression of inflammatory genes and structure of hippocampal neurons were analyzed at 48 h. Results: The chemical analysis revealed five major compounds in EAOr: gallic acid, rutin, ellagic acid, and glucoside and rhamnoside quercetin. EAOr prevented neurological deficit 24 h after I/R; led to the early activation of the AIF and GFAP genes; reduced Nfkb1, IL-1beta, Il-6 and Casp3 gene expression; and protected hippocampal neurons. Conclusions: Our findings demonstrate that EAOr contains polyphenol-type compounds, which could exert a therapeutic effect through the inhibition of neuroinflammation and neuronal death genes, thus maintaining hippocampal neurons. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke (AIS) is a challenging disease, which needs urgent comprehensive management. Endovascular thrombectomy (EVT), alone or combined with iv thrombolysis, is currently the most effective therapy for patients with acute ischemic stroke (AIS). However, only a limited number of patients are eligible for this time-sensitive treatment. Even though there is still significant room for improvement in the management of this group of patients, up until now there have been no alternative therapies approved for use in clinical practice. However, there is still hope, as clinical research with novel emerging therapies is now generating promising results. These drugs happen to stop or palliate some of the underlying molecular mechanisms involved in cerebral ischemia and secondary brain damage. The aim of this review is to provide a deep understanding of these mechanisms and the pathogenesis of AIS. Later, we will discuss the potential therapies that have already demonstrated, in preclinical or clinical studies, to improve the outcomes of patients with AIS. [ABSTRACT FROM AUTHOR]

Aims: To distinguish between the genuine cellular impact of the ischemic cascade by leukocytes and unspecific effects of edema and humoral components, two knock‐in mouse lines were utilized. Mouse lines Y731F and Y685F possess point mutations in VE‐cadherin, which lead to a selective inhibition of transendothelial leukocyte migration or impaired vascular permeability. Methods: Ischemic stroke was induced by a model of middle cerebral artery occlusion. Analysis contained structural outcomes (infarct volume and extent of brain edema), functional outcomes (survival analysis, rotarod test, and neuroscore), and the extent and spatial distribution of leukocyte migration (heatmaps and fluorescence‐activated cell sorting (FACS) analysis). Results: Inhibition of transendothelial leukocyte migration as in Y731F mice leads to smaller infarct volumes (52.33 ± 4719 vs. 70.43 ± 6483 mm3, p =.0252) and improved motor skills (rotarod test: 85.52 ± 13.24 s vs. 43.06 ± 15.32 s, p =.0285). An impaired vascular permeability as in Y685F mice showed no effect on structural or functional outcomes. Both VE‐cadherin mutations did not influence the total immune cell count or spatial distribution in ischemic brain parenchyma. Conclusion: Selective inhibition of transendothelial leukocyte migration by VE‐cadherin mutation after ischemic stroke in a mouse model leads to smaller infarct volumes and improved motor skills. [ABSTRACT FROM AUTHOR]

Retinal ischemia gives rise to a complex spectrum in which the cumulative profile of ischemia of the middle and inner retina can be highly variable. We reviewed the current knowledge on paracentral acute middle maculopathy (PAMM) pathophysiology and accompanying risk factors, the middle and inner retinal vasculature and blood flow, and the vulnerability of the middle retina in vaso-occlusive disorders. The inner nuclear layer (INL) is easily affected by slight degrees of retinal hypoperfusion and ischemia. INL infarction starts at perivenular sites, manifesting as skip PAMM lesions and a fern-like appearance in cross-sectional and en face views, respectively. With horizontal progression, INL infarction may develop into diffuse globular PAMM. If vertical progression occurs, the entire middle and inner portions of the retina can be affected. Transmural infarction of the middle and inner retina would be at the end of this spectrum. This gradient of ischemic progression resembles an ischemic cascade. We review the evidence supporting the term "retinal ischemic cascade," which encompasses a broad continuum of manifestations with roots in middle retinal infarction. With this terminology, variations in spatial and temporal progression and resolution of ischemia can also be delivered; it further enables addressing the possible associations between the middle and inner retinal ischemic patterns. [ABSTRACT FROM AUTHOR]

Objectives: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events.Material and methods: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events.Results: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events.Conclusion: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events.Key Points: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events.Graphical Abstract: This single-center retrospective study evaluated the long-term (~5 years) prognostic value of dipyridamole stress cardiac magnetic resonance (CMR) in patients with known or suspected coronary artery disease (CAD), assessing the impact of both key phases of the ischemic cascade (perfusion and wall motion).We considered 322 consecutive patients who underwent dipyridamole stress CMR. Abnormal wall motion at rest and after dipyridamole, perfusion at stress and at rest, and late gadolinium enhancement (LGE) were analyzed. End-points were non-fatal myocardial infarction, unplanned late revascularization (60 days after CMR), and cardiac death.Forty-four patients were excluded because they underwent early revascularization (within 60 days after stress CMR), leading to a final population of 278 patients (73 females, 62.42 ± 10.50 years). A positive stress CMR was found in 78 (28.1%) patients; 50 patients had a reversible stress perfusion defect in at least one myocardial segment and 28 had a reversible stress perfusion defect plus worsening of stress wall motion in comparison with the rest. During a mean follow-up time of 59.34 ± 31.72 months, 37 (13.3%) cardiac events were recorded: 10 cardiac deaths, one non-fatal myocardial infarction, and 26 late revascularization after unstable angina or myocardial infarction. According to the Cox regression analysis, age, diabetes mellitus, previous revascularization, left ventricular ejection fraction (LVEF), reversible perfusion and perfusion + motion defect, and LGE were significant univariate prognosticators. The presence of associated wall motion abnormality (WMA) did not provide additional prognostic stratification in comparison to the only perfusion defect. In the multivariate Cox regression, the independent predictive factors were diabetes (hazard-ratio-HR = 5.64, p < 0.0001), reversible perfusion defect and reversible perfusion + motion defect vs normal stress CMR (HR = 6.43, p < 0.0001, and HR = 4.57, p = 0.004; respectively), and LVEF (HR = 0.96, p = 0.010).A positive dipyridamole stress CMR predicted a higher long-term risk of cardiovascular events, but the presence of inducible WMA did not show any additional prognostic value over the reversible perfusion defect.QuestionThe long-term incremental prognostic value of inducible wall motion abnormalities by stress cardiac MR in patients with known or suspected CAD requires investigation.FindingsThe presence of inducible wall motion abnormalities did not offer additional prognostic value in comparison to the only reversible perfusion defect.Clinical relevanceIndependent from the presence of wall motion abnormalities, more aggressive management may be appropriate in patients with reversible perfusion defects to reduce the long-term risk of cardiovascular events. [ABSTRACT FROM AUTHOR]

Stroke is among the leading causes of death and disability worldwide. However, despite long-term research yielding numerous candidate neuroprotective drugs, there remains a lack of effective neuroprotective therapies for ischemic stroke patients. Among the factors contributing to this deficiency could be that single-target therapy is insufficient in addressing the complex and extensive mechanistic basis of ischemic brain injury. In this context, lipids serve as an essential component of multiple biological processes and play important roles in the pathogenesis of numerous common neurological diseases. Moreover, in recent years, fatty acid-binding proteins (FABPs), a family of lipid chaperone proteins, have been discovered to be involved in the onset or development of several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. However, comparatively little attention has focused on the roles played by FABPs in ischemic stroke. We have recently demonstrated that neural tissue-associated FABPs are involved in the pathological mechanism of ischemic brain injury in mice. Here, we review the literature published in the past decade that has reported on the associations between FABPs and ischemia and summarize the relevant regulatory mechanisms of FABPs implicated in ischemic injury. We also propose candidate FABPs that could serve as potential therapeutic targets for ischemic stroke. [ABSTRACT FROM AUTHOR]

Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade. [ABSTRACT FROM AUTHOR]

Ischemic stroke, characterized by the sudden loss of blood flow in specific area(s) of the brain, is the leading cause of permanent disability and is among the leading causes of death worldwide. The only approved pharmacological treatment for acute ischemic stroke (intravenous thrombolysis with recombinant tissue plasminogen activator) has significant clinical limitations and does not consider the complex set of events taking place after the onset of ischemic stroke (ischemic cascade), which is characterized by significant pro-oxidative events. The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of a great number of antioxidant and/or defense proteins, has been pointed as a potential pharmacological target involved in the mitigation of deleterious oxidative events taking place at the ischemic cascade. This review summarizes studies concerning the protective role of Nrf2 in experimental models of ischemic stroke, emphasizing molecular events resulting from ischemic stroke that are, in parallel, modulated by Nrf2. Considering the acute nature of ischemic stroke, we discuss the challenges in using a putative pharmacological strategy (Nrf2 activator) that relies upon transcription, translation and metabolically active cells in treating ischemic stroke patients. [ABSTRACT FROM AUTHOR]