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Purpose To present select cases of paracentral acute middle maculopathy (PAMM) demonstrating progressive vascular occlusion and the ischemic cascade, and illustrate scenarios in which therapeutic intervention may be considered. Design Perspective. Methods Review and interpretation of selected literature, with perspective on the evaluation and management of patients with PAMM lesions. Multimodal imaging, including cross sectional and en face optical coherence tomography (OCT), of three illustrative cases of PAMM are presented, with progressive vascular occlusion and evidence of the ischemic cascade noted in two of the cases. Results All three cases showed evidence of PAMM at baseline, including perivenular PAMM in two of the cases. Progression from a mild central retinal vein occlusion (CRVO) to a more severe CRVO was noted in the first case, while the second case progressed from an incomplete to complete central retinal artery occlusion. In the third case, there was resolution of PAMM lesions associated with partial CRAO after the patient was started on aspirin. Conclusions Perivenular PAMM can be the only presenting sign of retinal vascular occlusion. In such cases it is important to differentiate between partial CRVO and incomplete CRAO as the underlying cause. This Perspective provides guidance on making this important distinction, which plays a critical role in directing the nature and urgency of the systemic work up. In patients with PAMM caused by partial retinal arterial occlusion, a benign empirical approach such as low-dose aspirin (81 mg) may be reasonable to reduce the likelihood of subsequent vision loss from progression to complete arterial occlusion. A clinical trial, however, is necessary to support such a strategy.

Introduction.The prevalence of cerebral vascular diseases is steadily increasing worldwide. Cerebral stroke represents the most serious of them, being one of the leading causes of mortality and disability of the population. Reduction of morbidity and mortality from stroke can be achieved by improving preventive measures aimed at the correction of risk factors. The review presents domestic and foreign literature data on the risk factors of ischemic stroke and the system of primary prevention of acute ischemic brain lesions.Materials and methods.Data from eLibrary, MedLine, Scopus, Springerlink, and the scientific electronic library «Cyberleninka» were analyzed.Results and Discussion.The authors give an overview of pathological conditions that can lead to the development of cerebral vascular accident. Methods of primary prevention of ischemic stroke are considered in accordance with the European guidelines on stroke management. Current views on the correction of modifiable risk factors (arterial hypertension, diabetes mellitus, hyperlipidemia, heart and vascular pathology, etc.) are presented. Recommendations on lifestyle and body weight reduction are given. In addition to the well-known information, the authors present the data of new studies on the role of vitamin D in the ischemic cascade and consider the possible pathogenetic mechanisms of this effect. The review also provides information on the association of vitamin D deficiency with other pathological conditions that are the causes of ischemic stroke and the effect of vitamin D on the volume of ischemic lesions, the severity of the outcome and the risks of repeated vascular accidents.Conclusion.The study of risk factors for ischemic stroke and the development of primary prevention methods is one of the priority areas of modern neurology, since it will improve the system of care for patients with cerebrovascular disease.

Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs in vivo, achieve effective drug accumulation at the target site, enhance the therapeutic effect and meanwhile reduce the side effect. In this review, we comprehensively describe the pathophysiology of stroke, traditional treatment strategies and emerging nanomedicines, summarize the barriers and methods for transporting nanomedicine to the lesions, and illustrate the latest progress of nanomedicine in treating ischemic stroke, with a view to providing a new feasible path for the treatment of cerebral ischemia., Graphical abstract This review summarizes various nanomedicines, including liposomes, micelles, dendrimer, nanoparticles, and exosomes, which have been applied for the treatment of ischemic stroke. It especially focuses on their abilities to normalize various abnormalities at different phases of ischemic cascade, such as dissolving the clot and salvaging the penumbra.Image 1

Stroke is the second, and in some countries the third cause of mortality in the population and one of the causes of disability in the adult population. According to statistics, in 2018, 15 million cases of stroke and 6 million deaths were diagnosed,The only currently approved treatments for acute stroke are intravenous tissue plasminogen activator (rtPA) and intra-arterial thrombectomy, which are used in less than 10% and 1% of patients, respectively.The literature review is devoted to the pathophysiology and molecular mechanisms of damage in cerebral ischemia. The modern concept of two strategies of cell therapy is discussed: neuroprotection and remodeling; the role of stem cells in reducing local and systemic inflammation, neurogenesis and angiogenesis, increasing neuronal plasticity, and protecting the blood-brain barrier, the role of paracrine factors and extracellular vesicles is shown.Methods of stem cell delivery are described: direct intracerebral transplantation, intraventricular and intrathecal, intravenous and intraarterial; the number of cells, their type and optimal delivery time depending on the acute, subacute and chronic periods of stroke. We also described recently designed the radially branched deployment (RBD) device and Cleveland multiport catheter for convection-enhanced delivery in which a cell-delivery catheter can be deployed at various angles and depths from a single longitudinal cannula. Finally, data on the completed 15 clinical trials from 2015 to the present, in which 513 patients took part, are presented. A detailed analysis of the efficacy and safety of cell therapy has been carried out.

Stroke is a leading cause of death and disability worldwide. Several mechanisms are involved in the pathogenesis of ischemic stroke (IS). The contributory role of the inflammatory and immunity processes was demonstrated both in vitro and in animal models, and was confirmed in humans. IS evokes an immediate inflammatory response that involves complex cellular and molecular mechanisms. All components of the innate and adaptive immunity systems are involved in several steps of the ischemic cascade. In the early phase, inflammatory and immune mechanisms contribute to the brain tissue damage, whereas, in the late phase, they participate to the tissue repair processes. In particular, damage-associated molecular patterns (DAMPs) appear critical for the promotion of altered blood brain barrier permeability, leukocytes infiltration, tissue edema and brain injury. Conversely, the activation of regulatory T lymphocytes (Tregs) plays protective effects. The identification of specific cellular/molecular elements belonging to the inflammatory and immune responses, contributing to the brain ischemic injury and tissue remodeling, offers the advantage to design adequate therapeutic strategies. In this article, we will present an overview of the knowledge on inflammatory and immunity processes in IS, with a particular focus on the role of DAMPs and leukocytes infiltration. We will discuss evidence obtained in preclinical models of IS and in humans. The main molecular mechanisms useful for the development of novel therapeutic approaches will be highlighted. The translation of experimental findings to the human disease is still a difficult step to pursue. Further investigations are required to fill up the existing gaps.

Обзор посвящен рассмотрению современных подходов к фармакологической модуляции структурно-функционального состояния митохондриального аппарата нейронов как перспективной стратегии терапии ишемического инсульта головного мозга, составляющего по современным оценкам до 85% всех случаев острого нарушения мозгового кровообращения. В обзоре проведен анализ классических представлений о нейропротекции как терапии, направленной на блокирование ключевых патогенетических звеньев «ишемического каскада», в контексте современного понимания приоритетной роли коррекции митохондриальной дисфункции в ограничении механизмов повреждения при церебральной ишемии. Обсуждаются возможности применения препаратов плейотропного нейропротекторного действия, реализующих митохондриально-направленные защитные эффекты через модуляцию активности транскрипционного коактиватора PGC-1α (peroxisome proliferator-activated receptor-1γ coactivator-1α), контролирующего процессы биогенеза митохондрий, ангиогенеза, ферментативное звено антиоксидантной системы. The review addresses modern approaches to pharmacological modulation of structure and function of the neuronal mitochondrial apparatus. This is a promising strategy for therapy of ischemic stroke, which accounts for up to 85% of all cases of acute cerebrovascular disease. The review analyzes classical concepts of neuroprotection as a therapy aimed at blocking key pathogenetic components of the “ischemic cascade”. These concepts are based on current ideas about the importance of correcting mitochondrial dysfunction for alleviation of damage in cerebral ischemia. The authors discussed possibilities of using pleiotropic neuroprotectors that implement mitochondrial-targeted protective effects by modulating the activity of transcriptional coactivator, peroxisome proliferator-activated receptor-1γ coactivator-1α (PGC-1α), which controls mitochondrial biogenesis, angiogenesis, and the enzymatic antioxidant system.

According to the World Health Organization, about 5 million people die every year from cerebrovascular disease. At the same time, the proportion of cerebral infarction, or ischemic stroke (IS), among forms of acute cerebrovascular accident reaches 80-85%. Despite the active study of biochemical and morphological changes leading to acute cerebrovascular ischemia, the problem of early diagnosis, prevention, as well as predicting the outcome of this disease is still relevant. There is no doubt that the interruption of the ischemic cascade at earlier stages can be accompanied by a greater effect of treatment. A timely and effective pharmacological intervention requires a clear understanding of the pathochemical and biological processes underlying acute ischemia at the molecular level. High mortality and disability accompanying acute IS, dictate the need to create new diagnostic and prognosis algorithms both in the acute period of IS, and in the recovery period. According to some authors, elucidation of the pathways that underlie the pathogenetic mechanisms acting in the penumbra are of great clinical interest for the development of new diagnostic and therapeutic strategies. Studying the mechanisms of apoptosis and autophagy of neurons in the dynamics of the acute period of IS, modulation of the autophagy process in the penumbra zone can contribute to the development of new methods for the diagnosis and treatment of acute IS. The review presents the results of the latest experimental studies on the role of apoptosis and autophagy in the development of acute cerebral ischemia and attempts to modulate these processes in order to influence the ischemic cascade. The review was based on sources from such international and national data bases as Scopus, Web of Science, Springer, RINC.

Stroke is a neurological emergency, where the mechanism of the blood supply to the brain is impaired, resulting in brain cell ischemia and death. Neuroinflammation is a key component in the ischemic cascade that results in cell damage and death after cerebral ischemia. The triggering receptor expressed on myeloid cells-1 (TREM-1) modulates neuroinflammation after acute ischemic stroke. In the present study, 60 patients with acute ischemic stroke, who had been subjected to neurological examinations and National Institutes of Health Stroke Scale (NIHSS) and brain magnetic resonance imaging studies, were enrolled in the emergency room of Kaohsiung Chang Gung Memorial Hospital. Twenty-four healthy volunteers were recruited as controls. The serum levels of soluble TREM-1 (sTREM-1), human S100 calcium-binding protein B (S100B), and proinflammatory cytokines and chemokines, including tumor necrosis &alpha, (TNF-&alpha, ), interleukin 1&beta, interleukin 6 (IL-6), interleukin 8, and interferon-&gamma, were measured immediately after acute ischemic stroke. The serum levels of sTREM-1, TNF&alpha, IL-6, and S100B were correlated with the stroke volume and NIHSS, after acute ischemic stroke. Additionally, the serum levels of sTREM-1 were significantly positively correlated with S100B. The functional outcomes were evaluated 6 months after ischemic stroke by the Barthel index, which was correlated with the age and levels of sTREM-1 and S100B. We suggest that acute ischemic stroke induces neuroinflammation by the activation of the TREM-1 signaling pathway and the downstream inflammatory machinery that modulates the inflammatory response and ischemic neuronal cell death. From a translational perspective, our results may allow for the development of a new therapeutic strategy for acute ischemic stroke by targeting the TREM-1 signaling pathway.

Objective To evaluate the distribution of capillary non-perfusion (CNP) in superficial and deep capillary plexuses (SCP and DCP) in eyes with diabetic retinopathy (DR). Methods In this retrospective case series, macular optical coherence tomography angiography (OCTA) images were obtained from eyes with DR without diabetic macular edema (DME). The area of CNP in SCP and DCP was delineated using an automated approach after excluding the foveal avascular zone (FAZ) and major retinal vessels. The distribution and spatial correlation of the CNP in each layer were analyzed. Results Forty-three eyes of 27 patients with DR with a mean age of 59.10 ± 9.05 years were included. The mean CNP area in SCP was statistically significantly higher than DCP (0.722 ± 0.437 mm2 vs. 0.184 ± 0.145 mm2 , respectively, p Conclusion In DR, SCP is more ischemic than DCP. This is in contrast to the previously described oxygenation-dependent ischemic cascade following acute retinal vascular occlusions. This study provides further insight into the retinal ischemia in DR.

Statistics of the World Health Organization (WHO) show that the cerebrovascular disease is the second most frequent cause of death and the third – as the main disabling factor in the working age population. Timely treatment is the key to quickly recovering ischemic tissue. According to the different ischemic cascade stages, the variety of the treatment combinations are proposed. American Stroke Association guidelines 2018 contains no neuroprotectors. In this regard, there remains a need for a biochemical agent successfully blocking one or more stages of the ischemic cascade, preventing cell apoptosis. Melatonin is also considered as such substance due to its neuroprotective properties. The main function of melatonin is the regulation of the sleep-wake cycle. The nuclear and membrane receptors in various organs determines other biological effects of this hormone. The ability of melatonin to regulate the blood pressure, oncogenesis, ovaries cycle, retina function and differentiation of osteoblasts was found. The significant neuroprotective potential of melatonin is realized through the antioxidant, anti-excitotoxic and anti-inflammatory properties. The positive effect on the ischemic lesion size and stroke-related pathological conditions (delirium, insomnia) has been demonstrated both in animal experiments and in clinical studies.

The ischemic cascade is initiated in the hypoperfused region of the brain that leads to neuronal cell death. Identification of multi-target inhibitor against prominent molecular mediators of ischemic cascade might be a suitable strategy to combat cerebral ischemic stroke. The present study is designed to evaluate the neuroprotective efficacy of chlorogenic acid (CGA) in the global cerebral ischemic rat model. The effective dose of CGA was evaluated on the basis of reduction in cerebral infarction area percentage, Evans blue extravasation, and restoration of brain water content. The expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and caspase-3 was evaluated by immunohistochemistry and morphological and cellular alterations in the cortex were observed by brain histology. The level of glutamate, calcium, and nitrate in different regions of the brain, as well as cerebrospinal fluid (CSF), was evaluated. The level of calcium and nitrate was compared with ifenprodil-an antagonist of N-methyl-D-aspartate receptor (NMDAR) and 7-nitroindazole-an inhibitor of neuronal nitric oxide synthase (nNOS) respectively. Further, molecular docking was performed to compare the inhibition potential of CGA against NMDAR and nNOS with their inhibitors. Dose optimization results revealed that intranasal administration of CGA (10 mg/kg b.w.) significantly reduced the cerebral infarction area, Evans blue extravasation and restored the brain water content compared with ischemia group. It also significantly reduced the calcium, nitrate, and glutamate levels compared with ischemia group in the cortex, hippocampus cerebellum, and CSF. Immunohistochemical analysis revealed that CGA significantly reduced the expression of TNF-α, iNOS, and caspase-3 as compared with the ischemia group. In molecular docking study, CGA displayed similar binding interaction as that of Ifenprodil and 7-nitroindazole with NMDAR and nNOS respectively. The current findings suggest that the treatment with CGA confers neuroprotection in global ischemic insult by inhibiting and downregulating the different molecular markers of cerebral ischemia.

The advent of mechanical thrombectomy and increasing alteplase use have transformed the care of patients with acute ischemic stroke. Patients with major arterial occlusions with poor outcomes now have a chance of returning to independent living in more than half of the cases. However, many patients with these severe strokes suffer major disability despite these therapies. The search is ongoing for agents that can be combined with thrombectomy to achieve better recovery through halting infarct growth and mitigating injury after ischemic stroke. Several studies in animals and humans have demonstrated that therapeutic hypothermia (TH) offers potential to interrupt the ischemic cascade, reduce infarct volume, and improve functional independence. We performed a literature search to look up recent advances in the use of TH surrounding the science, efficacy, and feasibility of inducing TH in modern stroke treatments. While protocols remain controversial, there is a real opportunity to combine TH with the existing therapies to improve outcome in adults with acute ischemic stroke.

Purpose To demonstrate the ability of widefield en face swept source optical coherence tomography (OCT) imaging to monitor peri-venular fern-like patterns of paracentral acute middle maculopathy (PAMM) associated with retinal arterial occlusions. Observations The peri-venular fern-like pattern of PAMM was diagnosed on the 12 × 12 mm en face structural OCT images from three patients. Fluorescein angiography images were unremarkable. Over time, all three patients demonstrated significant improvement in visual acuity with resolution of their peri-venular PAMM. Conclusions The peri-venular fern-like pattern of PAMM is usually associated with retinal vein occlusions, but we identified three cases with this pattern in eyes with presumed incomplete retinal arterial occlusions. Our cases support the ischemic cascade theory that begins within the deep capillary plexus and ascends in the retina depending on the severity of the ischemic event. Using the 12 × 12 mm en face structural OCT images, we are able to demonstrate a wider area of ischemia in PAMM compared with the traditional 6 × 6 mm scans.

Ischemic Stroke precedes depression . Post Stroke Depression (PSD) is a major driver for poor recovery, negative quality of life, poor rehabilitation outcomes and poor functional ability. This systematic reviews confirmed the post stroke depression as the norm as complex ischemic cascade involve the bioenergetic failure, deranged iron homeostasis ( calcium influx, Na influx, potassium efflux etc) excitotoxicity, acidotoxicity,disruption of the blood brain barrier, cytokine mediated cytotoxicity, reactive oxygen mediated toxicity , activation of cyclooxygenase pathway and generation of toxic products, infiltration of immune mediated cells resulting the cell death and deranged neuronal networks in mood related brain regions. This review focus on the pathobiology of stroke in the context and make the argument that PSD is the norm after a stroke rather than the exception.

Objectives: Baseline-core-infarct volume is a critical factor in patient selection and outcome in acute ischemic stroke (AIS) before mechanical thrombectomy (MT). We determined whether oxygen extraction efficiency and arterial collaterals, two different physiologic components of the cerebral ischemic cascade, interacted to modulate baseline-core-infarct volume in patients with AIS-LVO undergoing MT triage.Methods: Between January 2015 and March 2018, consecutive patients with an AIS and M1 occlusion considered for MT with a baseline MRI and perfusion-imaging were included. Variables such as baseline-core-infarct volume [mL], arterial collaterals (HIR: TMax > 10 s volume/TMax > 6 s), high oxygen extraction (HOE, presence of the brush-sign on T2*) were assessed. A linear-regression was used to test the interaction of HOE and HIR with baseline-core-infarct volume, after including potential confounding variables.Results: We included 103 patients. Median age was 70 (58–78), and 63% were female. Median baseline-core-infarct volume was 32 ml (IQR 8–74.5). Seventy six patients (74%) had HOE. In a multivariate analysis both favorable HIR collaterals (p = 0.02) and HOE (p = 0.038) were associated with lower baseline-core-infarct volume. However, HOE significantly interacted with HIR (p = 0.01) to predict baseline-core-infarct volume, favorable collaterals (low HIR) with HOE was associated with small baseline-core-infarct whereas patients with poor collaterals (high HIR) and HOE had large baseline-core-infarct.Conclusion: While HOE under effective collateral blood-flow has the lowest baseline-core-infarct volume of all patients, the protective effect of HOE reverses under poor collateral blood-flow and may be a maladaptive response to ischemic stroke as measured by core infarctions in AIS-LVO patients undergoing MT triage.

Purpose To report a case of paracentral acute middle maculopathy (PAMM) and evidence of the ischemic cascade documented with spectral domain optical coherence tomography (SD-OCT) following radiation treatment of a choroidal melanoma. Observations A healthy young patient was evaluated for an asymptomatic choroidal nevus in the left eye. Fundus examination was remarkable for a choroidal melanocytic lesion that measured 1.8 mm in thickness by initial B-scan ultrasound. Clinical examination 6 months later showed growth of the tumor at several margins with new subretinal fluid, and a B-scan measured thickness of 1.9 mm. The lesion was diagnosed as a small choroidal melanoma and treated with gamma knife radiation with a dose of 3000 cGy. Sixteen months later, examination showed signs of radiation retinopathy including cotton wool spots and PAMM via SD-OCT and OCT angiography and evidence of the ischemic cascade i.e. alternating zones of middle and combined middle and inner retinal layer infarction. Conclusions and Importance: Radiation retinopathy can include signs of microvascular damage and ischemia including lesions such as cotton wool spots and PAMM. A case is presented in this report of radiation retinopathy with OCT evidence of PAMM and the ischemic cascade.

Cerebral ischemia constitutes the most frequent type of cerebrovascular disease. The reduction of blood supply to the brain initiates the ischemic cascade starting from ionic imbalance to subsequent glutamate excitotoxicity, neuroinflammation and oxidative stress, eventually causing neuronal death. Previously, the authors have demonstrated the in vitro cytoprotective and antioxidant effects of a new arylidene malonate derivative, KM-34, against oxidizing agents like hydrogen peroxide, glutamate or Fe3+/ascorbate. Here, we examined for the first time the neuroprotective effect of KM-34 on ischemia/reperfusion models. In vitro, treatment with 10 and 50 μM KM-34 reduced the cellular death (propidium iodide incorporation) induced by oxygen glucose deprivation (OGD) in rat organotypic hippocampal slices cultures. In vivo, stroke was induced in male Wistar rats through middle cerebral artery occlusion (MCAO), followed by 23 h of reperfusion. KM-34 was orally administered 105 min after MCAO onset. We noticed that 1 mg/kg KM-34 reduced infarct volume and neurological score, and increased the latency to fall in the Hanging Wire test compared to vehicle-treated ischemic animals. While ischemic and sham-operated groups showed similar horizontal locomotor activity, vertical counts decreased after MCAO, suggesting that vertical movements are more sensitive to the ischemic injury. Treatment with KM-34 also alleviated the mitochondrial impairment (ROS generation, swelling and membrane potential dissipation) induced by transient MCAO but not significant alterations were found in oxidative stress parameters. Overall, the study provides preclinical evidences confirming the neuroprotective effects of a novel synthetic molecule and paved the way for future investigations regarding its therapeutic potential against brain ischemia/reperfusion injury.

To report a case of branch retinal artery occlusion associated with paracentral acute middle maculopathy on spectral-domain optical coherence tomography presumably related to heavy cannabis consumption.Retrospective case report. Spectral-domain optical coherence tomography, fluorescein angiography, and optical coherence tomography angiography were performed.A 21-year-old healthy man described the acute onset of superior visual field loss in his right eye. He admitted smoking approximately 15 g daily of cannabis for several weeks during COVID-19 confinement. Ophthalmoscopic examination of the right eye showed inferotemporal retinal whitening. Spectral-domain optical coherence tomography illustrated evidence of the ischemic cascade with diffuse hyperreflectivity of the inner and middle retinal layers within the central region of the retinal infarct and paracentral acute middle maculopathy at the border of the infarct. Optical coherence tomography angiography demonstrated predominant flow signal loss at the level of the deep retinal capillary plexus. Fluorescein angiography and complete systemic workup were unremarkable.Branch retinal artery occlusion and paracentral acute middle maculopathy may be related to heavy cannabis use as the result of transient arterial vasospasm.

This review is aimed at understanding the clinical connect betweenischemia and tissue changes by firstly, describing the historical and clinicopathophysiologicalperspective of deformation imaging and secondly clinical advances of tissue imaging; nextthe body of evidence currently available for this methodology; and finally, the feasibility andbarriers to clinical translation. There will also be a brief review of the feasibility and currentuse of contrast for perfusion with flash imaging Myocardial contrast echocardiography (MCE) for the detection of ischemia. Myocardial ischemia detection has come a long way since the clinicalsymptom was scientifically described several centuries ago and matched withpathophysiological correlation. The majority of cases are atherosclerotic macro-vesselobstruction or thrombosis and lesser degree various other forms of obstruction includingdynamic changes in both small and large vascular beds. On a statistical level most lifethreatening cases are atherosclerotic and correlated physiologically with an ischemiccascade. With the identification of non-linearity of ischemic cascade and hence concepts ofischemic constellation, it is increasingly clear that circumstances can determine which aspectof the cascade is noted and altering the probability of significant ischemi a. Myocardial deformation and perfusion imaging adds a novel perspective of myocardial performance under stress.

The complexity of the ischemic cascade is based on the integrated crosstalk of every cell type in the neurovascular unit. Depending on the features of the ischemic insult, several cell death mechanisms are triggered, such as apoptosis, necroptosis, ferroptosis/oxytosis, ETosis or pyroptosis, leading to reactive astrogliosis. However, emerging evidence demonstrates a dual role for the immune system in stroke pathophysiology, where it exerts both detrimental and also beneficial functions. In this review, we discuss the relevance of several cell death modalities and the dual role of the immune system in stroke pathophysiology. We also provide an overview of some emerging immunomodulatory therapeutic strategies, amongst which saponins, which are promising candidates that exert multiple pharmacological effects., Highlights • Several cell death mechanisms coexist in stroke pathophysiology. • Neurons are more vulnerable to necroptosis than glial cells. • Inhibitors of receptor-interacting protein kinases and of ferroptosis induce neuroprotection. • Saponins exert modulatory effects on inflammation and neuronal cell death in stroke.

Background Stroke is a leading cause of death and disability worldwide. Recently, brain secondary damage has been hypothesized to be a key aggravating element in an ischemic cascade. However, the interaction between cerebral infarction and immune organs has yet to be fully understood. In this study, we investigated the changes in the rat brain, spleen, thymus, mesenteric lymph node, and liver at 3, 7, and 13 days after transient middle cerebral artery occlusion (tMCAO) by immunohistochemistry. Material and methods Rat models of stroke were made by tMCAO. Functional assessment was performed 3 h, and 1, 3, 5, 7, 9, 11, and 13 days after MCAO. Rat organs were harvested for 2,3,5-triphenyltetrazolium chloride staining and Immunohistochemistry. Results The CD8α+ T cells was found to decrease in the spleen, thymus, mesenteric lymph node, and liver, whereas it increased in the brain. Those of Iba1+ and CD68+ macrophages were decreased in the spleen, thymus, and mesenteric lymph node, whereas they were elevated in the brain and liver. Ki67+ cells showed the same characteristics as macrophages, and increased numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells were found in the spleen, mesenteric lymph node, liver, and brain. Conclusions The present results demonstrated that stroke is a systemic disease, which not only affects the brain, but also induces responses of immune organs. On the basis of these results, a systemic treatment might be a good strategy for clinical stroke care.

Item does not contain fulltext Non-invasive imaging plays a growing role in the diagnosis and management of ischemic heart disease from its earliest manifestations of endothelial dysfunction to myocardial infarction along the myocardial ischemic cascade. Experts representing the North American Society for Cardiovascular Imaging and the European Society of Cardiac Radiology have worked together to organize the role of non-invasive imaging along the framework of the ischemic cascade. The current status of non-invasive imaging for ischemic heart disease is reviewed along with the role of imaging for guiding surgical planning. The issue of cost effectiveness is also considered. Preclinical disease is primarily assessed through the coronary artery calcium score and used for risk assessment. Once the patient becomes symptomatic, other imaging tests including echocardiography, CCTA, SPECT, PET and CMR may be useful. CCTA appears to be a cost-effective gatekeeper. Post infarction CMR and PET are the preferred modalities. Imaging is increasingly used for surgical planning of patients who may require coronary artery bypass.

For decades, numerous pharmacological and non-pharmacological strategies have been evaluated without success to limit the consequences of the ischemic cascade, but more rarely the therapies were explored as add on remedies on individuals also receiving reperfusion therapies. It is plausible that these putative neuroprotectants never reached the ischemic brain in adequate concentrations. Currently, the concept of neuroprotection incorporates cerebral perfusion as an obligatory substrate upon which ischemic brain survival depends, and it is plausible that some of the compounds tested in previous neuroprotection trials might have resulted in more favorable results if reperfusion therapies had been co-administered. Nonetheless, pharmacological or mechanical thrombectomy are frequently powerless to fully reperfuse the ischemic brain despite achieving a high rate of recanalization. This review covers in some detail the importance of the microcirculation, and the barriers that may hamper flow reperfusion at the microcirculatory level. It describes the main mechanisms leading to microcirculatory thrombosis including oxidative/nitrosative stress and refers to recent efforts to ameliorate brain perfusion in combination with the co-administration of neuroprotectants mainly aimed at harnessing oxidative/nitrosative brain damage.

Fast and accurate diagnosis of stroke is crucial for the immediate application of the right therapy to patients. However, rapid diagnosis is still a challenge since an ischemic stroke cannot be identified based only on clinical assessment. CT or MRI imaging is required to rule out hemorrhagic stroke since thrombolytic therapy can lead to increased intracranial bleeding and further aggravation of hemorrhagic stroke. In addition, clinical situations that imitate the signs and symptoms of stroke may also impede the rapid diagnosis and treatment of stroke victims. It is therefore of value to discover non-invasive tests that aim to quickly distinguish stroke from stroke mimics and distinguish ischemic from hemorrhagic stroke. Identifying blood biomarkers of stroke is an active area of research since their potential use is not limited to diagnosis and differentiation, but can be applied to prognosis and patient monitoring - monitoring the effectiveness of applied therapy and/or diagnose possible complications. However, their use has been limited so far not only for reasons related to patients and the disease (heterogeneity of stroke etiology, the complexity of the ischemic cascade, the impact of the blood-brain barrier (BBB) on diffusion of blood biomarkers, and difficulties in obtaining consent from stroke patients) but also for reasons that related to laboratory measurement of these biomarkers (pre-analytical and analytical issues as well as interpretation of laboratory measurements). Until today, many biomarkers have been identified, however none so far have shown sufficient sensitivity and specificity in order to be used in the clinical setting. In this review, we will focus on ischemic stroke and we aim to highlight these problems and also investigate if these are due to stroke complexity or due to our limited knowledge of pre-analytical requirements for many of these molecules and the questionable quality of the assays used.

The article shows the world experience of metabolic therapy use in the treatment of ischemic stroke. The issue still remains prominent. The reasonability of prescribing metabolic drugs is not completely clear, its effectiveness has not been fully proved, despite numerous studies which show only trends. The article presents an overview of the most popular drugs of different pharmacological groups with a metabolic effect which affect different parts of the ischemic cascade. Ethylmethylhydroxypyridine succinate and cytoflavin have predominantly antihypoxic effect, improve functional outcome and neurological functions, and normalize overall well-being and adaptation. Cerebrolysin is a complex of low molecular weight biologically active peptides derived from the pig’s brain. It has a multimodal effect on the brain, helps to reduce the volume of cerebral infarction, restores neurologic functions and improves the functional outcome. Cortexin is a mixture of cattle brain polypeptides, also has a complex action that provides the most complete reversion of neurological deficit, improves cognitive functions and the functional outcome, reduces the level of paroxysmal convulsive readiness and improves bioelectric activity of the brain. Citicoline is a precursor of cell membrane key ultrastructures, contributes to significant reduction in the volume of cortical brain damage, improves cholinergic transmission, which results in better clinical outcome, even despite the questionable impact on the neurological status. Choline Alfoscerate is a precursor of choline, and the use of the drug significantly limits the growth of the cerebral infarction area starting from the first day of therapy, leads to reversion of neurological symptoms and achievement of rehabilitation goals. Actovegin is deproteinized derivative of calf blood, activates metabolism in tissues, improves trophism and stimulates regeneration. In a large study, it was shown that Actovegin improved cognitive function in patients who had experienced a stroke,. The drug does not significantly improve the neurological status of patients after a stroke, but it reduces the risk of the stroke development in the next 10 years. Thus, we analyzed mechanisms of medical substances action and data of experimental and clinical studies, including ones after thrombolytic therapy and with inclusion of drugs for primary and secondary prevention of ischemic stroke. The reasonability and effectiveness of prescribing a combination of drugs of different pharmacological groups affecting brain metabolism remains controversial, since the excessive drug treatment may have complications. The safety of metabolic therapy is in doubt, and some of authors views presented confirm the need for additional large independent studies.

Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate. Vinpocetine's actions to improve cation channel permeability and cell marker immunoreactivity following ischemia appeared to be limited to NMDA activation with no changes observed following kainate stimulation. Vinpocetine's actions were lost in the presence of an NMDA receptor inhibitor further suggesting they may be secondary to NMDA receptor activation. NMDA receptor function was also necessary for vinpocetine's actions on glucose availability during ischemia but not lactate dehydrogenase (LDH) activity in the ischemic retina suggesting not all of vinpocetine's actions are linked to NMDA receptor function. These results may explain vinpocetine's effectiveness as a neuroprotective agent as the NMDA receptor is implicated in the pathogenesis of ischemia in a range of tissues of the central nervous system.

Ischemic lesion is a common cause of various diseases in humans. Brain tissue is especially sensitive to this type of damage. A common reason for the appearance of an ischemic area is a stop in blood flow in some branch of the vasculature system. Then, a decreasing concentration gradient results in a low mean level of oxygen in surrounding tissues. After that, the biochemical ischemic cascade spreads. In this review, we examine these well-known events from a new angle. It is stressed that there is essential evidence to predict the formation of an ischemic micro-area at the base of vascular bifurcation geometries. Potential applications to improve neuroprotection are also discussed.

Stroke represents one of the most common causes of brain's vulnerability for many millions of people worldwide. The plethora of physiopathological events associated with brain ischemia are regulate through multiple signaling pathways leading to the activation of oxidative stress process, Ca dyshomeostasis, mitochondrial dysfunction, proinflammatory mediators, excitotoxicity and/or programmed neuronal cell death. Understanding this cascade of molecular events is mandatory in order to develop new therapeutic strategies for stroke. In this review article, we have highlighted the pleiotropic effects of melatonin to counteract the multiple processes of the ischemic cascade. Additionally, experimental evidence supports its actions to ameliorate ischemic long-term behavioural and neuronal deficits, preserving the functional integrity of the blood-brain barrier, inducing neurogenesis and cell proliferation through receptor-dependent mechanism, as well as improving synaptic transmission. Consequently, the synthesis of melatonin derivatives designed as new multitarget-directed products has focused a great interest in this area. This latter has been reinforced by the low cost of melatonin and its reduced toxicity. Furthermore, its spectrum of usages seems to be wide and with the potential for improving human health. Nevertheless, the molecular and cellular mechanisms underlying melatonin¿s actions need to be further exploration and accordingly, new clinical studies should be conducted in human patients with ischemic brain pathologies., CdlR thanks IS Carlos III, research contract under Miguel Servet Program (CP10/00531) and FIS project (grant PI13/00789IS) for support. JE thanks IS Carlos III, research contract under Miguel Servet Program (CP14/00008) for support.

In stroke (cerebral ischemia), despite continuous efforts both at the experimental and clinical level, the only approved pharmacological treatment has been restricted to tissue plasminogen activator (tPA). Stroke is the leading cause of functional disability and mortality throughout worldwide. Its pathophysiology starts with energy pump failure, followed by complex signaling cascade that ultimately ends in neuronal cell death. Ischemic cascade involves excessive glutamate release followed by raised intracellular sodium and calcium influx along with free radicals’ generation, activation of inflammatory cytokines, NO synthases, lipases, endonucleases and other apoptotic pathways leading to cell edema and death. At the pre-clinical stage, several agents have been tried and proven as an effective neuroprotectant in animal models of ischemia. However, these agents failed to show convincing results in terms of efficacy and safety when the trials were conducted in humans following stroke. This article highlights the various agents which have been tried in the past but failed to translate into stroke therapy along with key points that are responsible for the lagging of experimental success to translational failure in stroke treatment.

Ischemic stroke is one of the leading causes of adult disability and cognitive impairment worldwide. Thrombolysis has been a standard treatment for ischemic stroke. However, due to the short time-window for thrombolytic agent administration, most patients cannot benefit from rt-PA treatment by missing this therapeutic time-window. Neuroprotection aims to improve the survival of brain tissues by impeding the devastating ischemic cascade events. Even though the neuroprotectant can be applied in the acute, subacute, and chronic stages of ischemic stroke, their therapeutic efficiencies are compromised by the blood-brain barrier (BBB) that restricts brain drug uptake. Therefore, specifically increasing neuroprotectant delivery in brain ischemia will improve the treatment efficiency. In this chapter, we first introduce the dynamics of structure, permeability, and transcytosis of BBB after the onset of ischemic stroke. Temporarily increasing para-endothelial diffusion, taking advantage of the up-regulated intra-endothelial transcytosis, and attenuating the pro-inflammatory response are summarized as the key issues to increase drug delivery efficiency in the acute, subacute, and chronic stages, respectively. Finally, recent reported strategies facilitating brain delivery of neuroprotectants by overcoming the BBB via intra-endothelial transcytosis or para-endothelial diffusion are introduced. Overall, elucidating BBB dynamics after ischemic attack helps to design new drug delivery vectors to maximize neuroprotective response, but minimize the potential side effects induced by the vascular leakage. Up-regulating neuroprotectant uptake in brain ischemia will benefit majority of ischemic stroke patients who lost the chance for thrombolytic treatment.

Cardiovascular diseases are a large contributor to the global mortality rate. Non-invasive imaging techniques, such as computed tomography (CT) imaging, have been playing a growing role in the risk assessment, diagnosis, and prognosis of coronary artery disease (CAD). One of the main challenges in the evaluation of CAD is the establishment of the optimal workflow to evaluate the anatomical as well as the functional aspects of CAD in all phases of the ischemic cascade.The research described in this thesis investigates the possibilities of CT to perform both morphological and functional evaluation of CAD and it is debated whether CT can be used clinically for the visualization of the entire ischemic cascade.Results show that the diagnostic and prognostic value of CT procedures for coronary artery disease evaluation can be improved by adding additional functional information to the anatomical evaluation. This was concluded from research done on two new technologies analyzing the blood flow through the coronaries and through the heart muscle. Besides that, important questions regarding protocol optimization and standardization have been investigated. Although CT shows great potential for the evaluation of CAD, the clinical workflow and combination of techniques to be used is yet to be optimized. Automating processes, for example with the use of Artificial Intelligence (AI), can enhance the clinical implementation and can help the field of cardiac radiology deal with the increased demand for cardiac imaging.

MPI evaluates myocardial perfusion defect (PD) and changes in blood flow (MBF) that occur early in the ischemic cascade, eventually leading to angina. Few data exist on link between MPI findings and health status. Health status was collected using the Seattle Angina Questionnaire (SAQ-7, 0-100

Myocardial perfusion abnormalities are the first sign of the ischemic cascade in the development of coronary artery disease (CAD). Thus, the early detection of myocardial perfusion abnormalities is significant for the prevention of CAD. Recently, a novel noninvasive method named Cardiodynamicsgram (CDG) has been proposed for early detection of CAD. This study aims to evaluate the predictive value of CDG in myocardial perfusion abnormalities for suspected ischemic heart disease. In the study, 86 suspected patients were enrolled. Standard 12-lead ECG and CDG were performed simultaneously before single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Diagnostic accuracy of CDG for myocardial perfusion abnormalities detection is assessed using SPECT MPI as the reference standard. Of these 86 suspected patients, 37 patients were positive in CDG, 49 patients were negative in CDG. Diagnostic accuracy of CDG at presentation for myocardial perfusion abnormalities was 84.9%, sensitivity 84.0%, and specificity 89.4%. Furthermore, of the 10 patients whose SPECT MPI results are reverse redistribution, 9 patients were positive in CDG. Underlying causes of false positive CDG findings included the factors that can change the stability of cardiac electrical conduction and measurement noise. Myocardial remodeling in patients with old myocardial infarction might be the major cause of false negative findings. Results show a good consistency between the CDG and SPECT MPI in evaluating myocardial perfusion abnormalities. It suggests that CDG might be used as a cost-effective tool for assessing the myocardial perfusion abnormalities in the clinic.

Neuroprotective treatments in ischemic stroke are focused to reduce the pernicious effect of excitotoxicity, oxidative stress and inflammation. However, those cellular and molecular mechanisms may also have beneficial effects, especially during the late stages of the ischemic stroke. The objective of this study was to investigate the relationship between the clinical improvement of ischemic stroke patients and the time-dependent excitotoxicity and inflammation. We included 4295 ischemic stroke patients in a retrospective study. The main outcomes were intra and extra-hospital improvement. High glutamate and IL-6 levels at 24 hours were associated with a worse intra-hospital improvement (OR:0.993, 95%CI: 0.990–0.996 and OR:0.990, 95%CI: 0.985–0.995). High glutamate and IL-6 levels at 24 hours were associated with better extra-hospital improvement (OR:1.13 95%CI, 1.07–1.12 and OR:1.14, 95%CI, 1.09–1.18). Effective reperfusion after recanalization showed the best clinical outcome. However, the long term recovery is less marked in patients with an effective reperfusion. The variations of glutamate and IL6 levels in the first 24 hours clearly showed a relationship between the molecular components of the ischemic cascade and the clinical outcome of patients. Our findings suggest that the rapid reperfusion after recanalization treatment blocks the molecular response to ischemia that is associated with restorative processes.

To study an effect of cortexin on neurological symptoms and oxidative stress as part of the ischemic cascade in chronic cerebral ischemia (CCI), I-II stages.The multicenter randomized controlled study included 189 patients with CCI, 42 (22.2%) men and 147 (77.8%) women, mean age 64.3±0.5 years. Patients were randomized into three groups. Group 1 received intramuscular injection of 20 mg of cortexin, group 2 received 10 mg of cortexin; group 3 received basic treatment only. The duration of treatment was 10 days, the treatment course was repeated after 6 months. The patients were examined at baseline and during treatment (in total 5 times). Along with clinical and neurological examinations, some scales and tests ('Fedin Outpatient scale of chronic brain ischemia', MFI-20, Spiegel sleep scale, the Zung self-rating depression scale, Spielberger's inventory, the clock-drawing test, the 5-word test) were used. The severity of oxidation stress was assessed by the content of reduced SH-groups and total superoxide dismutase activity.A dose-dependent effect of cortexin on the severity of neurological disorders, asthenia, sleep disturbance was shown. Antidepressant and anxiolytic effects were insignificant and were determined after repeated courses of the drug. The laboratory data confirmed the antioxidant effect regardless of the dose of cortexin. The safety and good tolerability of the drug were shown.Цель исследования. Изучение дозозависимого эффекта кортексина при неврологических нарушениях и его влияния на некоторые звенья ишемического каскада (выраженность окислительного стресса) при хронической ишемии мозга (ХИМ) I-II стадии. Материал и методы. Обследовали 189 больных (42 мужчины и 147 женщин) с ХИМ; средний возраст 64,3±0,5 года. Больные были разделены на три группы: пациентам 1-й группы было назначено внутримышечное введение 20 мг кортексина в сутки, 2-й группы - 10 мг в сутки, 3-я группа (сравнения) получала базовую терапию. Первый курс лечения продолжался 10 сут, повторный проводили через 6 мес. До лечения и в процессе наблюдения (5 визитов) проводили общее клиническое и неврологическое обследования с применением следующих шкал: амбулаторной шкалы хронической ишемии мозга А.И. Федина, астении MFI-20, сна Шпигеля, депрессии Цунга, тревоги Спилбергера, а также нейропсихологические тесты ('рисование часов' и '5 слов'). Выраженность окислительного стресса определялась по содержанию восстановленных SH-групп. Результаты и заключение. Выявлено дозозависимое терапевтическое действие препарата на общую выраженность неврологических нарушений, астенический синдром, диссомнию. Динамика когнитивных показателей была выраженной в обеих группах,получавших терапию кортексином, но не зависела от дозировки препарата. Антидепрессивный и анксиолитический эффекты были незначительными и проявляли себя после назначения повторных курсов препарата. Данные лабораторных исследований подтвердили не зависевшее от дозы антиоксидантное действие кортексина. Была подтверждена безопасность применения препарата и его хорошая переносимость.

Purpose To analyze the spectrum of ischemia associated with paracentral acute middle maculopathy (PAMM) in eyes with acute retinal vascular occlusion and to describe an ischemic cascade. Design A retrospective observational case series. Methods Patients presenting with PAMM secondary to acute retinal vascular occlusion were identified. Analysis of multimodal imaging was performed at baseline and at follow-up visits to elucidate the patterns and progression of ischemia within the retinal layers. Results Multimodal retinal imaging from 16 eyes of 16 patients with acute retinal vascular occlusion associated with PAMM was studied. Analysis of en face optical coherence tomography (OCT) segmentation of the inner nuclear layer (INL) identified distinct patterns of PAMM correlating with the severity of ischemia and not the type of occlusion. A perivenular fern-like PAMM pattern was associated with better visual outcomes (average final visual acuity was 20/25). This pattern was noted to sequentially progress in 2 cases to a diffuse globular PAMM pattern in the INL, or to a pattern of ischemia involving both the middle and inner retinal layers with commensurate vision loss. Globular patterns of PAMM or ischemia involving both the middle and inner retina correlated with poorer visual outcomes (average final visual acuity was counting fingers at 5.5 ft). These various patterns of ischemia developed in eyes with retinal vascular occlusions in which blood flow through the retinal capillary plexuses was present but was significantly reduced and delayed. Conclusions This study describes OCT findings suggestive of an ischemic cascade in eyes with retinal vascular occlusion. The middle retina at the level of the deep capillary plexus, especially at the venular pole, may be more vulnerable to ischemic injury.

The treatment of acute ischemic stroke is still an unresolved clinical problem since the only approved therapeutic intervention relies on early blood flow restoration through pharmacological thrombolysis, mechanical thrombus removal, or a combination of both strategies. Due to their numerous complications and to the narrow time-window for the intervention, only a minority of stroke patients can actually benefit from revascularization procedures, highlighting the urgent need of identifying novel strategies to prevent the progression of an irreversible damage in the ischemic penumbra. During the past three decades, the attempts to target the pathways implicated in the ischemic cascade (e.g., excitotoxicity, calcium channels overactivation, reactive oxygen species (ROS) production) have failed in the clinical setting. Based on a better understanding of the pathobiological mechanisms and on a critical reappraisal of most failed trials, numerous findings from animal studies have demonstrated that targeting the immune system may represent a promising approach to achieve neuroprotection in stroke. In particular, given the dualistic role of distinct components of both the innate and adaptive arms of the immune system, a strategic intervention should be aimed at establishing the right equilibrium between inflammatory and reparative mechanisms, taking into consideration their spatio-temporal recruitment after the ischemic insult. Thus, the application of immunomodulatory drugs and their ability to ameliorate outcomes deserve validation in patients with acute ischemic stroke.

Stroke is an important cause of mortality and disability worldwide. Immediately after stroke onset, the ischemic cascade initiates and deleteriously affects neural cells. Time to reperfusion therapy is a critical determinant of functional recovery in stroke patients. Although recent trials have shown the significant efficacy of endovascular thrombectomy, either alone or with intravenous tissue plasminogen activator, in improving the functional outcomes of stroke patients with large vessel occlusion, hours can pass before patients receive reperfusion therapy. Moreover, many patients do not meet the eligibility criteria to receive reperfusion treatments. Therefore, an adjunct and alternative agent that can protect ischemic neuronal tissue during the hyperacute phase until reperfusion therapy can be administered may prevent further brain damage and enhance functional recovery. Memantine is a US Food and Drug Administration approved drug for the treatment of Alzheimer’s disease. Memantine blocks overstimulated N-methyl-d-aspartate receptors and prevents neurotoxicity caused by massive glutamate release. Preclinical studies show that memantine decreases infarction volume and improves neurologic outcomes. However, few clinical studies have evaluated the safety and efficacy of memantine in stroke patients. This review article summarizes the current evidence for the role of memantine in the treatment of ischemic stroke and highlights areas for future research.

Nowadays, there are two complementary approaches to treatment of patients with ischemic stroke: reperfusion and neuroprotection. The main purpose of neuroprotection is to intervene ischemic cascade at every stage of the pathological process and thus avoid the death of nerve cells and expand the therapeutic window for reperfusion therapy. The use of drugs with neurotrophic, antioxidant and neuroregenerative effects is pathogenically explained at all stages of post stroke rehabilitation. Ethylmethylhydroxypyridine succinate (mexidol) is a derivative of succinic acid with antihypoxic, membrane protective, nootropic, anticonvulsant and sedative action. The majority of researchers confirmed the positive effect of mexidol expressed as the marked regression of neurological deficit and wider opportunities for further early rehabilitation. The results of the randomized double blind multicenter placebo-controlled, parallel-group trial of the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA) were published in 2017. The results of the study showed the best positive dynamics of neurological function recovery in case of timely treatment with mexidol with the following two month therapy. The safety of the long-term use of mexidol was confirmed.На сегодняшний день существуют два взаимодополняющих направления в ведении больных с ишемическим инсультом: максимально ранние восстановление кровотока (реперфузия) и защита мозговой ткани от ишемического поражения (нейропротекция). Основная цель нейропротекции - вмешаться в события ишемического каскада, заблокировать звенья патологического процесса, предотвратить гибель нервных клеток в зоне ишемической полутени и расширить 'терапевтическое окно' для реперфузионной терапии. Применение препаратов, обладающих нейротрофическими, антиоксидантными и нейрорегенеративными эффектами, патогенетически обосновано на всех этапах восстановительного лечения после инсульта. Этилметилгидроксипиридина сукцинат (мексидол) представляет собой производное янтарной кислоты. Препарат оказывает антигипоксическое, мембранопротективное, ноотропное, противосудорожное, анксиолитическое действие. При изучении нейропротективного препарата мексидол у больных с инсультами абсолютным большинством исследователей отмечен положительный эффект в виде выраженного регресса неврологического дефицита, более широких возможностей для последующей ранней реабилитации. В 2017 г. опубликованы результаты мультицентрового проспективного двойного слепого плацебо-контролируемого исследования эффективности и безопасности мексидола при длительной последовательной терапии у пациентов в остром и раннем восстановительном периодах полушарного ишемического инсульта (ЭПИКА). Результаты исследования продемонстрировали лучшую положительную динамику восстановления нарушенных неврологических функций при раннем назначении мексидола и продолжении терапии до 2 мес. В ходе исследования была доказана безопасность длительного применения мексидола.

Therapeutic hypothermia (TH) is a potent neuroprotective therapy in experimental cerebral ischemia, with multiple effects at several stages of the ischemic cascade. In animals, TH is so powerful that all preclinical stroke studies require strict temperature control. In humans, multiple clinical studies documented powerful protection with TH after accidental neonatal hypoxic-ischemic injury and global cerebral ischemia with return of spontaneous circulation after cardiac arrest. National and international guidelines recommend TH for selected survivors of global ischemia, with profound benefits seen. Recently, a study comparing target temperature 33-36°C failed to demonstrate significant effects in cardiac arrest patients. Additionally, clinical trials of TH for head trauma and stroke have so far failed to confirm benefit in humans despite a vast preclinical literature. Therefore, it is now critical to understand the fundamental explanation for the success of TH in some, but famously not all, clinical trials. TH in animals appears to work when used soon after ischemia onset; for a short duration; and at a deep target temperature.

Dipyridamole stress cardiac magnetic resonance (CMR) evaluates the key phases (perfusion and wall motion) of the ischemic cascade. We sought to determine the prognostic value of dipyridamole stress-CMR in consecutive patients symptomatic for chest pain. Seven hundred and ninety-three consecutive patients symptomatic for chest pain underwent dipyridamole stress-CMR and were followed up for 810 ± 665 days. Patients were classified in group 1 (no- reversible ischemia), group 2 (stress perfusion defect alone), and group 3 [stress perfusion defect plus abnormal wall motion (AWM)]. End points were "all cardiac events" (myocardial infarction, cardiac death and revascularization) and "hard cardiac events" (all cardiac events excluding revascularization). One hundred and ninety-five (24 %) all cardiac events and 53 (7 %) hard cardiac events were observed. All and hard cardiac event rates in groups 1, 2, and 3 were 11 %, 49 %, 69 % and 4 %, 8 %, 21 %, respectively, with a higher rate in group 2 vs. group 1 (p

Developing new treatment strategies for acute ischemic stroke in the last twenty years has offered some important successes, but also several failures. Most trials of neuroprotective therapies have been uniformly negative to date. Recent research has reported how excitatory amino acids act as the major excitatory neurotransmitters in the cerebral cortex and hippocampus. Furthermore, other therapeutic targets such as free radical scavenger strategies and the anti-inflammatory neuroprotective strategy have been evaluated with conflicting data in animal models and human subjects with acute ischemic stroke. Whereas promising combinations of neuroprotection and neurorecovery, such as citicoline, albumin and cerebrolysin have been tested with findings worthy of further evaluation in larger randomized clinical trials. Understanding the complexities of the ischemic cascade is essential to developing pharmacological targets for acute ischemic stroke in neuroprotective or flow restoration therapeutic strategies.

On a subcellular level, atherogenesis is characterized by the translocation of proatherogenic lipoproteins into the arterial wall. An inflammatory response involving complex repair mechanisms subsequently causes maladaptive vascular changes resulting in coronary stenosis or occlusion. The chronology of the underlying processes occurring from atherosclerosis to myocardial ischemia affect the selection and interpretation of diagnostic testing. An understanding of the ischemic cascade, atherosclerosis, coronary remodeling, plaque morphology, and their relationship to clinical syndromes is essential in determining which diagnostic modalities are useful in clinical practice.

Caveolae are specialized plasma membrane micro-invaginations of most mammalian cell types. The organization and function of caveolae are carried out by their coat proteins, caveolins and adaptor proteins, cavins. Caveolae/caveolins physically interact with membrane-associated signaling molecules and function in cholesterol incorporation, signaling transduction and macromolecular transport/permeability.Recent investigations have implicated a check-and-balance role of caveolae in the pathophysiology of cerebral ischemia. Caveolin knockout mice displayed exacerbated ischemic injury, whereas caveolin peptide exerted remarkable protection against ischemia/reperfusion injury. This review attempts to provide a comprehensive synopsis of how caveolae/caveolins modulate blood-brain barrier permeability, pro-survival signaling, angiogenesis and neuroinflammation, and how this may contribute to a better understanding of the participation of caveolae in ischemic cascade. The role of caveolin in the preconditioning-induced tolerance against ischemia is also discussed.Caveolae represent a novel target for cerebral ischemia. It remains open how to manipulate caveolin expression in a practical way to recapitulate the beneficial therapeutic outcomes. Caveolin peptides and associated antagomirs may be efficacious and deserve further investigations for their potential benefits for stroke.

Glutamate receptors are the integral cellular components associated with excitotoxicity mechanism induced by the ischemic cascade events. Therefore the glutamate receptors have become the major molecular targets of neuroprotective agents in stroke researches. Recent studies have demonstrated that a Group I metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) preconditioning elicits neuroprotection in the hippocampal slice cultures exposed to toxic level of N-methyl-d-aspartate (NMDA). We further investigated the preconditioning effects of (S)-3,5-DHPG on acute ischemic stroke rats. One 10 or 100μM of (S)-3,5-DHPG was administered intrathecally to Sprague-Dawley adult male rats, 2h prior to induction of acute ischemic stroke by middle cerebral artery occlusion (MCAO). After 24h, neurological deficits were evaluated by modified stroke severity scores and grid-walking test. All rats were sacrificed and infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining. The serum level of neuron-specific enolase (NSE) of each rat was analyzed by enzyme-linked immunosorbent assay (ELISA). One and 10μM of (S)-3,5-DHPG preconditioning in the stroke rats showed significant improvements in motor impairment (P0.01), reduction in the infarct volume (P0.01) and reduction in the NSE serum level (P0.01) compared to the control stroke rats. We conclude that 1 and 10μM (S)-3,5-DHPG preconditioning induced protective effects against acute ischemic insult in vivo.

Background: Stroke is the second cause of mortality in the world and third leading cause of disability in surviving victims. Cerebral ischemic cascade involves multiple pathways that can result in motor and cognitive deficits. The current treatment strategy focuses mainly on motor recovery, and the management of post-stroke cognitive impairment is largely neglected. Similarly, very few studies have explored the prophylactic combined synergetic treatment strategies that have the potential to target multiple pathways in the ischemic cascade to alleviate vascular cognitive impairment (VCI) in the event of an ischemic stroke. Choline and docosahexaenoic acid (Cho-DHA) are both essential neuronal membrane phospholipid precursors, known to be important in enhancing cognitive functions. The objective of present study was to explore the prophylactic efficacy of combined Cho-DHA supplementation (Cho-DHA suppl.) in attenuating VCI in a rodent model of ischemic brain injury. Methods: An 10-months-old male Wistar rats were subdivided into four groups (n=8/group); normal control (NC), bilateral common carotid artery occlusion (BCCAO) induced ischemic brain injury group, sham BCCAO (S-BCCAO) group, and prophylactic combined Cho-DHA suppl. BCCAO group. Subsequently, all groups of rats were tested for cognition and neuro-morphological changes in the hippocampus. Results: BCCAO rats showed significant learning and memory deficits (p

Background and Purpose— Transient ischemic attack (TIA) initiates an ischemic cascade without resulting in frank infarction and, as such, represents a novel model to study the effects of this ischemic cascade and secondary neurodegeneration in humans. Methods— Patients with suspected TIA underwent acute brain perfusion imaging, and those with acute ischemia were enrolled into a prospective observational study. We collected baseline and 90-day magnetic resonance imaging, including MP-RAGE (high-resolution T1 sequence) and cognitive assessment with the Montreal Cognitive Assessment. Brain morphometry and within patient statistical analysis were performed to identify changes between baseline and 90-day imaging and clinical assessments. Results— Fifty patients with TIA with acute perfusion lesions were studied. All patients experienced a decrease in global cortical gray matter ( P =0.005). Patients with anterior circulation TIA (n=31) also had a significant reduction in the volume of the pons ( P P P =0.002), frontal lobe ( P P =0.003), and thalamus ( P =0.016). Patients with an anterior perfusion lesion on acute imaging also had a significant decrease in Montreal Cognitive Assessment between baseline and day 90 ( P =0.027), which may be related to the volume of thalamic atrophy ( R 2 =0.28; P =0.009). Conclusions— In a prospective observational study, patients with TIA confirmed by acute perfusion imaging experienced a significant reduction in global gray matter and focal structural atrophy related to the area of acute ischemia. The atrophy also resulted in a proportional decreased cognitive performance on the Montreal Cognitive Assessment. Further studies are required to identify the mechanisms of this atrophy.

Ischemic stroke is a major cause of death and disability worldwide. Thrombolysis by tissue plasminogen activator is the only pharmacological treatment approved for clinical practice, but has a narrow therapeutic window and poor efficacy when the cell death cascade is activated. Numerous drugs that are thought to protect neurons against injury have previously failed in human trials despite showing efficacy in experimental models of stroke. Herein, we reviewed the main pre-clinical results of the neuroprotective effects of JM-20, a new hybrid molecule, against brain ischemia. JM-20 appears to protect the brain from ischemic damage by interfering with several elements of the ischemic cascade: antiexcitotoxic, anticalcic, antioxidant, antiapoptotic, and anti-inflammatory. Its ability to protect not only neurons but also glial cells together with its ability to target and preserve mitochondrial function makes JM-20 a promising molecule that may be able to shield the whole neurovascular unit. The multimodal and multi-cell action of JM-20 may explain the high degree of protection observed in a rat model of brain ischemia, as assayed through histological (hematoxylin-eosin, and luxol fast blue staining), neurochemical (glutamate and aspartate levels in cerebrospinal fluid), mitochondrial functionality and behavioural (neurological scale) analysis at doses of 4 and 8mg/kg. Furthermore, the wide therapeutic window of JM-20 of 8h also suggests that this molecule could be of potential interest in situations where brain perfusion is compromised.

Stroke is a devastating disorder that significantly contributes to death, disability and healthcare costs. In ischemic stroke, the only current acute therapy is recanalization, but the narrow therapeutic window less than 6 h limits its application. The current challenge is to prevent late cell death, with concomitant therapy targeting the ischemic cascade to widen the therapeutic window. Among potential neuroprotective drugs, cyclin-dependent kinase inhibitors such as (S)-roscovitine are of particular relevance. We previously showed that (S)-roscovitine crossed the blood–brain barrier and was neuroprotective in a dose-dependent manner in two models of middle cerebral artery occlusion (MCAo). According to the Stroke Therapy Academic Industry Roundtable guidelines, the pharmacokinetics of (S)-roscovitine and the optimal mode of delivery and therapeutic dose in rats were investigated. Combination of intravenous (IV) and continuous sub-cutaneous (SC) infusion led to early and sustained delivery of (S)-roscovitine. Furthermore, in a randomized blind study on a transient MCAo rat model, we showed that this mode of delivery reduced both infarct and edema volume and was beneficial to neurological outcome. Within the framework of preclinical studies for stroke therapy development, we here provide data to improve translation of pre-clinical studies into successful clinical human trials.

Background: Sensitivity of dipyridamole stress echocardiography (SE) is often lower than required. The aim of the present work is the evaluation of the association of dipyridamole and exercise echocardiography. Methods: From June 2007 to January 2011, 259 consecutive patients referred to Camposampiero Echocardiography Laboratory underwent SE. Stress protocol started with dipyridamole infusion of 0.84 mg/kg over 6 min. In patients without a new dyssynergy after dipyridamole, SE was carried on with supine exercise. If endocardial border detection was suboptimal, ultrasound contrast agent was used. Coronary angiography was performed in positive patients. The events recorded during the follow-up were cardiac death, nonfatal myocardial infarction (hard events), and coronary revascularization. Results: Of 259 patients, 74 had a positive result: 37 were positive after infusion of dipyridamole, and 37 became positive during exercise. All 74 positive patients underwent coronary angiography: 67 had significant coronary artery disease (36 positive with dipyridamole, and 31 positive with exercise), and 7 had not significant artery disease. In positive patients, the coronary revascularizations were 40. Furthermore, 3 of the 185 negative patients underwent coronary revascularization. During follow-up of 20 ± 10 months, 6 (8.1%) hard events occurred in positive patients. No hard event was observed in negative patients. Conclusions: Dipyridamole SE with the addition of exercise can be proposed as a strategy to carry on the ischemic cascade and to identify the patients who elude the dipyridamole alone SE. A negative result is suggestive of a very good prognosis, free from hard events at 20 ± 10 months.