Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here

This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.     

Motor recovery after stroke: Lessons from functional brain imaging

Abstract

Several theories have been proposed to explain recovery from stroke. Functional brain imaging offers an opportunity to evaluate these theories and visualize recovery after stroke. Functional brain imaging has proven to be an effective tool to map brain areas activated during a specific task. This paradigm can extend our understanding of the mechanisms of motor recovery after stroke. Functional brain imaging tools such as functional MRI, PET, transcranial Doppler ultrasonography, and transcranial magnetic stimulation can be used to evaluate motor activation after stroke. Functional imaging is proving useful in identifying areas, pathways and mechanisms involved in motor recovery after stroke. Studies have shown changes in motor organization with rehabilitation. Functional brain imaging may assist in the selection of rehabilitation methods that best foster recovery. [Neurol Res 2002; 24: 453-458]     

Emerging Concepts in Vascular Dementia: A Review

ObjectiveVascular dementia (VaD) is the second most common cause of dementia and a major health concern worldwide. A comprehensive review on VaD is warranted for better understanding and guidance for the practitioner. We provide an updated overview of the epidemiology, pathophysiological mechanisms, neuroimaging patterns as well as current diagnostic and therapeutic approaches.Materials and methodsA narrative review of current literature in VaD was performed based on publications from the database of PubMed, Scopus and Google Scholar up to January, 2021.ResultsVaD can be the result of ischemic or hemorrhagic tissue injury in a particular region of the brain which translates into clinically significant cognitive impairment. For example, a cerebral infarct in the speech area of the dominant hemisphere would translate into clinically significant impairment as would involvement of projection pathways such as the arcuate fasciculus. Specific involvement of the angular gyrus of the dominant hemisphere, with resultant Gerstman's syndrome, could have a pronounced effect on functional ability despite being termed a “minor stroke”. Small vessel cerebrovascular disease can have a cumulate effect on cognitive function over time. It is unfortunately well recognized that “good” functional recovery in acute ischemic or haemorrhagic stroke, including subarachnoid haemorrhage, does not necessarily translate into good cognitive recovery. The victim may often be left unable to have gainful employment, drive a car safely or handle their affairs independently.ConclusionsThis review should serve as a compendium of updated information on VaD and provide guidance in terms of newer diagnostic and potential therapeutic approaches.     

Pathogenic mechanisms following ischemic stroke

Stroke is the second most common cause of death and the leading cause of disability worldwide. Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis. Moreover, there is a mechanistic link between brain ischemia, innate and adaptive immune cells, intracranial atherosclerosis, and also the gut microbiota in modifying the cerebral responses to ischemic insult. There are very few treatments for stroke injuries, partly owing to an incomplete understanding of the diverse cellular and molecular changes that occur following ischemic stroke and that are responsible for neuronal death. Experimental discoveries have begun to define the cellular and molecular mechanisms involved in stroke injury, leading to the development of numerous agents that target various injury pathways. In the present article, we review the underlying pathophysiology of ischemic stroke and reveal the intertwined pathways that are promising therapeutic targets.     

Mapping cortical hand motor representation using TMS: A method to assess brain plasticity and a surrogate marker for recovery of function after stroke?

ObjectiveStroke is associated with reorganization within motor areas of both hemispheres. Mapping the cortical hand motor representation using transcranial magnetic stimulation may help to understand the relationship between motor cortex reorganization and motor recovery of the affected hand after stroke.MethodsA standardized review of the pertinent literature was performed.ResultsWe identified 20 trials, which analyzed the relationship between the extent and/or location of cortical hand motor representation using transcranial magnetic stimulation and motor function and recovery of the affected hand. Several correlations were found between cortical reorganization and measures of hand motor impairment and recovery.ConclusionA better understanding of the relationships between the extent and location of cortical hand motor representation and the motor impairment and motor recovery of the affected hand after stroke may contribute to a targeted use of non-invasive brain stimulation protocols. In the future motor mapping may help to guide brain stimulation techniques to the most effective motor area in an affected individual.     

The effect of fecal microbiota transplantation on stroke outcomes: A systematic review

Background and PurposeFecal microbiota transplantation (FMT) is a novel microbiota-based therapeutic method that transfers stool from donor into a recipient and its application is under investigating for neurological disorders such as stroke. In this systematic review, we assessed the effect of FMT in progression and treatment of stroke and recovery of post-stroke complications.MethodsPreliminary studies were searched in MEDLINE via PubMed, Scopus, COCHRANE library and Google Scholar, databases up to February 2022. The search strategy was restricted to articles about FMT in stroke. The initial search yielded 4570 articles, of which 19 publications were included in our systematic review.ResultsBased on outcomes transferring microbiome from healthy or ischemic donor to other ischemic recipient can affect brain infarct volume and survival rate, neurological and behavioral outcomes, and inflammatory pathways.ConclusionsOur systematic review on preclinical studies showed that manipulating gut microbiota via FMT can be a possible therapeutic approach for treatment of stroke and recovery of post-stroke complications.     

Long-term neuroprotection induced by regional brain cooling with saline infusion into ischemic territory in rats: a behavioral analysis

Abstract

The neuroprotective effect of hypothermia has long been recognized. Our recent studies have demonstrated the significant therapeutic value of local brain cooling in the ischemic territory prior to reperfusion in stroke, with reduced infarction and inflammatory responses up to 48 hours of reperfusion. The goal of this study was to determine if local brain cooling, produced by infusion of cold saline, could induce long-term functional improvement after stroke. A hollow filament was used to block the middle cerebral artery (MCA) for 3 hours, and then to locally infuse the ischemic territory with 6 ml cold saline (20°C) for 10 minutes prior to reperfusion. This brain cooling infusion induced a significant (p < 0.01) decrease in neurologic deficits and significantly (p < 0.01) improved motor behavior in ischemic rats after 14 days of reperfusion, compared with ischemic rats without local cold saline infusion. This improvement continued for up to 28 days after reperfusion. No significant difference in motor performance was observed between the brain cooling infusion and normal control groups. Significant (p < 0.01) reductions in infarct volume were also evident. In conclusion, a local cerebral hypothermia induced by local saline infusion prior to reperfusion produced a long-term functional recovery after ischemic stroke. A therapeutic procedure, which combines prereperfusion infusion into an ischemic region with coincident cerebral hypothermia and perhaps subsequent recanalization of an occluded intracranial vessel, may improve the outcome for stroke patients.     

Prognostication Value of Descending Corticospinal Tract DWI Signal in Neonatal Cerebral Sinovenous Thrombosis

BackgroundDescending corticospinal tract diffusion-weighted magnetic resonance imaging (MRI) signal is predictive of poor motor outcome in neonatal and childhood arterial ischemic stroke. However, descending corticospinal tract diffusion-weighted MRI signal has not been documented in the setting of cerebral sinovenous thrombosis, and its role is not understood.ObjectiveWe describe a neonate with cerebral sinovenous thrombosis, extensive diffusion restriction, and bilateral descending corticospinal tract diffusion-weighted MRI signal on MRI of the brain. We discuss the underlying mechanisms and implications of these findings in venous ischemia.ConclusionThe prognostic value of descending corticospinal tract diffusion-weighted MRI signal differs when observed in cerebral sinovenous thrombosis from when observed in arterial ischemic stroke. Consequently, caution should be exercised in using descending corticospinal tract diffusion-weighted MRI signal to predict outcome in children with cerebral sinovenous thrombosis.     

Cognitive Reserve Modifies the Relationship Between Neural Function,Neural Injury and Upper-Limb Recovery After Stroke

ObjectiveTo investigate whether cognitive reserve modifies the relationship between functional connectivity, lesion volume, stroke severity and upper-limb motor impairment and recovery in stroke survivors.MethodsTen patients with first-ever ischemic middle cerebral artery stroke completed the Cognitive Reserve Index Questionnaire at baseline. Upper-limb motor impairment and functional connectivity were assessed using the Fugl-Meyer Assessment and electroencephalography respectively at baseline and 3-months post-stroke. A debiased weighted phase lag index was computed to estimate functional connectivity between electrodes. Partial least squares (PLS) regression identified a connectivity model that maximally predicted variance in the degree of upper-limb impairment. Regression models were generated to determine whether cognitive reserve modified the relationship between neural function (functional connectivity), neural injury (lesion volume), stroke severity (National Institutes of Health Stroke Scale) and upper-limb motor impairment at baseline and recovery at 3-months (Fugl-Meyer Assessment).ResultsThe addition of cognitive reserve to a regression model with a dependent variable of upper-limb motor recovery and independent variables of functional connectivity between the ipsilesional motor cortex and parietal cortex, stroke severity and lesion volume improved model efficiency (?BIC=-7.07) despite not reaching statistical significance (R²=0.90, p=0.07). Cognitive reserve did not appear to improve regression models examining motor impairment at baseline.ConclusionsPreliminary observations suggest cognitive reserve might modify the relationship between neural function, neural injury, stroke severity and upper-limb motor recovery. Further investigation of cognitive reserve in motor recovery post-stroke appears warranted.     

Pediatric stroke: rehabilitation of focal injury in the developing brain

This review provides an overview of pediatric ischemic stroke to serve as a foundation for the discussion of rehabilitation strategies following focal injury in the developing brain. Cerebrovascular disease is an important cause of acquired brain injury in neonates and children. Ischemic strokes are caused by a multitude of risk factors and advances in neuroimaging have improved diagnosis and understanding of pathophysiology. Pediatric stroke provides the ideal model for the study of injury and recovery in a plastic nervous system. Though their brains likely posses greater potential and unique reorganizational skills, most children suffer neurological morbidity after stroke. An improved understanding of these systems is helping us understand, validate, and improve traditional approaches to rehabilitation while opening the door to new opportunities to improve outcome. All aspects of a patient's function, from the physical to psychological, including issues unique to children and their families, must be addressed and are reviewed. New advances and future directions for research are highlighted.     

Perinatal Arterial Ischemic Stroke: Presentation,Risk Factors,Evaluation, and Outcome

BackgroundPerinatal arterial ischemic stroke is as common as large vessel arterial ischemic stroke in adults and leads to significant morbidity. Perinatal arterial ischemic stroke is the most common identifiable cause of cerebral palsy and can lead to cognitive and behavioral difficulties that are amortized over a lifetime.MethodsThe literature on perinatal arterial ischemic stroke was reviewed and analyzed.ResultsRisk factors for perinatal arterial ischemic stroke include those that are maternal, neonatal, and placental. The most common clinical signs at presentation are seizures and hemiparesis. Evaluation should begin with thorough history acquisition and physical examination followed by magnetic resonance imaging of the brain, with consideration of magnetic resonance angiography of the head and neck, echocardiogram, and thrombophilia evaluation. Treatment beginning early to include physical, speech, and occupational therapies including constraint-induced movement therapy and close cognitive and developmental follow-up may be beneficial. Future treatments may include transcranial magnetic stimulation, hypothermia, and erythropoietin.ConclusionsPerinatal arterial ischemic stroke comprises a group of arterial ischemic injuries that can occur in the prenatal, perinatal, and postnatal periods in term and preterm infants with different types of perinatal arterial ischemic stroke having different clinical presentations, risk factors, and long-term outcomes.     

Potential nanotherapeutic strategies for perioperative stroke

AimsBased on the complex pathological environment of perioperative stroke, the development of targeted therapeutic strategies is important to control the development of perioperative stroke.DiscussionsRecently, great progress has been made in nanotechnology, and nanodrug delivery systems have been developed for the treatment of ischemic stroke.ConclusionIn this review, the pathological processes and mechanisms of ischemic stroke during perioperative stroke onset were systematically sorted. As a potential treatment strategy for perioperative stroke, the review also summarizes the multifunctional nanodelivery systems based on ischemic stroke, thus providing insight into the nanotherapeutic strategies for perioperative stroke.     

Cerebral ischemia and angiogenesis

Angiogenesis occurs in a wide range of conditions. As ischemic tissue usually depends on collateral blood flow from newly produced vessels, acceleration of angiogenesis should be of therapeutic value to ischemic disorders. Indeed, therapeutic angiogenesis reduced tissue injury in myocardial or limb ischemia. In ischemic stroke, on the other hand, angiogenic factors often increase vascular permeability and thus may deteriorate tissue damage. In order to apply safely the therapeutic angiogenesis for ischemic stroke treatment, elucidating precise mechanism of brain angiogenesis is mandatory. In the present article, we review previous reports which investigated molecular mechanisms of angiogenesis. Endothelial cell mitogens, enzymes that degrade surrounding extracellular matrix, and molecules implicated in endothelial cells migration are induced rapidly in the ischemic brain. Their possible neuroprotective or injury exacerbating effects are discussed. Because therapeutic potential of angiogenic factors application had gained much attention, we here extensively reviewed relevant previous reports. In the future however, there is a need to consider angiogenesis in relation with regenerative medicine, as angiogenic factors sometimes possess neuron producing property.     

Functional Imaging of Stroke Recovery: An Ecological Review from a Neural Network Perspective with an Emphasis on Motor Systems

Functional imaging is beginning to outline the brain's functional architecture and mechanisms of recovery from injury. I will review primarily the motor‐function literature from normal populations, learning trials, stroke recovery, and rehabilitation with a neural network approach that may prove fruitful in further advancing our understanding of brain plasticity in response to focal lesions. A key consideration in this review will be how the development of distributed motor networks might constrain recovery as a function of the altered connectivity between damaged and nondamaged areas. It will be argued that this connectivity is central to both recovery from injury and response to treatment.     

缺血性卒中后的神经炎性反应

神经炎性反应在缺血性卒中后的病理损伤中起重要作用。越来越多的证据表明,神经炎性反应是一把"双刃剑",在加重急性期卒中脑损伤的同时,亦可促进卒中后的神经修复。本文阐述了缺血性卒中后神经炎性反应的关键因素,如炎性细胞、炎性介质和黏附分子的变化,探讨了其可能的神经损伤及神经保护作用;同时,对缺血性卒中后神经炎性反应相关研究的进展及前景进行了综述。     

The role of peptidase neurolysin in neuroprotection and neural repair after stroke

Current experimental stroke research has evolved to focus on detailed understanding of the brain's self-protective and restorative mechanisms, and harness this knowledge for development of new therapies. In this context, the role of peptidases and neuropeptides is of growing interest. In this focused review, peptidase neurolysin(Nln) and its extracellular peptide substrates are briefly discussed in relation to pathophysiology of ischemic stroke. Upregulation of Nln following stroke is viewed as a compensatory cerebroprotective mechanism in the acute phase of stroke, because the main neuropeptides inactivated by Nln are neuro/cerebrotoxic(bradykinin, substance P, neurotensin, angiotensin II, hemopressin), whereas the peptides generated by Nln are neuro/cerebroprotective(angiotensin-(1–7), Leu-/Met-enkephalins). This notion is confirmed by experimental studies documenting aggravation of stroke outcomes in mice after inhibition of Nln following stroke, and dramatic improvement of stroke outcomes in mice overexpressing Nln in the brain. The role of Nln in the(sub)chronic phase of stroke is less clear and it is likely, that this peptidase does not have a major role in neural repair mechanisms. This is because, the substrates of Nln are less uniform in modulating neurorestorative mechanisms in one direction, some appearing to have neural repair enhancing/stimulating potential, whereas others doing the opposite. Future studies focusing on the role of Nln in pathophysiology of stroke should determine its potential as a cerebroprotective target for stroke therapy, because its unique ability to modulate multiple neuropeptide systems critically involved in brain injury mechanisms is likely advantageous over modulation of one pathogenic pathway for stroke pharmacotherapy.     

Urokinase-type plasminogen activator is a modulator of synaptic plasticity in the central nervous system:implications for neurorepair in the ischemic brain

The last two decades have witnessed a rapid decrease in mortality due to acute cerebral ischemia that paradoxically has led to a rapid increase in the number of patients that survive an acute ischemic stroke with various degrees of disability.Unfortunately,the lack of an effective therapeutic strategy to promote neurological recovery among stroke survivors has led to a rapidly growing population of disabled patients.Thus,understanding the mechanisms of neurorepair in the ischemic brain is a priority with wide scientific,social and economic implications.Cerebral ischemia has a harmful effect on synaptic structure associated with the development of functional impairment.In agreement with these observations,experimental evidence indicates that synaptic repair underlies the recovery of neurological function following an ischemic stroke.Furthermore,it has become evident that synaptic plasticity is crucial not only during development and learning,but also for synaptic repair after an ischemic insult.The plasminogen activating system is assembled by a cascade of enzymes and their inhibitors initially thought to be solely involved in the generation of plasmin.However,recent work has shown that in the brain this system has an important function regulating the development of synaptic plasticity via mechanisms that not always require plasmin generation.Urokinase-type plasminogen activator(uPA)is a serine proteinase and one of the plasminogen activators,that upon binding to its receptor(uPAR)not only catalyzes the conversion of plasminogen into plasmin on the cell surface,but also activates cell signaling pathways that promote cell migration,proliferation and survival.The role of uPA is the brain is not fully understood.However,it has been reported while uPA and uPAR are abundantly found in the developing central nervous system,in the mature brain their expression is restricted to a limited group of cells.Remarkably,following an ischemic injury to the mature brain the expression of uPA and uPAR increases to levels comparable to those observed during development.More specifically,neurons release uPA during the recovery phase from an ischemic injury,and astrocytes,axonal boutons and dendritic spines recruit uPAR to their plasma membrane.Here we will review recent evidence indicating that binding of uPA to uPAR promotes the repair of synapses damaged by an ischemic injury,with the resultant recovery of neurological function.Furthermore,we will discuss data indicating that treatment with recombinant uPA is a potential therapeutic strategy to promote neurological recovery among ischemic stroke survivors.     

Mechanisms of perinatal arterial ischemic stroke

The incidence of perinatal stroke is high, similar to that in the elderly, and produces a significant morbidity and severe long-term neurologic and cognitive deficits, including cerebral palsy, epilepsy, neuropsychological impairments, and behavioral disorders. Emerging clinical data and data from experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. These studies have revealed that, far from just being a smaller version of the adult brain, the neonatal brain is unique with a very particular and age-dependent responsiveness to hypoxia–ischemia and focal arterial stroke. In this review, we discuss fundamental clinical aspects of perinatal stroke as well as some of the most recent and relevant findings regarding the susceptibility of specific brain cell populations to injury, the dynamics and the mechanisms of neuronal cell death in injured neonates, the responses of neonatal blood–brain barrier to stroke in relation to systemic and local inflammation, and the long-term effects of stroke on angiogenesis and neurogenesis. Finally, we address translational strategies currently being considered for neonatal stroke as well as treatments that might effectively enhance repair later after injury.     

Pathophysiology of an hypoxic-ischemic insult during the perinatal period

Hypoxia-ischemia is a leading cause of morbidity and mortality in the perinatal period with an incidence of 1/4000 live births. Biochemical events such as energy failure, membrane depolarization, brain edema, an increase of neurotransmitter release and inhibition of uptake, an increase of intracellular Ca(2+), production of oxygen-free radicals, lipid peroxidation, and a decrease of blood flow are triggered by hypoxia-ischemia and may lead to brain dysfunction and neuronal death. These abnormalities can result in mental impairments, seizures, and permanent motor deficits, such as cerebral palsy. The physical and emotional strain that is placed on the children affected and their families is enormous. The care that these individuals need is not only confined to childhood, but rather extends throughout their entire life span, so it is very important to understand the pathophysiology that follows a hypoxic-ischemic insult. This review will highlight many of the mechanisms that lead to neuronal death and include the emerging area of white matter injury as well as the role of inflammation and will provide a summary of therapeutic strategies. Hypothermia and oxygen will also be discussed as treatments that currently lack a specific target in the hypoxic/ischemic cascade.