Gut Microbiota, Bacterial Translocation, and Stroke: Current Knowledge and Future Directions.

Stroke is one of the most devastating pathologies in terms of mortality, cause of dementia, major adult disability, and socioeconomic burden worldwide. Despite its severity, treatment options remain limited, with no pharmacological therapies available for hemorrhagic stroke (HS) and only fibrinolytic therapy or mechanical thrombectomy for ischemic stroke (IS). In the pathophysiology of stroke, after the acute phase, many patients develop systemic immunosuppression, which, combined with neurological dysfunction and hospital management, leads to the onset of stroke-associated infections (SAIs).

Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice.

Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits.

Neutrophil β adrenoceptor blockade blunts stroke-associated neuroinflammation.

Background And Purpose: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes.

Influence of metabolic syndrome on post-stroke outcome, angiogenesis and vascular function in old rats determined by dynamic contrast enhanced MRI.

Stroke affects primarily aged and co-morbid people, aspects not properly considered to date. Since angiogenesis/vasculogenesis are key processes for stroke recovery, we purposed to determine how different co-morbidities affect the outcome and angiogenesis/vasculogenesis, using a rodent model of metabolic syndrome, and by dynamic enhanced-contrast imaging (DCE-MRI) to assess its non-invasive potential to determine these processes. Twenty/twenty-two month-old corpulent (JCR:LA-Cp/Cp), a model of metabolic syndrome and lean rats were used.

Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance.

Background and Purpose- Recanalization of the occluded artery is a primary goal in stroke treatment. Unfortunately, endovascular treatment is not always available, and tPA (tissue-type plasminogen activator) therapy is limited by its narrow therapeutic window; importantly, the rate of early arterial recanalization after tPA administration is low, especially for platelet-rich thrombi. The mechanisms for this tPA resistance are not well known.

Toll-like receptor 4 regulates subventricular zone proliferation and neuroblast migration after experimental stroke.

Ischemic stroke is one of the leading causes of death and disability with an urgent need for innovative therapies, especially targeting the chronic phase. New evidence has emerged showing that Toll-Like Receptor 4 (TLR4), a key mediator of brain damage after stroke, may be involved in brain repair by neurogenesis modulation. The aim of this study is to analyze the role of TLR4 in the different stages of neurogenesis initiated in the subventricular zone (SVZ) over time after stroke in mice.

Myeloid cells as therapeutic targets in neuroinflammation after stroke: Specific roles of neutrophils and neutrophil-platelet interactions.

Ischemic brain injury causes a local inflammatory response, involving the activation of resident brain cells such as microglia and the recruitment of infiltrating immune cells. Increasing evidence supports that plasticity of the myeloid cell lineage is determinant for the specific role of these cells on stroke outcome, from initiation and maintenance to resolution of post-ischemic inflammation. The aim of this review is to summarize some of the key characteristics of these cells and the mechanisms for their recruitment into the injured brain through interactions with platelets, endothelial cells and other leukocytes.

TLR4-Binding DNA Aptamers Show a Protective Effect against Acute Stroke in Animal Models.

Since Toll-like receptor 4 (TLR4) mediates brain damage after stroke, development of TLR4 antagonists is a promising therapeutic strategy for this disease. Our aim was to generate TLR4-blocking DNA aptamers to be used for stroke treatment. From a random oligonucleotide pool, we identified two aptamers (ApTLR#1R, ApTLR#4F) with high affinity for human TLR4 by systematic evolution of ligands by exponential enrichment (SELEX).

Multi-modal imaging of long-term recovery post-stroke by positron emission tomography and matrix-assisted laser desorption/ionisation mass spectrometry.

Rationale: Stroke is a leading cause of disability worldwide. Understanding the recovery process post-stroke is essential; however, longer-term recovery studies are lacking. In vivo positron emission tomography (PET) can image biological recovery processes, but is limited by spatial resolution and its targeted nature.

Toll-Like Receptor 4 Mediates Hemorrhagic Transformation After Delayed Tissue Plasminogen Activator Administration in In Situ Thromboembolic Stroke.

Background And Purpose: Hemorrhagic transformation is the main complication of revascularization therapies after stroke. Toll-like receptor 4 (TLR4) is implicated in cerebral damage and inflammation in stroke. This study was designed to determine the role of TLR4 in hemorrhagic transformation development after tissue plasminogen activator (tPA) administration.

Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke.

Background And Purpose: Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms.

Reparative effects of interleukin-1 receptor antagonist in young and aged/co-morbid rodents after cerebral ischemia.

Neuroprotective strategies for ischemic stroke have failed to translate from bench to bedside, possibly due to the lack of consideration of key clinical co-morbidities. Stroke and co-morbidities are associated with raised levels of the pro-inflammatory cytokine interleukin-1 (IL-1). Inhibition of IL-1 by the administration of interleukin-1 receptor antagonist (IL-1Ra) has shown to be neuroprotective after experimental cerebral ischemia.

Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the Corpulent Rat Strain.

Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the rat model was developed with an autosomal recessive corpulent () trait resulting from a premature stop codon in the extracellular domain of the leptin receptor.

Imaging the role of toll-like receptor 4 on cell proliferation and inflammation after cerebral ischemia by positron emission tomography.

The influence of toll-like receptor 4 on neurogenesis and inflammation has been scarcely explored so far by using neuroimaging techniques. For this purpose, we performed magnetic resonance imaging and positron emission tomography with 3'-deoxy-3'-[(18)F]fluorothymidine and [(11)C]PK11195 at 2, 7, and 14 days following cerebral ischemia in TLR4(+/+)and TLR4(-/-)mice. MRI showed similar infarction volumes in both groups.

A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models.

Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

Background: Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals.

Toll-like receptor 4 modulates cell migration and cortical neurogenesis after focal cerebral ischemia.

Toll-like receptor 4 (TLR4) mediates brain damage after stroke. Now our objective is to determine TLR4 involvement in stroke-induced neurogenesis. Stroke was induced by permanent middle cerebral artery occlusion in wild-type and TLR4-deficient mice.

Streptococcus pneumoniae worsens cerebral ischemia via interleukin 1 and platelet glycoprotein Ibα.

Objective: Bacterial infection contributes to diverse noninfectious diseases and worsens outcome after stroke. Streptococcus pneumoniae, the most common infection in patients at risk of stroke, is a major cause of prolonged hospitalization and death of stroke patients, but how infection impacts clinical outcome is not known.

Methods: We induced sustained pulmonary infection by a human S.

Surgical manipulation compromises leukocyte mobilization responses and inflammation after experimental cerebral ischemia in mice.

Acute brain injury results in peripheral inflammatory changes, although the impact of these processes on neuronal death and neuroinflammation is currently unclear. To facilitate the translation of experimental studies to clinical benefit, it is vital to characterize the mechanisms by which acute brain injury induces peripheral inflammatory changes, and how these are affected by surgical manipulation in experimental models. Here we show that in mice, even mild surgical manipulation of extracranial tissues induced marked granulocyte mobilization (300%) and systemic induction of cytokines.

Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARγ and 5-LO-dependent pathways.

PPARγ-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved.

Silent information regulator 1 protects the brain against cerebral ischemic damage.

Background And Purpose: Sirtuin 1 (SIRT1) is a member of NAD+-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice.

The immune system in stroke: clinical challenges and their translation to experimental research.

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome.

Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke.

CDP-choline has shown neuroprotective effects in cerebral ischemia. In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline.

Iron overload, measured as serum ferritin, increases brain damage induced by focal ischemia and early reperfusion.

High levels of iron, measured as serum ferritin, are associated to a worse outcome after stroke. However, it is not known whether ischemic damage might increase ferritin levels as an acute phase protein or whether iron overload affects stroke outcome. The objectives are to study the effect of stroke on serum ferritin and the contribution of iron overload to ischemic damage.

Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats.

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals.