scholarly journals Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

2020 ◽  
Vol 4 (1) ◽  
pp. e100013 ◽  
Author(s):  
Sarah K McCann ◽  
Catherine B Lawrence
Keyword(s):  
Infarct Volume ◽  
Treatment Options ◽  
Response To Treatment ◽  
Experimental Stroke ◽  
Preclinical Studies ◽  
Stroke Patients ◽  
Mortality And Morbidity ◽  
Degree Of Protection ◽  
Stroke Research ◽  
Drug Interventions

Stroke is a significant cause of mortality and morbidity for which there are limited treatment options. Virtually all drug interventions that have been successful preclinically in experimental stroke have failed to translate to an effective treatment in the clinical setting. In this review, we examine one of the factors likely contributing to this lack of translation, the failure of preclinical studies to consider fully the advanced age and comorbidities (eg, hypertension or diabetes) present in most patients with stroke. Age and comorbidities affect the likelihood of suffering a stroke, disease progression and the response to treatment. Analysing data from preclinical systematic reviews of interventions for ischaemic stroke we show that only 11.4% of studies included an aged or comorbid model, with hypertension being the most frequent. The degree of protection (% reduction in infarct volume) varied depending on the comorbidity and the type of intervention. We consider reasons for the lack of attention to comorbid and aged animals in stroke research and discuss the value of testing a potential therapy in models representing a range of comorbidities that affect patients with stroke. These models can help establish any limits to a treatment’s efficacy and inform the design of clinical trials in appropriate patient populations.

scholarly journals MiR-29a Knockout Aggravates Neurological Damage by Pre-polarizing M1 Microglia in Experimental Rat Models of Acute Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Fangfang Zhao ◽  
Haiping Zhao ◽  
Junfen Fan ◽  
Rongliang Wang ◽  
Ziping Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Stroke ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Glutamate Release ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Neurological Damage ◽  
Stroke Patients ◽  
Rat Models

ObjectiveBy exploring the effects of miR-29a-5p knockout on neurological damage after acute ischemic stroke, we aim to deepen understanding of the molecular mechanisms of post-ischemic injury and thus provide new ideas for the treatment of ischemic brain injury.MethodsmiR-29a-5p knockout rats and wild-type SD rats were subjected to transient middle cerebral artery occlusion (MCAO). miR-29a levels in plasma, cortex, and basal ganglia of ischemic rats, and in plasma and neutrophils of ischemic stroke patients, as well as hypoxic glial cells were detected by real-time PCR. The infarct volume was detected by TTC staining and the activation of astrocytes and microglia was detected by western blotting.ResultsThe expression of miR-29a-5p was decreased in parallel in blood and brain tissue of rat MCAO models. Besides, miR-29a-5p levels were reduced in the peripheral blood of acute stroke patients. Knockout of miR-29a enhanced infarct volume of the MCAO rat model, and miR-29a knockout showed M1 polarization of microglia in the MCAO rat brain. miR-29a knockout in rats after MCAO promoted astrocyte proliferation and increased glutamate release.ConclusionKnockout of miR-29a in rats promoted M1 microglial polarization and increased glutamate release, thereby aggravating neurological damage in experimental stroke rat models.

Nanomedicinal Strategies as Emerging Therapeutic Avenues for the Management Cerebral Ischemia

2020 ◽  
Vol 19 ◽  
Author(s):  
Saman Fatima ◽  
Syed Naved Quadri ◽  
Shaheda Parveen ◽  
Sarwar Beg ◽  
Md Abul Barkat ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Health Risks ◽  
Global Scale ◽  
Preclinical Studies ◽  
Neuronal Regeneration ◽  
Stroke Patients ◽  
Mortality And Morbidity ◽  
The Brain

: Amongst the various diseases on global scale, the second leading cause of mortality and morbidity is ischemic stroke due to the unavailability of an effective therapy. With the growing occurrence and its related health risks along with the absence of effective therapeutics, the ischemic stroke demands the continued and intensive research to explore the effective and safe therapeutics. These therapies may positively affect the numerous pathways associated with neuroprotection thus, extending the advantages to a larger population of stroke patients. Several preclinical studies employing neuroprotectants have shown promising outcomes, but failed in clinical trials either because of the lack of safety or efficacy. The blood brain barrier (BBB) restricts delivery of various potent neuroprotectants to the specific areas of the brain. The application of nanovehicles for delivery of drugs in the brain however, could revolutionize the treatment of ischemic stroke. These nanovehicles loaded with the drug could readily traverse the BBB via carrier, receptor and adsorptive-mediated endocytosis into the brain without compromising the integrity of BBB. Recent advances in neuronanotherapeutics have resulted in the improved neuronal regeneration and recovery after the ischemic stroke. In this review, we have attempted to discuss unexploited neuronanotherapeutics potentials to treat and manage ischemic stroke.

Colonic bacterial translocation as a possible factor in stress-worsening experimental stroke outcome

2009 ◽  
Vol 296 (4) ◽  
pp. R979-R985 ◽  
Author(s):  
Javier R. Caso ◽  
Olivia Hurtado ◽  
Marta P. Pereira ◽  
Borja García-Bueno ◽  
Luis Menchén ◽  
...  
Keyword(s):  
Bacterial Translocation ◽  
Immunoglobulin A ◽  
Experimental Studies ◽  
Intestinal Flora ◽  
Enzyme Activation ◽  
Experimental Stroke ◽  
Main Role ◽  
Stroke Outcome ◽  
Stroke Patients ◽  
Mortality And Morbidity

Stress is known to be one of the risk factors of stroke, but only a few experimental studies have examined the possible mechanisms by which prior stress may affect stroke outcome. In stroke patients, infections impede neurological recovery and increase morbidity as well as mortality. We previously reported that stress induces a bacterial translocation and that prior immobilization stress worsens experimental stroke outcome through mechanisms that involve inflammatory mediators such as release of proinflammatory cytokines and enzyme activation. We now investigate whether bacterial translocation from the intestinal flora of rats with stress before experimental ischemia is involved in stroke outcome. We used an experimental paradigm consisting of exposure of Fischer rats to repeated immobilization sessions before permanent middle cerebral artery occlusion (MCAO). The presence of bacteria and the levels and expression of different mediators involved in the bacterial translocation were analyzed. Our results indicate that stress before stroke is related to the presence of bacteria in different organs (mesenteric nodes, spleen, liver, and lung) after MCAO and increases inflammatory colonic parameters (such as cyclooxygenase-2, inducible nitric oxide synthase, and myeloperoxidase), but decreases colonic immunoglobulin A, and these results are correlated with colonic inflammation and bacterial translocation. Understanding the implication of bacterial translocation during stress-induced stroke worsening is of great potential clinical relevance, given the high incidence of infections after severe stroke and their main role in mortality and morbidity in stroke patients.

scholarly journals Statistics in Experimental Cerebrovascular Research: Comparison of More than Two Groups with a Continuous Outcome Variable

2010 ◽  
Vol 30 (9) ◽  
pp. 1558-1563 ◽  
Author(s):  
Peter Schlattmann ◽  
Ulrich Dirnagl
Keyword(s):  
Null Hypothesis ◽  
Infarct Volume ◽  
Vessel Diameter ◽  
Experimental Stroke ◽  
Outcome Variable ◽  
Basic Principles ◽  
Continuous Outcome ◽  
Stroke Research ◽  
Post Hoc ◽  
Continuous Measures

A common setting in experimental cerebrovascular research is the comparison of more than two experimental groups. Often, continuous measures such as infarct volume, cerebral blood flow, or vessel diameter are the primary variables of interest. This article presents the principles of the statistical analysis of comparing more than two groups using analysis of variance (ANOVA). We will also explain post hoc comparisons, which are required to show which groups significantly differ once ANOVA has rejected the null hypothesis. Although statistical packages perform ANOVA and post hoc contrast at a key stroke, in this study, we use examples from experimental stroke research to reveal the simple math behind the calculations and the basic principles. This will enable the reader to understand and correctly interpret the readout of statistical packages and to help prevent common errors in the comparison of multiple means.

scholarly journals Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Laura McCulloch ◽  
Craig J. Smith ◽  
Barry W. McColl
Keyword(s):  
B Cells ◽  
Marginal Zone ◽  
Major Complication ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Marginal Zone B Cells ◽  
Mortality And Morbidity ◽  
Susceptibility To Infection ◽  
Infection Susceptibility ◽  
Improve Clinical Outcome

Abstract Infection is a major complication of acute stroke and causes increased mortality and morbidity; however, current interventions do not prevent infection and improve clinical outcome in stroke patients. The mechanisms that underlie susceptibility to infection in these patients are unclear. Splenic marginal zone (MZ) B cells are innate-like lymphocytes that provide early defence against bacterial infection. Here we show experimental stroke in mice induces a marked loss of MZ B cells, deficiencies in capturing blood-borne antigen and suppression of circulating IgM. These deficits are accompanied by spontaneous bacterial lung infection. IgM levels are similarly suppressed in stroke patients. β-adrenergic receptor antagonism after experimental stroke prevents loss of splenic MZ B cells, preserves IgM levels, and reduces bacterial burden. These findings suggest that adrenergic-mediated loss of MZ B cells contributes to the infection-prone state after stroke and identify systemic B-cell disruption as a target for therapeutic manipulation.

scholarly journals Short-duration hypothermia completed prior to reperfusion prevents intracranial pressure elevation following ischaemic stroke in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W. Bothwell ◽  
Debbie Pepperall ◽  
Daniel J. Beard ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Short Duration ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Post Stroke

AbstractReperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33 °C, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre- or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia may be an applicable early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.

scholarly journals Hypothermia and rewarming prior to reperfusion, prevents intracranial pressure elevation after ischaemic stroke in rats: an investigation to define the importance of cooling during reperfusion

2021 ◽  
Author(s):  
Daniel Omileke ◽  
Sara Azarpeykan ◽  
Steven W Bothwell ◽  
Debbie Pepperall ◽  
Daniel J Beard ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Ischaemic Stroke ◽  
Short Duration ◽  
Infarct Volume ◽  
Arterial Occlusion ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Post Stroke

Abstract Reperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18–24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion. We aimed to determine whether hypothermia-rewarming completed prior to reperfusion, also prevents ICP elevation 24 h post-stroke. Transient middle cerebral artery occlusion was performed on male outbred Wistar rats. Sixty-minute hypothermia to 33℃, followed by rewarming was induced prior to reperfusion in one group, and after reperfusion in another group. Normothermia controls received identical anaesthesia protocols. ΔICP from pre-stroke to 24 h post-stroke was measured, and infarct volumes were calculated. Rewarming pre-reperfusion prevented ICP elevation (ΔICP = 0.3 ± 3.9 mmHg vs. normothermia ΔICP = 5.2 ± 2.1 mmHg, p = 0.02) and reduced infarct volume (pre-reperfusion = 78.6 ± 23.7 mm3 vs. normothermia = 125.1 ± 44.3 mm3, p = 0.04) 24 h post-stroke. There were no significant differences in ΔICP or infarct volumes between hypothermia groups rewarmed pre-or post-reperfusion. Hypothermia during reperfusion is not necessary for prevention of ICP rise or infarct volume reduction. Short-duration hypothermia is a broadly applicable potential early treatment strategy for stroke patients prior to- during-, and after reperfusion therapy.

scholarly journals Evidence for the Use of Isoflurane as a Replacement for Chloral Hydrate Anesthesia in Experimental Stroke: An Ethical Issue

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Pétrault Maud ◽  
Ouk Thavarak ◽  
Lachaud Cédrick ◽  
Bastide Michèle ◽  
Bérézowski Vincent ◽  
...  
Keyword(s):  
Ethical Issue ◽  
Chloral Hydrate ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Analgesic Efficacy ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Research ◽  
Alternative Agent ◽  
Stroke Models

Since an ethical issue has been raised regarding the use of the well-known anesthetic agent chloral hydrate, owing to its mutagenic and carcinogenic effects in animals, attention of neuroscientists has turned to finding out an alternative agent able to meet not only potency, safety, and analgesic efficacy, but also reduced neuroprotective effect for stroke research. The aim of this study was to compare the potential of chloral hydrate and isoflurane for both modulating the action of the experimental neuroprotectant MK801 and exerting analgesia. After middle cerebral artery occlusion in rats, no difference was observed in 24 h survival rate, success of ischemia, or infarct volume reduction between both anesthetics. However, isoflurane exerted a more pronounced analgesic effect than chloral hydrate as evidenced by formalin test 3 hours after anesthesia onset, thus encouraging the use of isoflurane in experimental stroke models.

scholarly journals Geniposide Attenuates Post-Ischaemic Neurovascular Damage via GluN2A/AKT/ ERK-Dependent Mechanism

2017 ◽  
Vol 43 (2) ◽  
pp. 705-716 ◽  
Author(s):  
Baosheng Huang ◽  
Panhong Chen ◽  
Lei Huang ◽  
Shuai Li ◽  
Ronglan Zhu ◽  
...  
Keyword(s):  
Infarct Volume ◽  
Critical Factor ◽  
Iridoid Glycoside ◽  
Experimental Stroke ◽  
Stroke Patients ◽  
Medium Level ◽  
Dose Dependent ◽  
Natural Agent ◽  
Neurovascular Damage ◽  
Dependent Mechanism

Background/Aims: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke. Methods: We demonstrate that dose-dependent geniposide significantly decreased the infarct volume in tMCAO models. Results: A medium level of geniposide improved anti-apoptotic functions and inhibited BBB leakage/haemorrhage via elevating GluN2A-containing NMDAR expression in tMCAO rats. Importantly, these effects could be eliminated by co-treatment of geniposide with the GluN2A antagonist NVP but not the GluN2B inhibitor ifenprodil. Moreover, geniposide’s protection was due to the enhancement of GluN2A-dependent survival signals, including pAKT, pERK and PSD-95. Conclusion: The results suggest that geniposide protects neurons against post-ischaemic neurovascular injury through the activation of GluN2A/AKT/ERK pathways. As a very promising natural agent, geniposide may be a future therapeutic for stroke patients.

Abstract 178: Infarct Growth Rate Depends on Collateral Status in Acute Ischemic Stroke Patients

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Reza Hakimelahi ◽  
Karen A Buch ◽  
Thabele M Leslie-Mazwi ◽  
Joshua A Hirsch ◽  
James D Rabinov ◽  
...  
Keyword(s):  
Growth Rate ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Time Windows ◽  
Treatment Options ◽  
Contralateral Side ◽  
Stroke Onset ◽  
Lesion Volume ◽  
Stroke Patients

Introduction and Hypothesis: Multiple studies have demonstrated no statistically significant association between time after stroke onset and initial infarct volume. Factors other than time may play a role in infarct growth. We sought to investigate association between collateral status and infarct growth rate in acute ischemic stroke (AIS) patients. Methods: We included 130 consecutive patients with CTA showing ICA and/or proximal MCA occlusions who had DWI within 8 hours of stroke onset. Collateral status was categorized into three groups: poor (none or minimal), intermediate (present but < contralateral side) and good (≥ contralateral side). DWI lesion volumes were measured and infarct growth rate was calculated using MRI time after stroke onset. Mann-Whitney test and correlation coefficient were used for statistical analysis. Results: In our 130 patients, 62 female (48%), the average values (mean±SD) were: age 70 ± 17 years, NIHSS 16 ± 6, DWI volume 59 ± 65 mL, time after stroke onset 4 ± 2 hours, and infarct growth rate 17 ± 23 mL/hour. 19 (14.6%) had poor, 75 (57.7%) had intermediate, and 36 (27.7%) had good collaterals. Infarct growth rate and DWI lesion volume were significantly increased with decreased collateral quality (p<0.0004 for all group comparisons). Patients with good collaterals were younger (p=0.004 and p=0.018 compared to poor and intermediate groups respectively) and had lower NIHSS scores (p< 0.001). Time after stroke onset, gender, or occlusion site (ICA vs MCA) were not significantly different among different collateral groups. There was no correlation between time and DWI volume (r2=0.02, p=0.8) or collateral status (r2=0.05, p=0.6). There was significant correlation between collateral status and infarct growth (r2=-0.6,p<0.0001). Conclusion: AIS patients with good collaterals have small initial DWI lesion volumes and slower infarct growth rates. These patients may be candidates for treatment options outside traditional time windows.

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