Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke

Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg/kg and 100 mg/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt/β-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.

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Neuroprotection from Stem Cell-Derived Human Adipose Extracellular Vesicles Intranasally Administered 24 Hours After Stroke in Rats.

10.21203/rs.3.rs-300710/v1 ◽

2021 ◽

Author(s):

Francieli Rohden ◽

Luciele Varaschini Teixeira ◽

Luis Pedro Bernardi ◽

Pâmela Lukasewicz ◽

Mariana Colombo ◽

...

Keyword(s):

Ischemic Stroke ◽

Extracellular Vesicles ◽

Infarct Volume ◽

Human Adipose Tissue ◽

Long Term Memory ◽

Infarct Core ◽

Infarct Zone ◽

Stroke Treatment ◽

Administration Routes

Abstract Ischemic stroke is a major cause of death and disability, demanding innovative and accessible therapeutic strategies. Approaches presenting an optimal period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. We evaluated the potential neuroprotective properties of nasally administered human adipose tissue stem cells (hAT-MSCs)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. A single intranasal EV (200 µg/kg) was administered 24 h after a focal permanent ischemic stroke in rats. A higher tropism of EVs was observed in the peri-infarct zone surrounding the infarct core. In the same brain region, there was a significant decrease in the infarct volume, improvement of the blood-brain barrier, and re-stabilization of vascularization. In addition, EVs recovered the impairment of long-term motor and behavioral performance induced by an ischemic stroke. Surprisingly, one single intranasal EVs administration reestablished: i) front paws symmetry, ii) short- and long-term memory, and iii) anxiety-like behavior. In line with the findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

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Post-stroke Hyperglycemia in Non-diabetic Ischemic Stroke is Related With Worse Functional Outcome: A Cohort Study

Annals of Rehabilitation Medicine ◽

10.5535/arm.21124 ◽

2021 ◽

Vol 45 (5) ◽

pp. 359-367

Author(s):

Jin A Yoon ◽

Yong-Il Shin ◽

Deog Young Kim ◽

Min Kyun Sohn ◽

Jongmin Lee ◽

...

Keyword(s):

Cohort Study ◽

Ischemic Stroke ◽

Glucose Level ◽

Functional Outcomes ◽

Stroke Patients ◽

Nihss Score ◽

Post Stroke ◽

Significant Difference ◽

Functional Assessments

Objective To investigate long-term and serial functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.Methods The Korean Stroke Cohort for Functioning and Rehabilitation (KOSCO) is a large, multi-center, prospective cohort study of stroke patients admitted to participating hospitals in nine areas of Korea. From KOSCO, ischemic stroke patients without diabetes were recruited and divided into two groups: patients without diabetes without (n=779) and with post-stroke hyperglycemia (n=223). Post-stroke hyperglycemia was defined as a glucose level >8 mmol/L. Functional assessments were performed 7 days and 3, 6, and 12 months after stroke onset.Results There were no significant differences in baseline characteristics between the groups, except in the age of onset and smoking. Analysis of the linear correlation between the initial National Institutes of Health Stroke Scale (NIHSS) score and glucose level showed no significant difference. Among our functional assessments, NIHSS, Fugl-Meyer Assessment (affected side), Functional Ambulatory Category, modified Rankin Scale, and Korean Mini-Mental State Examination (K-MMSE) showed statistically significant improvements in each group. All functional improvements except K-MMSE were significantly higher in patients without post-stroke hyperglycemia at 7 days and 3, 6, and 12 months.Conclusion The glucose level of ischemic stroke patients without diabetes had no significant correlation with the initial NIHSS score. The long-term effects of stress hyperglycemia showed worse functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.

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Early and Sustained Increases in Leukotriene B4 Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients

Neurotherapeutics ◽

10.1007/s13311-019-00787-4 ◽

2019 ◽

Vol 17 (1) ◽

pp. 282-293 ◽

Cited By ~ 2

Author(s):

Su Jing Chan ◽

Mary P. E. Ng ◽

Hui Zhao ◽

Geelyn J. L. Ng ◽

Chuan De Foo ◽

...

Keyword(s):

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Infarct Volume ◽

Prognostic Significance ◽

Leukotriene B4 ◽

Stroke Patients ◽

Middle Cerebral Artery Infarction ◽

Post Stroke ◽

Stroke Models

Abstract Leukotriene B4 (LTB4) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB4 levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB4 levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB4 rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB4 levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A4 hydrolase (LTA4H), highlighting the pivotal contributions of neutrophils as a source of LTB4. Importantly, rise in plasma LTB4 levels corresponded with an increase in LTB4 amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB4 levels. Pre-stroke LTB4 loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB4 pathway might be a viable treatment strategy for acute ischemic stroke.

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Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.p806 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Junaith S Mohamed ◽

Peter J Ferrandi ◽

Paez G Hector ◽

Christopher R Pitzer ◽

Stephen E Alway

Keyword(s):

Skeletal Muscle ◽

Ischemic Stroke ◽

Muscle Atrophy ◽

Muscle Wasting ◽

Rna Seq ◽

Stroke Patients ◽

Post Stroke ◽

Cerebral Ischemic Stroke ◽

Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.

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Notoginsenoside R1 Improves Cerebral Ischemia/Reperfusion Injury by Promoting Neurogenesis via the BDNF/Akt/CREB Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.615998 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ting Zhu ◽

Lei Wang ◽

Weijie Xie ◽

Xiangbao Meng ◽

Yicheng Feng ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Neurological Function ◽

Long Term Effects ◽

Bdnf Expression ◽

Neuroprotective Effects

Notoginsenoside R1 (R1), a major component isolated from P. notoginseng, is a phytoestrogen that exerts many neuroprotective effects in a rat model of ischemic stroke. However, its long-term effects on neurogenesis and neurological restoration after ischemic stroke have not been investigated. The aim of this study was to evaluate the effects of R1 on neurogenesis and long-term functional recovery after ischemic stroke. We used male Sprague-Dawley rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). R1 was administered by intraperitoneal (i.p.) injection immediately postischemia. We showed that R1 significantly decreased infarct volume and neuronal loss, restored neurological function, and stimulated neurogenesis and oligodendrogenesis in rats subjected to MCAO/R. More importantly, R1 promoted neuronal proliferation in PC12 cells in vitro. The proneurogenic effects of R1 were associated with the activation of Akt/cAMP responsive element-binding protein, as shown by the R1-induced increase in brain-derived neurotrophic factor (BDNF) expression, and with the activation of neurological function, which was partially eliminated by selective inhibitors of BDNF and PI3K. We demonstrated that R1 is a promising compound that exerts neuroprotective and proneurogenic effects, possibly via the activation of BDNF/Akt/CREB signaling. These findings offer insight into exploring new mechanisms in long-term functional recovery after R1 treatment of ischemic stroke.

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Functional Recovery Caused by Human Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles Administered 24 h after Stroke in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms222312860 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12860

Author(s):

Francieli Rohden ◽

Luciele Varaschini Teixeira ◽

Luis Pedro Bernardi ◽

Pamela Cristina Lukasewicz Ferreira ◽

Mariana Colombo ◽

...

Keyword(s):

Adipose Tissue ◽

Stem Cell ◽

Ischemic Stroke ◽

Mesenchymal Stem Cell ◽

Extracellular Vesicles ◽

Infarct Volume ◽

Human Adipose Tissue ◽

Behavioral Impairment ◽

Stroke Treatment

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood–brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

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Abstract TP113: Delayed (21 Days) Post Stroke Treatment With RPh201, A Botany-Derived Compound, Improves Neurological Functional Recovery in a Rat Model of Embolic Stroke

Stroke ◽

10.1161/str.51.suppl_1.tp113 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Chunyang Wang ◽

Michael Chopp ◽

Rui Huang ◽

Yi Zhang ◽

William Golembieski ◽

...

Keyword(s):

Functional Recovery ◽

Infarct Volume ◽

Experimental Models ◽

Stroke Recovery ◽

Female Rats ◽

Male Rats ◽

Acute Stroke Care ◽

Stroke Treatment ◽

Post Stroke ◽

Male And Female Rats

Introduction: Despite the recent advances in the acute stroke care, treatment options for long-term disability are limited. RPh201 is a botany-derived bioactive compound that has been shown to exert beneficial effects in various experimental models of neural injury. However, the effect of RPh201 on stroke recovery has not been investigated. The present study evaluated the effect of RPh201 on functional recovery after stroke. Methods: Young adult Wistar rats subjected to embolic middle cerebral artery occlusion (MCAO) were randomized into the following experimental groups stratified by sex (n=20/group): 1) RPh201 treatment, and 2) vehicle (cottonseed oil). RPh201 (20 μl) or vehicle were subcutaneously administered twice a week for 16 consecutive weeks starting at 21 days after MCAO. An array of behavioral tests were performed during 120 days after treatment initiation. Results: Male, but not female, ischemic rats treated with RPh201 exhibited significant (p<0.05) improvement of neurological function measured by adhesive removal test, foot-fault test, and modified neurological severity score at 90 and 120 days after initiation of treatment. Immunohistochemistry analysis showed that RPh201 treatment robustly increased neurofilament heavy chain positive axons and myelin basic protein densities in the peri-infarct area by 61% and 31% in the male rats, respectively, when compared to the vehicle treatment, which were further confirmed by Western blot analysis. The RPh201 treatment did not reduce infarct volume in both male and female rats. Conclusions: Our data demonstrated that RPh201 has a therapeutic effect on improvement of functional recovery in male ischemic rats even when the treatment was initiated 21 days post stroke. Enhanced axonal and myelination densities by RPh201 in ischemic brain may contribute to improved stroke recovery.

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Effects of Glycemic Gap on Post-Stroke Cognitive Impairment in Acute Ischemic Stroke Patients

Brain Sciences ◽

10.3390/brainsci11050612 ◽

2021 ◽

Vol 11 (5) ◽

pp. 612

Author(s):

Minwoo Lee ◽

Jae-Sung Lim ◽

Yerim Kim ◽

Ju Hun Lee ◽

Chul-Ho Kim ◽

...

Keyword(s):

Ischemic Stroke ◽

Cognitive Impairment ◽

Acute Ischemic Stroke ◽

Sex Education ◽

Cognitive Domain ◽

P Value ◽

Stroke Severity ◽

Stroke Patients ◽

Stroke Treatment ◽

Post Stroke

Background: Post-stroke hyperglycemia is a frequent finding in acute ischemic stroke patients and is associated with poor functional and cognitive outcomes. However, it is unclear as to whether the glycemic gap between the admission glucose and HbA1c-derived estimated average glucose (eAG) is associated with post-stroke cognitive impairment (PSCI). Methods: We enrolled acute ischemic stroke patients whose cognitive functions were evaluated three months after a stroke using the Korean version of the vascular cognitive impairment harmonization standards neuropsychological protocol (K-VCIHS-NP). The development of PSCI was defined as having z-scores of less than −2 standard deviations in at least one cognitive domain. The participants were categorized into three groups according to the glycemic gap status: non-elevated (initial glucose − eAG ≤ 0 mg/dL), mildly elevated (0 mg/dL < initial glucose − eAG < 50 mg/dL), and severely elevated (50 mg/dL ≤ initial glucose − eAG). Results: A total of 301 patients were enrolled. The mean age was 63.1 years, and the median National Institute of Health Stroke Scale (NIHSS) score was two (IQR: 1–4). In total, 65 patients (21.6%) developed PSCI. In multiple logistic regression analyses, the severely elevated glycemic gap was a significant predictor for PSCI after adjusting for age, sex, education level, initial stroke severity, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and left hemispheric lesion (aOR: 3.65, p-value = 0.001). Patients in the severely elevated glycemic gap group showed significantly worse performance in the frontal and memory domains. Conclusions: In conclusion, our study demonstrated that an elevated glycemic gap was significantly associated with PSCI three months after a stroke, with preferential involvement of frontal and memory domain dysfunctions.

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Abstract 43: Neuroprotective Effects of Inhibition of α5β1 Integrin Following Experimental Stroke: A Dual Center Pre-Clinical Study

Stroke ◽

10.1161/str.48.suppl_1.43 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Danielle Edwards ◽

Biav Reber Kittani ◽

Gillian Grohs ◽

Mhairi Macrae ◽

Justin F Fraser ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Infarct Volume ◽

Experimental Stroke ◽

Β1 Integrin ◽

Integrin Receptor ◽

Post Stroke ◽

Enhanced Mri ◽

Bbb Permeability ◽

Α5β1 Integrin

Blood-brain barrier (BBB) dysfunction after ischemic stroke exacerbates brain damage by contributing to edema and inflammation. The β1 integrin receptor family may contribute to this dysfunction via alteration of BBB-forming tight junction proteins. We hypothesize that inhibition of the β1 integrin receptor subtype α5β1, which is acutely expressed in infarct and peri-infarct vasculature after experimental stroke, reduces BBB permeability, reduces infarct volume, and improves functional recovery. A randomized and blinded trial was conducted using transient middle cerebral artery occlusion (MCAO) in mice (60 min; n=8) and rats (90 min; n=15) in two independent laboratories. ATN-161 (α5β1 inhibitor; 1 mg/kg) was administered IV immediately upon reperfusion and on post-stroke day 1 and 2. Infarct volume was determined by cresyl violet (mice) and T 2 weighted MRI (rat) at day 3 post MCAO. Steady state contrast enhanced MRI was used to assess BBB breakdown in rats at day 3. ATN-161 resulted in a significant reduction in infarct volume in both mice and rats when measured at post-stroke day 3 (p<0.001). BBB permeability was decreased upon ATN-161 treatment in vivo as determined by reduced IgG and claudin-5 immunostaining in mice and reduced extent of Gadolinium enhanced MRI signal change in rats. Behavioral tests (open field, rotorod, sticky label and 28 point neuroscore), demonstrated significantly improved functional recovery in both mice and rats following treatment with ATN-161. Finally, in vitro studies where stroke was simulated using oxygen and glucose deprivation or TNF-α, ATN-161 (10 μM) treatment demonstrated decreased barrier permeability as measured by trans-endothelial cell electrical resistance, FITC-dextran permeability, and claudin-5 immunocytochemistry. Collectively, our results demonstrate that post-stroke inhibition of α5β1 integrin with the small peptide ATN-161 profoundly reduces infarct volume, improves functional outcome and decreases BBB permeability in both mice and rats using two different ischemic stroke models. Therefore, inhibition of α5β1 by ATN-161 could represent a novel stroke therapeutic target worthy of further investigation.

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Long term Post-Stroke Functional Outcomes: a comparison of diabetics and non-diabetics

Cerebrovascular Diseases Extra ◽

10.1159/000521442 ◽

2021 ◽

Author(s):

Deidre Anne de Silva ◽

Kaavya Narasimhalu ◽

Ian Wang Huang ◽

Fung Peng Woon ◽

John C. Allen ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Outcome ◽

Functional Outcomes ◽

Age Group ◽

Stroke Patients ◽

Poor Functional Outcome ◽

Post Stroke ◽

The Impact

Introduction: Diabetes mellitus (DM) is known to influence outcomes in the short-term following stroke. However, the impact of DM on long-term functional outcomes after stroke is unclear. We compared functional outcomes periodically over 7 years between diabetic and non-diabetic ischemic stroke patients and investigated the impact of DM on the long-term trajectory of post-stroke functional outcomes. We also studied the influence of age on the diabetes-functional outcome association. Methods: This is a longitudinal observational cohort study of 802 acute ischemic stroke patients admitted to the Singapore General Hospital from 2005 to 2007. Functional outcomes were assessed using the modified Rankin Scale (mRS) with poor functional outcome defined as mRS≥3. Follow-up data was determined at 6 months and at median follow-up durations of 29 and 86 months. Results: Among the 802 ischemic stroke patients studied (mean age 64 ± 12 years, male 63%), 42% had DM. In regression analyses adjusting for covariates, diabetic patients were more likely to have poor functional outcomes at 6 months (OR=2.12, 95% CI: 1.23–3.67) and at median follow-up durations of 29 months (OR=1.96, 95% CI: 1.37–2.81) and 86 months (OR=2.27, 95% CI: 1.58–3.25). In addition, age modulated the effect of DM, with younger stroke patients (≤65 years) more likely to have long term poor functional outcome at the 29-month (p=0.0179) and 86-month (p=0.0144) time points. Conclusions: DM was associated with poor functional outcomes following ischemic stroke in the long term with the effect remaining consistent throughout the 7-year follow-up period. Age modified the effect of DM in the long term, with an observed increase in risk in the ≤65 age group but not in the >65 age group.

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