Early Treatment with Poly(ADP-Ribose) Polymerase-1 Inhibitor (JPI-289) Reduces Infarct Volume and Improves Long-Term Behavior in an Animal Model of Ischemic Stroke

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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Hyper-acute EEG alterations predict functional and morphological outcomes in thrombolysis-treated ischemic stroke: a wireless EEG study

Medical & Biological Engineering & Computing ◽

10.1007/s11517-020-02280-z ◽

2020 ◽

Author(s):

Miloš Ajčević ◽

Giovanni Furlanis ◽

Marcello Naccarato ◽

Aleksandar Miladinović ◽

Alex Buoite Stella ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Treatment Strategies ◽

Alpha Power ◽

Prognostic Information ◽

Term Outcome ◽

Long Term Outcome ◽

Pre Treatment ◽

Wireless Eeg

AbstractOwing to the large inter-subject variability, early post-stroke prognosis is challenging, and objective biomarkers that can provide further prognostic information are still needed. The relation between quantitative EEG parameters in pre-thrombolysis hyper-acute phase and outcomes has still to be investigated. Hence, possible correlations between early EEG biomarkers, measured on bedside wireless EEG, and short-term/long-term functional and morphological outcomes were investigated in thrombolysis-treated strokes. EEG with a wireless device was performed in 20 patients with hyper-acute (< 4.5 h from onset) anterior ischemic stroke before reperfusion treatment. The correlations between outcome parameters (i.e., 7-day/12-month National Institutes of Health Stroke Scale NIHSS, 12-month modified Rankin Scale mRS, final infarct volume) and the pre-treatment EEG parameters were studied. Relative delta power and alpha power, delta/alpha (DAR), and (delta+theta)/(alpha+beta) (DTABR) ratios significantly correlated with NIHSS 7-day (rho = 0.80, − 0.81, 0.76, 0.75, respectively) and NIHSS 12-month (0.73, − 0.78, 0.74, 0.73, respectively), as well as with final infarct volume (0.75, − 0.70, 0.78, 0.62, respectively). A good outcome in terms of mRS ≤ 2 at 12 months was associated with DAR parameter (p = 0.008). The neurophysiological biomarkers obtained by non-invasive and portable technique as wireless EEG in the early pre-treatment phase may contribute as objective parameters to the short/long-term outcome prediction pivotal to better establish the treatment strategies.Graphical abstract

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Abstract W MP14: Early Infarct Growth Predicts Long-term Clinical Outcome in Ischemic Stroke

Stroke ◽

10.1161/str.45.suppl_1.wmp14 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Seung Min Kim ◽

Deok Hee Lee ◽

Sun U. Kwon ◽

Sang Joon Kim ◽

Jong S. Kim ◽

...

Keyword(s):

Ischemic Stroke ◽

Clinical Outcomes ◽

Infarct Volume ◽

Surrogate Marker ◽

Characteristic Analysis ◽

Prognostic Information ◽

Term Outcome ◽

Ischemic Lesion ◽

Long Term Outcome

Background: Ischemic lesion is dynamically evolving during acute phase of stroke. However, it is still controversial whether early changes in ischemic lesion have a prognostic information in addition to clinical variables. We hypothesized that early infarct growth on diffusion-weighted imaging (DWI) might be independently associated with long-term outcome. Methods: This was a prospective study of acute ischemic stroke patients who underwent DWI at baseline (within 24 hours) and at 5-day after stroke onset. Early infarct growth was defined as the difference between the final and the baseline infarct volume. Clinical outcomes were assessed using the modified Rankin Scale (mRS) at 3 months. Univariate and multivariate analyses were performed to assess the relationship between early infarct growth and clinical outcomes. The cut-off values of early infarct growth predicting long-term clinical outcomes were estimated using receiver operating characteristic analysis. Results: Of total 409 patients included, 345 (84.4%) showed any early infarct growth (median, 0.63cm 3 , interquartile range, 0.11-6.33cm 3 ). After adjusting age, diabetes, baseline National Institutes of Health Stroke Scale, and baseline infarct volume by multiple logistic analysis, infarct growth was an independent predictor of poor clinical outcomes (for mRS 2-6, odds ratio [OR], 1.03, 95% confidence interval [CI], 1.002-1.06, p=0.04; and for mRS 3-6, OR, 1.03, 95% CI, 1.01-1.05, p=0.01). The cut-off values of early infarct growth discriminating between good and poor outcomes were 0.99cm 3 for mRS 0-1 vs. 2-6 (area under curve [AUC], 0.685, p<0.001) and 8.86cm 3 for mRS 0-2 vs. 3-6 (AUC, 0.736, p<0.001). Conclusions: Infarct growth within a week of symptom onset independently predicts 3-month clinical outcomes. This suggests that short-term changes in infarct volume may serve as a surrogate marker of long-term clinical outcomes after ischemic stroke.

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

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.596039 ◽

2021 ◽

Vol 13 ◽

Author(s):

Hongfei Ge ◽

Chao Zhang ◽

Yang Yang ◽

Weixiang Chen ◽

Jun Zhong ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Infarct Volume ◽

Basic Knowledge ◽

Brain Disorders ◽

Potential Mechanism ◽

Stroke Patients ◽

Stroke Treatment ◽

Post 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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Adiponectin Treatment Attenuates Cerebral Ischemia-Reperfusion Injury through HIF-1α-Mediated Antioxidation in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5531048 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Chan Zhang ◽

Luming Zhen ◽

Zongping Fang ◽

Liang Yu ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Term Outcome ◽

Long Term Outcome ◽

Cellular Apoptosis ◽

Cerebral Ischemia Reperfusion Injury

Adiponectin (ADPN) plays an important role in cerebral ischemia-reperfusion injury. Although previous studies have confirmed that ADPN pretreatment has a protective effect on ischemic stroke, the therapeutic effect of ADPN on ischemic stroke and the underlying mechanism are still unclear. In order to clarify these questions, focal transient cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice and ADPN was administered for three times at 6 h, 24 h, and 48 h after reperfusion. Meanwhile, a virus-delivered HIF-1α siRNA was used before ADPN administration. The infarct volume, neurological score, cellular apoptosis, and oxidative stress were assessed at 72 h after reperfusion. The long-term outcome of mice after stroke was recorded as well. The results indicated that ADPN treatment reduced the infarct volume ( P = 0.032 ), neurological deficits ( P = 0.047 ), cellular apoptosis ( P = 0.041 ), and oxidative responses ( P = 0.031 ) at 72 h after MCAO. Moreover, ADPN increased both the protein level and transcriptional activity of HIF-1α as evidenced by the transcription levels of VEGF ( P = 0.046 ) and EPO ( P = 0.043 ) at 72 h after MCAO. However, knockdown of HIF-1α partially reversed the antioxidant and treatment effect of ADPN after cerebral ischemia. In the observation of long-term outcome after ADPN treatment, it demonstrated that ADPN not only prevented the cerebral atrophy ( P = 0.031 ) and the neurological function decline ( P = 0.048 ), but also promoted angiogenesis ( P = 0.028 ) after stroke. In conclusion, our findings suggest that ADPN is effective in treatment of ischemic stroke which could be attributed to the increased antioxidant capacity regulated by HIF-1α.

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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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Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19875201 ◽

2019 ◽

Vol 39 (12) ◽

pp. 2392-2405 ◽

Cited By ~ 7

Author(s):

Haiping Zhao ◽

Guangwen Li ◽

Sijia Zhang ◽

Fangfang Li ◽

Rongliang Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Neuronal Loss ◽

Predictive Biomarker ◽

Acute Stage ◽

Negative Regulator ◽

Experimental Stroke ◽

Cerebral Ischemic

HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke.

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Distinct Commensal Bacterial Signature in the Gut Is Associated With Acute and Long-Term Protection From Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.029262 ◽

2020 ◽

Vol 51 (6) ◽

pp. 1844-1854 ◽

Cited By ~ 3

Author(s):

Corinne Benakis ◽

Carrie Poon ◽

Diane Lane ◽

David Brea ◽

Giulia Sita ◽

...

Keyword(s):

Ischemic Stroke ◽

16S Rrna ◽

16S Rrna Gene ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Bacterial Density ◽

Rrna Gene ◽

Preventive Strategy ◽

Long Term Outcome

Background and Purpose— Commensal gut bacteria have a profound impact on stroke pathophysiology. Here, we investigated whether modification of the microbiota influences acute and long-term outcome in mice subjected to stroke. Methods— C57BL/6 male mice received a cocktail of antibiotics or single antibiotic. After 4 weeks, fecal bacterial density of the 16S rRNA gene was quantitated by qPCR, and phylogenetic classification was obtained by 16S rRNA gene sequencing. Infarct volume and hemispheric volume loss were measured 3 days and 5 weeks after middle cerebral artery occlusion, respectively. Neurological deficits were tested by the Tape Test and the open field test. Results— Mice treated with a cocktail of antibiotics displayed a significant reduction of the infarct volume in the acute phase of stroke. The neuroprotective effect was abolished in mice recolonized with a wild-type microbiota. Single antibiotic treatment with either ampicillin or vancomycin, but not neomycin, was sufficient to reduce the infarct volume and improved motorsensory function 3 days after stroke. This neuroprotective effect was correlated with a specific microbial population rather than the total bacterial density. In particular, random forest analysis trained for the severity of the brain damage revealed that Bacteroidetes S24.7 and the enzymatic pathway for aromatic metabolism discriminate between large versus small infarct size. Additionally, the microbiota signature in the ampicillin-treated mice was associated with a reduced gut inflammation, long-term favorable outcome shown by an amelioration of the stereotypic behavior, and a reduction of brain tissue loss in comparison to control and was predictive of a regulation of short-chain fatty acids and tryptophan pathways. Conclusions— The findings highlight the importance of the intestinal microbiota in short- and long-term outcomes of ischemic stroke and raises the possibility that targeted modification of the microbiome associated with specific microbial enzymatic pathways may provide a preventive strategy in patients at high risk for stroke. Visual Overview— An online visual overview is available for this article.

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