Minocycline promotes functional recovery in ischemic stroke by modulating microglia polarization through STAT1/STAT6 pathways

2021 ◽  
Vol 186 ◽  
pp. 114464
Author(s):  
Yunnan Lu ◽  
Mingming Zhou ◽  
Yun Li ◽  
Yan Li ◽  
Ye Hua ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Microglia Polarization

Minocycline Promotes Functional Recovery in Ischemic Stroke by Modulating Microglia Polarization Through STAT1/STAT6 Pathways

2021 ◽  
Author(s):  
Yunnan Lu ◽  
Mingming Zhou ◽  
Yun Li ◽  
Yan Li ◽  
Ye Hua ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Neuronal Injury ◽  
Reactive Gliosis ◽  
Rotarod Test ◽  
M2 Microglia ◽  
Microglia Polarization ◽  
M1 Phenotype ◽  
Corner Turning ◽  
Turning Test

Abstract BackgroundIncreasing evidence suggests that microglia experience two distinct phenotypes after acute ischemic stroke (AIS): a deleterious M1 phenotype and a neuroprotective M2 phenotype. Promoting the phenotype shift of M1 microglia to M2 microglia is thought to improve functional recovery after AIS. Minocycline, a tetracycline antibiotic, can improve functional recovery after cerebral ischemia in pre-clinical and clinical research. However, the role and mechanisms of minocycline in microglia polarization is unclear.MethodsUsing the transient middle cerebral artery occlusion - reperfusion (MCAO/R) model, we treated mice with saline or different minocycline concentration (10, 25, or 50 mg/kg, i.p., daily for 2 wk) at 24 h after reperfusion. Neurobehavioral evaluation, rotarod test, and corner turning test were carried out on day 14 after reperfusion. Then, neuronal injury, reactive gliosis, and microglia polarization were performed on day 7 following MCAO/R. Finally, we treated primary microglial cultures with LPS (Lipopolysaccharide; 100 ng/mL) plus IFN-γ (20 ng/mL) 24 h to induce M1 phenotype and observed the effects of minocycline on the M1/M2-related mRNAs and the STAT1/STAT6 pathway.ResultsWe found that a 14-day treatment with minocycline increased the survival rate and promoted functional outcomes evaluated with neurobehavioral evaluation, rotarod test, and corner turning test. Meanwhile, minocycline reduced the brain infarct volume, alleviated neuronal injury, and suppressed reactive gliosis on day 7 following MCAO/R. Moreover, we observed an additive effect of minocycline on microglia polarization to the M1 and M2 phenotypes in vivo and in vitro. In the primary microglia, we further found that minocycline prevented neurons from OGD/R-induced cell death in neuron-microglia co-cultures via regulating M1/M2 microglia polarization through the STAT1/STAT6 pathway. ConclusionMinocycline promoted microglial M2 polarization and inhibited M1 polarization, leading to neuronal survival and neurological functional recovery. The findings deepen our understanding of the mechanisms underlying minocycline-mediated neuroprotection in AIS.

Role of S100β Glial Protein as a Serological Marker for Analysis of Acute Ischemic Stroke

2021 ◽  
pp. 251660852110112
Author(s):  
Kiran Buddharaju ◽  
Mahendra Javali ◽  
Anish Mehta ◽  
R Srinivasa ◽  
Purushottam Acharya
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Recovery ◽  
Protein Level ◽  
Serological Marker ◽  
Protein Levels ◽  
S100β Protein ◽  
Asymptomatic Volunteers ◽  
Scale Scores

Background: Stroke is a major cause of neurological disability, which can be often predicted with serological markers. Glial-derived S100β protein is a potential biomarker for cerebral ischemia and may be helpful in predicting the severity, outcome, and recovery of stroke. Aim: This study aimed to study the role of S100β glial protein as a serological marker in predicting the severity of acute ischemic stroke (AIS), outcome, and functional recovery after 1 month. Methods: A hospital-based prospective case control study included 43 consecutive patients, >18 years old, who were admitted with acute middle cerebral artery (MCA) territory infarcts within 72 h of onset of neurological deficits. Control group comprised of 43 age-matched asymptomatic volunteers. Independent t-test and chi square test were used to compare the means and evaluate the association between protein level and various parameters. P ≤ .05 was statistically significant. Results: S100β protein level in AIS patients was significantly higher compared to controls ( P < .05). Elevated serum S100β protein level was found to be associated with larger infarct volumes, higher National Institute Health Stroke Scale scores, and higher modified Rankin Scale scores at admission ( P < .05). Patients with higher S100β protein levels at admission had poor recovery at 1 month compared to patients having normal S100β protein levels. Conclusion: S100β protein levels at admission after an acute MCA territory infarct may be used as a reliable serological tool in predicting the severity, outcome, and functional recovery in stroke.

scholarly journals Impact of Post-Stroke Recanalization on General and Upper Limb Functioning: A Prospective, Observational Study

2021 ◽  
Vol 13 (1) ◽  
pp. 46-58
Author(s):  
João Paulo Branco ◽  
Filipa Rocha ◽  
João Sargento-Freitas ◽  
Gustavo C. Santo ◽  
António Freire ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Observational Study ◽  
Acute Ischemic Stroke ◽  
Upper Limb ◽  
Functional Recovery ◽  
Prospective Observational Study ◽  
Positive Impact ◽  
Rehabilitation Program ◽  
Patient Functioning ◽  
The Impact

The objective of this study is to assess the impact of recanalization (spontaneous and therapeutic) on upper limb functioning and general patient functioning after stroke. This is a prospective, observational study of patients hospitalized due to acute ischemic stroke in the territory of the middle cerebral artery (n = 98). Patients completed a comprehensive rehabilitation program and were followed-up for 24 weeks. The impact of recanalization on patient functioning was evaluated using the modified Rankin Scale (mRS) and Stroke Upper Limb Capacity Scale (SULCS). General and upper limb functioning improved markedly in the first three weeks after stroke. Age, gender, and National Institutes of Health Stroke Scale (NIHSS) score at admission were associated with general and upper limb functioning at 12 weeks. Successful recanalization was associated with better functioning. Among patients who underwent therapeutic recanalization, NIHSS scores ≥16.5 indicate lower general functioning at 12 weeks (sensibility = 72.4%; specificity = 78.6%) and NIHSS scores ≥13.5 indicate no hand functioning at 12 weeks (sensibility = 83.8%; specificity = 76.5%). Recanalization, either spontaneous or therapeutic, has a positive impact on patient functioning after acute ischemic stroke. Functional recovery occurs mostly within the first 12 weeks after stroke, with greater functional gains among patients with successful recanalization. Higher NIHSS scores at admission are associated with worse functional recovery.

Chemogenetic activation of glutamatergic neurons in the motor cortex promotes functional recovery after ischemic stroke in rats

2019 ◽  
Vol 359 ◽  
pp. 81-88 ◽  
Author(s):  
Ke-hui Hu ◽  
Yang-an Li ◽  
Wei Jia ◽  
Guang-yan Wu ◽  
Lin Sun ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Motor Cortex ◽  
Functional Recovery ◽  
Glutamatergic Neurons

Treatment targets for M2 microglia polarization in ischemic stroke

2018 ◽  
Vol 105 ◽  
pp. 518-525 ◽  
Author(s):  
Ji wang ◽  
Hongyi xing ◽  
Lin wan ◽  
Xingjun jiang ◽  
Chen wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Treatment Targets ◽  
M2 Microglia ◽  
Microglia Polarization

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

Abstract TP96: Functional Recovery and White Matter Repair After Exosomes Administration in Different Experimental Animal Models of Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Laura Otero Ortega ◽  
María Gutiérrez Fernández ◽  
Berta Rodríguez Frutos ◽  
Jaime Ramos Cejudo ◽  
Irene Lorenzo Llorente ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Functional Recovery ◽  
Brain Plasticity ◽  
Trophic Factors ◽  
Lesion Volume ◽  
Axonal Sprouting ◽  
Control Groups ◽  
Myelin Formation ◽  
White Matter Repair

Introduction: Extracellular vesicles such as exosomes has opened a new field of research. Exosomes are able to transfer DNAs, mRNAs, microRNAs, non-coding RNAs, proteins, trophic factors and lipids associated with brain plasticity enhancement after stroke. Aim: To investigate white matter repair after exosomes administration in two experimental models of subcortical stroke: ischemic and hemorrhage. Material/Methods: Subcortical ischemic stroke was induced by Endothelin-1 and Collagenase IV was used to induce subcortical hemorrhagic stroke into striatum. Intravenous exosomes or saline only were administrated at 24h after cerebral infarct as treatment. Exosomes were isolated from culture of adipose mesenchymal stem cell and they were characterized by Nanoshight, Electronic microscope, Western blot and Immunofluorescence. Proteins contained into exosomes were analyzed by Orbitrab. We analyzed functional recovery by Rotarod, beam walking and Rogers tests. Lesion volume and tract connectivity were studied by magnetic resonance image. Anterograde and retrograde tracers were used to analyze axonal sprouting. Myelin formation was analyzed by cryomielin. Results: Proteomics analysis of exosomes identified more than 1400 proteins, many of them involved in intercellular communication. DiI labeled-Exosomes were detected in brain and peripheral organs (liver, lung and spleen). After 28 days, treated groups showed smaller functional deficit compared to control groups in both hemorrhagic and ischemic models. Moreover, treated group showed an increase in tract connectivity at 7 and 28 days compared to control groups. Also, animals which received exosomes showed an increase axonal sprouting and myelin formation at 28 days after stroke in both hemorrhagic and ischemic stroke. The treated groups also showed higher levels of white matter-associated markers in the injured area than the control groups. Conclusion: White matter integrity in different subcortical strokes is in part restored by exosomes treatment, probably mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery in both kinds of strokes.

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