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

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.

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Abstract T P80: Inhibition of Ezh2 Leads to Decreased M1 and Enhanced M2 Microglia Phenotypes

Stroke ◽

10.1161/str.46.suppl_1.tp80 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Edward Koellhoffer ◽

Jeremy Grenier ◽

Rodney Ritzel ◽

Louise McCullough

Keyword(s):

Ischemic Stroke ◽

Pcr Analysis ◽

M2 Polarization ◽

M2 Microglia ◽

M1 Polarization ◽

Glial Cultures ◽

M2 Response ◽

M1 Phenotype ◽

Cayman Chemical ◽

M2 Phenotype

Background: Ischemic stroke results in the activation of microglia, which may polarize toward a pro-inflammatory (M1) phenotype or an anti-inflammatory, neuroprotective (M2) phenotype. Thus, simultaneously suppressing the M1 response and promoting the M2 response could be beneficial in the treatment of stroke. Recently, the epigenetic modulator Jmjd3 has been shown to be essential for M2 polarization. However, Jmjd3 is antagonized by Ezh2 which is associated with M1 polarization. Thus, we hypothesized that inhibition of Ezh2 tilts the balance between Jmjd3 and Ezh2, thereby enhancing polarization toward an M2 phenotype and improved outcome in ischemic stroke. Methods: Mixed glial cultures were isolated from P0.5-P2 C57BL/6J mice and cultured for 14 days before microglial isolation. Microglia were rested for 24 hours before treatment every other day with 6uM GSK343 (Cayman Chemical) or DMSO vehicle control. After 7 days, microglia were stimulated with LPS or IL-4 and RNA was isolated at 4hr and 24hr post-stimulation for qRT-PCR analysis. Results: LPS-induced IL6 and IL1B expression was significantly abrogated by 71% and 53%, respectively (p<0.05), at 24hr when Ezh2 was inhibited. Additionally, Ezh2 inhibition both increased baseline expression of M2-associated genes ARG1, CD206, and IRF4 by 196%, 257%, and 395%, respectively (p<0.05), and rescued their expression in the presence of LPS at 24hr (p<0.05) in which they were otherwise significantly down-regulated. Conclusion: Pharmacological inhibition of Ezh2 limits microglial M1 polarization and enhances M2 polarization.

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Treatment targets for M2 microglia polarization in ischemic stroke

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.05.143 ◽

2018 ◽

Vol 105 ◽

pp. 518-525 ◽

Cited By ~ 29

Author(s):

Ji wang ◽

Hongyi xing ◽

Lin wan ◽

Xingjun jiang ◽

Chen wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Treatment Targets ◽

M2 Microglia ◽

Microglia Polarization

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PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury

Experimental Neurology ◽

10.1016/j.expneurol.2021.113854 ◽

2021 ◽

pp. 113854

Author(s):

Sisi Li ◽

Xuyun Hua ◽

Mouxiong Zheng ◽

Jiajia Wu ◽

Zhenzhen Ma ◽

...

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Functional Recovery ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Stat3 Signaling ◽

Cerebral Ischemia Reperfusion ◽

M2 Microglia ◽

Microglia Polarization ◽

Cerebral Ischemia Reperfusion Injury

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Melatonin reduces neuroinflammation and improves axonal hypomyelination by modulating M1/M2 microglia polarization via JAK2-STAT3-telomerase pathway in postnatal rats exposed to lipopolysaccharide

10.21203/rs.3.rs-422990/v1 ◽

2021 ◽

Author(s):

Qiuping Zhou ◽

Lanfen Lin ◽

Haiyan Li ◽

Shuqi Jiang ◽

Huifang Wang ◽

...

Keyword(s):

Inflammatory Mediators ◽

Periventricular White Matter ◽

Microglial Polarization ◽

Proinflammatory Mediators ◽

M2 Microglia ◽

Microglia Polarization ◽

M1 Phenotype ◽

Anti Inflammatory ◽

Postnatal Rats

Abstract Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be through modulating microglial polarization from M1 phenotype to M2 through JAK2/STAT3/telomerase pathway. We reported here that melatonin, indeed, not only can it reduce the neurobehavioral disturbances in LPS injected rats, but it can also dampen microglia mediated inflammation. Thus, in LPS + melatonin group, expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with TERT or MT1. In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. That melatonin can improve hypomyelination was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the melatonin effects on LPS treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization that would ultimately contribute to attenuation of PWMD.

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Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

Neurobiology of Disease ◽

10.1016/j.nbd.2016.09.013 ◽

2016 ◽

Vol 96 ◽

pp. 248-260 ◽

Cited By ~ 55

Author(s):

Jin Hwan Lee ◽

Zheng Z Wei ◽

Wenyuan Cao ◽

Soonmi Won ◽

Xiaohuan Gu ◽

...

Keyword(s):

Ischemic Stroke ◽

Therapeutic Hypothermia ◽

Inflammatory Cytokines ◽

Functional Recovery ◽

Microglia Polarization

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

Biochemical Pharmacology ◽

10.1016/j.bcp.2021.114464 ◽

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

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The relationship of leukoaraiosis severity and the degree of functional recovery after atherothrombotic ischemic stroke

Ukrainian Neurological Journal ◽

10.30978/unj2020-1-28 ◽

2020 ◽

Vol 0 (1—2) ◽

pp. 28-33

Author(s):

L. V. Panteleienko

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Relationship Of ◽

The Relationship

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

Journal of Stroke Medicine ◽

10.1177/25166085211011284 ◽

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.

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

Neurology International ◽

10.3390/neurolint13010005 ◽

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.

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