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

Abstract

Background Increasing 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. Methods Using 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

Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

“…Minocycline is an antibiotic of the tetracycline family and it is the main compound used to abrogate inflammation induced by microglia activation [ 54 ]. Minocycline promotes a switch between microglial phenotypes, reducing the expression of M1 profile mRNA levels (IL-1β, IL-6, iNOS, and TNFα) and increasing typical M2 mRNAs (Arg-1, IL-10, TGF-β, and Ym1) [ 55 ]. Such an effect results in a reduction of the amoeboid morphology near the ischemic cortex and the infarct area [ 56 ].…”

“…Such an effect results in a reduction of the amoeboid morphology near the ischemic cortex and the infarct area [ 56 ]. Minocycline is also known to reduce cell death through the STAT1/STAT6 pathway [ 55 ]. Moreover, LPS-activated BV-2 microglial cell line presented a reduction in pro-inflammatory markers (CCL2, IL-6, and iNOS), with a concomitant decrease in caspase 3/7 activity and cell death [ 57 ].…”

Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases

“…At the molecular level, mechanisms of neuroinflammation have been unraveled in the last few years by ex vivo transcriptomic comparisons of microglial subpopulations (or single cells) dissociated after micro-dissection of the damaged brain regions in experimental animal models of disease or injuries at critical stages, as compared to analogous samples coming from the respective controls. Microglia was purified from primary cell suspensions by fluorescence-activated cell sorter (FACS) using for instance CD11b-fluorescent immunolabeling, and subjected to RNA-sequencing ( Keren-Shaul et al, 2017 ; Krasemann et al, 2017 ; Madore et al, 2020 ; Masuda et al, 2020b ; Li et al, 2021 ; Liu et al, 2021 ; Lu et al, 2021 ; Muzio et al, 2021 ; Yusuying et al, 2021 ). The key results of these approaches are summarized in Table 1 to facilitate comparison between the different pathological contexts of neuroinflammation.…”

“… Summarized from (i) Li et al, 2021 ; Liu et al, 2021 ; Lu et al, 2021 ; Yusuying et al, 2021 (for ischemia-reperfusion), (ii) Keren-Shaul et al, 2017 ; Krasemann et al, 2017 ; Butovsky and Weiner, 2018 ; Madore et al, 2020 (for Alzheimer’disease and amyotrophic lateral sclerosis), (iii) Muzio et al, 2021 (for aging); (iv) Madore et al, 2020 ; Li et al, 2021 (for Parkinson’s disease). Bold-italic: messengers secreted by microglial cells.…”

Cannabinoids as Glial Cell Modulators in Ischemic Stroke: Implications for Neuroprotection

“…This oligodendrocyte-protective effect has also been observed in an animal model of bilateral common carotid artery stenosis, where the treatment with the immunomodulatory drug Fingolimod promotes the polarization of microglia towards the M2-like phenotype leading to increased survival of OPCs and favoring myelin repair processes ( Qin et al, 2017 ). In light of the complex microglial response in stroke and the dual effect of the phenotypes described, the search for new therapeutic options with a modulating effect on cell polarization in stroke has intensified in recent years ( Qin et al, 2017 ; Liu et al, 2019 ; Lu et al, 2021 ).…”