Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke

Qin, Jin; Cheng, Jian; Liu, Yang; Wu, Jian; Wang, Xiaoyu; Wei, Shanwen; Zhou, Xiaomei; Qin, Zheng‐Hong; Jia, Jia; Zhen, Xuechu

doi:10.1016/j.bbi.2014.03.003

Cited by 262 publications

(187 citation statements)

References 35 publications

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“…Thus, it is very likely, based on the MC-21 monocyte-depletion experiment, that the effect of the MDMs with a bias toward anti-inflammatory activity on recovery is not mediated through neuroprotection but by creating an immunological microenvironment that supports tissue remodeling. In agreement with our findings, poststroke chronic treatment with the adenosine 5Ј-monophosphate-activated protein kinase activator metformin promoted functional recovery and tissue repair via an anti-inflammatory-polarization mechanism after experimental stroke without affecting ischemic lesion volume (Jin et al, 2014). This treatment resulted in fewer cells immunopositive to anti-inflammatory markers, such as CD32 and IL-1␤, and increased numbers of cells expressing anti-inflammatory markers, such as CD206, Arginase 1, and IL-10.…”

Section: Discussionsupporting

confidence: 79%

“…It is well established that ischemic stroke leads to brain inflammation, involving activated astrocytes and microglia, as well as infiltration of myeloid cells and lymphocytes into the ischemic brain hemisphere (Kochanek and Hallenbeck, 1992;Tomita and Fukuuchi, 1996;Stoll et al, 1998;Campanella et al, 2002;Stevens et al, 2002;Danton and Dietrich, 2003;Gelderblom et al, 2009;Denes et al, 2010;Jin et al, 2010;Miró -Mur et al, 2016). Although excitotoxicity causes neuronal death shortly after the onset of the ischemic insult, the inflammatory reaction is part of the repair mechanism that takes days to reach its peak and, therefore, gives a reasonable window for therapeutic interventions (Dirnagl et al, 1999;Shechter and Schwartz, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have demonstrated increased expression of TGF␤ (Lehrmann et al, 1998;Martinez et al, 2001;Doyle et al, 2010;Pál et al, 2012) and its receptor (Pál et al, 2014) after stroke, mostly in macrophages (Lehrmann et al, 1998;Martinez et al, 2001;Doyle et al, 2010). TGF␤ has been shown to suppress excessive neuroinflammation during the subacute phase after brain ischemia, as evidenced by decreased expression of the proinflammatory microglia/macrophage markers CD68 and iNOS (Cekanaviciute et al, 2014), and is also able to directly inhibit LPSmediated activation of microglia (Kim et al, 2004;Le et al, 2004). Zhou et al (2012) recently demonstrated that TGF␤ enhances IL-4-induced alternative activation of microglia by strongly increasing the expression of Ym1.…”

Section: Discussionmentioning

confidence: 99%

“…Mice were then perfused transcardially with sterile cold saline solution until the blood was completely washed out. Brains were quickly removed and placed in cold hibernation medium (Kawamoto and Barrett, 1986). Brains were dissociated using Neural Tissue Dissociation kit (Miltenyi Biotec) according to the instructions of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…Notably, all mice were head protected during the irradiation that precedes the bone marrow transplantation (Shechter et al, 2009). In CX3CR1-GFP mice, CX3CR1 ϩ monocytes and microglia are GFP ϩ (Jung et al, 2000). However, in the chimeric animals, only bone marrow-derived monocytes are GFP ϩ , which allows identification of MDMs with both immunocytochemistry and flow cytometry (Mildner et al, 2007).…”

Section: E)mentioning

confidence: 99%

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Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

et al. 2016

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Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in longterm spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltrating MDMs exhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGF␤, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: E)mentioning

confidence: 99%

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Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

et al. 2016

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Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase ( AMPK ), atypical protein kinase C ζ ( aPKC ζ), and insulin receptor substrate 1 ( IRS 1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK , aPKC ζ/λ, and IRS 1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

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Engineering Stem Cell Derived Biomimetic Vesicles for Versatility and Effective Targeted Delivery

Jiang

et al. 2020

Adv Funct Materials

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To date, only few a types of nanomedicines have been made available for clinical use even in the most common liposomal delivery systems, due to significant constraints, including poor targeting of specific cells, hindered penetration, and accelerated clearance. Various intricate designs have been generated and show improvements, while also bringing new problems. Biological cells, possessing advantages like low immunogenicity, long circulation time, receptors integration, and innate targeting capability. Herein, liposomes are innovatively functionalized with a stem cell membrane through a facile approach. The biomimetic vesicles achieve controlled release, exhibit better stability, longer circulation time, and targeted delivery. Loading with curcumin leads to enhanced survival rate of ischemic stroke mice with a single injection (from ≈30% to over 90%). The versatility of the method is verified by differently charged liposomes modification and erythrocyte membrane derived vesicles preparation. Overall, the cell membrane derived biomimetic vesicles achieve targeted delivery and versatility prepared by a facile approach, as well as effortless preparation.

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Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke

Cited by 262 publications

References 35 publications

Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Engineering Stem Cell Derived Biomimetic Vesicles for Versatility and Effective Targeted Delivery

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