The anti-inflammatory and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain

Abstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis. However, microglial VPS35’s role in the cortex in response to ischemic stroke remains largely unclear. Methods We used mice with VPS35 cKO (conditional knockout) in microglial cells and examined and compared their responses to ischemic stroke with control mice. The brain damage, cell death, changes in glial cells and gene expression, and sensorimotor deficits were assessed by a combination of immunohistochemical and immunofluorescence staining, RT-PCR, Western blot, and neurological functional behavior tests. Results We found that microglial VPS35 loss results in an increase of anti-inflammatory microglia in mouse cortex after ischemic stroke. The ischemic stroke-induced brain injury phenotypes, including brain damage, neuronal death, and sensorimotor deficits, were all attenuated by microglial VPS35-deficiency. Further analysis of protein expression changes revealed a reduction in CX3CR1 (CX3C chemokine receptor 1) in microglial VPS35-deficient cortex after ischemic stroke, implicating CX3CR1 as a potential cargo of VPS35 in this event. Conclusion Together, these results reveal an unrecognized function of microglial VPS35 in enhancing ischemic brain injury-induced inflammatory microglia, but suppressing the injury-induced anti-inflammatory microglia. Consequently, microglial VPS35 cKO mice exhibit attenuation of ischemic brain injury response.

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Proinflammatory and Anti-inflammatory Genes in Stroke Pathogenesis

Current Pharmaceutical Design ◽

10.2174/1381612826666200701212859 ◽

2020 ◽

Vol 26 (34) ◽

pp. 4220-4233

Author(s):

Mengmeng Jiang ◽

Penglin Yin ◽

Xiaodan Bai ◽

Liji Yang ◽

Junping Zhang ◽

...

Keyword(s):

Inflammatory Process ◽

Ischemic Brain ◽

Inflammatory Genes ◽

Proinflammatory Mediators ◽

Inflammatory Mechanism ◽

Ischemic Brain Tissue ◽

Anti Inflammatory ◽

The Brain

The brain's response to ischemic injury is an acute and long-term inflammatory process. This process involves activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. However, the exact pathogenesis of proinflammatory or anti-inflammatory genes in this process has not yet been elucidated. This review aims to investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of stroke. We also summarize the current clinical trials of drugs that target the inflammatory mechanism for intervention.

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Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms

Neurobiology of Disease ◽

10.1016/j.nbd.2009.12.010 ◽

2010 ◽

Vol 37 (3) ◽

pp. 711-722 ◽

Cited By ~ 59

Author(s):

Hongxia Shen ◽

Xiaoming Hu ◽

Can Liu ◽

Suping Wang ◽

Wenting Zhang ◽

...

Keyword(s):

Cell Death ◽

Brain Injury ◽

Ethyl Pyruvate ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Hypoxic Ischemic Brain Injury ◽

Anti Inflammatory

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Probucol plus cilostazol attenuate hypercholesterolemia-induced exacerbation in ischemic brain injury via anti-inflammatory effects

International Journal of Molecular Medicine ◽

10.3892/ijmm.2014.1848 ◽

2014 ◽

Vol 34 (3) ◽

pp. 687-694 ◽

Cited By ~ 6

Author(s):

JI HYUN KIM ◽

KI WHAN HONG ◽

SUN SIK BAE ◽

YONG-IL SHIN ◽

BYUNG TAE CHOI ◽

...

Keyword(s):

Brain Injury ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Anti Inflammatory

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Abstract TP279: Brain-Derived Microparticles Mediate Neuroinflammation After Stroke

Stroke ◽

10.1161/str.51.suppl_1.tp279 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Zhili Chen ◽

Michael Chopp ◽

Alex Zacharek ◽

Wei Li ◽

Poornima Venkat ◽

...

Keyword(s):

Inflammatory Cell ◽

Inflammatory Cell Infiltration ◽

Neurological Deficits ◽

Cell Infiltration ◽

Control Group ◽

Lesion Volume ◽

Inflammatory Factor ◽

Ischemic Brain ◽

Factor Expression ◽

Anti Inflammatory

Background and Purpose: Microparticles (MPs, ~ size between 0.1-1mm) are lipid encased containers, and are involved in intercellular communication and regulate inflammation. Stroke increases brain derived MP (BDMP) secretion which induces neuroinflammation. Milk fat globule-EGF factor-8 (MFGE8) promotes apoptotic cell clearance and limits pathogenic antigen cross presentation. In this study, we investigate whether BDMP affects stroke-induced neuroinflammation; whether MFGE8 treatment reduces stroke or BDMP-induced neuroinflammation and improves functional outcome after stroke. Method: 1) BDMPs were extracted from ischemic brain 24h after dMCAo by ultracentrifugation. 2) Adult (8 months) male C57BL/6J mice were subjected to dMCAo and were injected via tail vein 3h after stroke with: A) PBS (n=5/group); B) +BDMP(1.5х10 8 ,n=6/group); C)+MFGE8 (Lactadherin, 400ug/kg, n=5/group); D) +BDMP+MFGE8 (n=6/group). A battery of neurological function outcomes and immunostaining were performed. Blood plasma was used for Western blot assay. Result: 1) Compared with the Stroke+PBS control group, Stroke+BDMP significantly increases inflammatory factor expression in the circulation, increases lesion volume, neurological deficits, blood brain barrier (BBB) leakage, microglial activation, and inflammatory cell infiltration (CD45, microglia/macrophage, Neutrophils) and inflammatory factor (TNFα, IL6, IL1β) expression in brain, and increases axon/white matter (WM) damage; 2) Compared to Stroke+PBS and Stroke+BDMP groups, Stroke+MFGE8 and Stroke+BDMP+MFGE8 mice exhibited significantly improved neurological outcome; decreased lesion volume and BBB leakage, reduced axon/WM damage, and decreased inflammatory cell infiltration and inflammatory factor expression in the ischemic border, respectively. MFGE8 treatment significantly increased anti-inflammatory factor (IL10) expression in ischemic brain, and decreased IL1β expression in circulation compared to Stroke+PBS and Stroke+BDMP groups, respectively. Conclusion: BDMP increases neuroinflammation and induces worse brain damage after stroke. MFGE8 treatment reduces stroke and BDMP-induced neurological deficits possibly via its anti-inflammatory effects.

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Neuroprotective and Anti-Inflammatory Effects of the Flavonoid-Enriched Fraction AF4 in a Mouse Model of Hypoxic-Ischemic Brain Injury

PLoS ONE ◽

10.1371/journal.pone.0051324 ◽

2012 ◽

Vol 7 (12) ◽

pp. e51324 ◽

Cited By ~ 21

Author(s):

Paul G. W. Keddy ◽

Kate Dunlop ◽

Jordan Warford ◽

Michel L. Samson ◽

Quinton R. D. Jones ◽

...

Keyword(s):

Brain Injury ◽

Mouse Model ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Hypoxic Ischemic Brain Injury ◽

Anti Inflammatory

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Graptopetalum paraguayense E. Walther Leaf Extracts Protect Against Brain Injury in Ischemic Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x10008019 ◽

2010 ◽

Vol 38 (03) ◽

pp. 495-516 ◽

Cited By ~ 23

Author(s):

Tsung-Kuei Kao ◽

Yen-Chuan Ou ◽

Shue-Ling Raung ◽

Wen-Ying Chen ◽

Yu-Ju Yen ◽

...

Keyword(s):

Brain Injury ◽

Inos Expression ◽

Microglia Activation ◽

Janus Kinase ◽

Mechanistic Study ◽

Ischemic Brain Injury ◽

Leaf Extracts ◽

Ischemic Brain ◽

Ifn Γ ◽

Anti Inflammatory

As practice in folk medicine, Graptopetalum paraguayense E. Walther possesses several biological/pharmacological activities including hepatoprotective, anti-oxidant, and anti-inflammatory. We investigated the neuroprotective potential of Graptopetalum paraguayense E. Walther leaf extracts on inflammation-mediated ischemic brain injury. Water (GWE), 50% alcohol (GE50) extracts of Graptopetalum paraguayense E. Walther, and extracts obtained from further extraction of GE50 with ethyl acetate (GEE) were used. Oral administration of GEE, but not GWE or GE50, for 2 weeks protected animals against cerebral ischemia/reperfusion brain injury. The neuroprotective effect of GEE was accompanied by reductions in brain infarction, neurological deficits, caspase-3 activity, malondialdehyde content, microglia activation, and inducible nitric oxide synthase (iNOS) expression. Since microglia-mediated inflammation plays critical roles in ischemic brain injury, anti-inflammatory potential of Graptopetalum paraguayense E. Walther leaf extracts was further investigated on lipopolysaccharide (LPS)/interferon-γ (IFN-γ-activated BV-2 microglial cells. GEE decreased H2O2 - and LPS/IFN-γ-induced free radical generation and LPS/IFN-γ-induced iNOS expression. Mechanistic study revealed that the neuroactive effects of GEE were markedly associated with anti-oxidative potential, activation of serine/threonine and tyrosine phosphatases, and down-regulation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, Akt, Src, Janus kinase-1, Tyk2, signal transducer and activator of transcription-1, and NF-κB and might be attributed to the presence of polyphenolic compounds such as gallic acid, genistin, daidzin, and quercetin. Together, our findings point out its potential therapeutic strategies that target microglia activation, oxidative stress, and iNOS expression to reduce ischemic brain injury and suggest that Graptopetalum paraguayense E. Walther leaf extracts represent a valuable source for the development of neuroprotective agents.

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Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization

International Journal of Molecular Sciences ◽

10.3390/ijms22189999 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9999

Author(s):

Dashdulam Davaanyam ◽

Il-Doo Kim ◽

Ja-Kyeong Lee

Keyword(s):

Amino Acid ◽

Infarct Volume ◽

Critical Role ◽

Neuroprotective Effects ◽

Ischemic Brain ◽

Rgd Motif ◽

Arginase 1 ◽

M2 Polarization ◽

Severity Scores ◽

Anti Inflammatory

Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs, in an animal model of transient focal ischemia and demonstrated that its anti-inflammatory, pro-angiogenic, and phagocytosis inducing functions are responsible for the neuroprotective effects. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motifs (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S), and their neuroprotective efficacy was examined in a rat middle cerebral artery occlusion (MCAO) model. Intranasal administration of all four peptides significantly reduced infarct volume; OPNpt7R (VPNGRGD), the 7-amino-acid peptide containing an RGD motif, was determined to be the most potent, with efficacy comparable to that of OPNpt20. Additionally, sensory–motor functional deficits of OPNpt7R-administered MCAO animals were significantly improved, as indicated by the modified neurological severity scores and rotarod test. Notably, the expression of M1 markers was suppressed, whereas that of M2 markers (Arginase 1, CD206, and VEGF) was significantly enhanced in OPNpt7R-treated primary microglia cultures. Inflammation resolution by OPNpt7R was further confirmed in MCAO animals, in which upregulation of anti-inflammatory cytokines (Arg1, IL-10, IL-4, and CD36) and enhanced efferocytosis were detected. Moreover, studies using three mutant peptides (OPNpt7R-RAA or OPNpt7R-RAD, where RGD was replaced with RAA or RAD, respectively, and OPNpt7R-sc containing scrambled sequences) revealed that the RGD motif plays a vital role in conferring neuroprotection. In conclusion, the RGD-containing OPN heptamer OPNpt7R exhibits neuroprotective effects in the post-ischemic brain by suppressing M1 markers and augmenting M2 polarization of microglia and the RGD motif plays a critical role in these activities.

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