Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia

He, Shucheng; Liu, Rui; Li, Binbin; Huang, Liangliang; Fan, Wenxiang; Tembachako, Charmaine Ruvimbo; Zheng, Xiufen; Xiong, Xiaoxing; Miyata, Masaaki; Xu, Baohui; Li, Yunman; Fang, Weirong

doi:10.1016/j.neuint.2019.02.010

Cited by 30 publications

(22 citation statements)

References 51 publications

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“…We found that the expression of IL-17 in the ischemic cortex and hippocampus of stroke mice treated with As IV was decreased remarkably by both immunohistochemistry and Western blot analysis (Figures 3A, B) and the expression of IL-17 increased gradually and slowly after stroke as time went on and lagged far behind the appearance of apoptosis ( Figure 3C). Consistently, previous results also suggest that the over expression of IL-17 indicates a poorer treatment effect and prognosis for ischemic stroke (He et al, 2019;Tian et al, 2019;Zhou et al, 2019), which always abolishes some neuroprotective effect (Ma et al, 2018;Sun et al, 2018;Zhao et al, 2019) and it can be reduced by As IV (Jin et al, 2017;Zhang et al, 2018). So, IL-17 expression is upregulated remarkably by ischemic stroke, which can be reversed by As IV, indicating IL-17 is a key regulation factor for As IV's neuroprotective effect on ischemic stroke.…”

Section: A B C Dsupporting

confidence: 80%

“…Some innate lymphocytes, like brain-infiltrating interleukin-17 (IL-17)-positive gd T cells, are established as major initial IL-17 producers in acute stroke (Arunachalam et al, 2017). IL-17 is an important inflammatory factor and its over-expression indicates a poorer treatment effect and prognosis for ischemic stroke (He et al, 2019;Tian et al, 2019;Zhou et al, 2019), which always abolishes some neuroprotective effect (Sun et al, 2018;Ma et al, 2018;Zhao et al, 2019). IL-17 has a quite complex role in regulating adult neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

et al. 2020

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Background: Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing, and Astragaloside IV (As IV), a primary bioactive compound of Radix Astragali: Astragalus mongholicus Bunge (Fabaceae), may be a promising stroke therapy. Methods: To access the effect of As IV on adult mice after ischemic stroke, a photochemical ischemia model was established on C57BL/6 mice, which were intravenously administered As IV for three consecutive days later. And then the cognitive benefits and hippocampal neurogenesis were evaluated by Morris Water Maze (MWM) test, Golgi staining, and immunohistochemical staining in vivo and in vitro. Furthermore, to find out the underlying mechanism, interleukin-17 (IL-17) knockout (KO) mice were used, through RNA sequence (RNA-seq) analysis and immunohistochemistry. Then the mechanism of neurogenesis promoted by As IV was observed by western blot both in vivo and in vitro. Specifically, As IV, recombinant mouse IL-17A and IL-17F, and Wingless/integrated (Wnt)-expressing virus was administered respectively in neural stem cells (NSCs), and then their diameters and protein expression of Nestin, IL-17, and Wnt pathway relevant protein, were measured in vitro. Results: Administering As IV resulted in significant amelioration of stroke-induced cognitive deficits. And more hippocampal neurons with normal morphology, significant increments in the length of the apical dendrites, and the density of their spines were observed in As IV-treated mice. Furthermore, the immunohistochemistry staining of DCX/ BrdU and Sox2/Nestin showed As IV could promote hippocampal neurogenesis and NSC proliferation after ischemic stroke, as well as in vitro. For the mechanism underlying, IL-17 expression was downregulated significantly by As IV treatment and knocking out IL-17 was associated with nervous regeneration and synapse repair according to the analysis of RNA-seq. Consistent to As IV treatment, knocking out IL-17 showed some promotion on hippocampal neurogenesis and proliferation of NSCs, with activating Wnt pathway after

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Section: A B C Dsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

et al. 2020

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“…However, recent studies suggest that activated microglia contribute to neural plasticity and neuro-restoration following insult [ 41 ]. In response to various signals, microglia/macrophages polarize to two major phenotypes: pro-inflammatory (M1) and anti-inflammatory (M2) [ 41 , 43 ]. Although the M1 population of microglia/macrophages mainly exhibits destructive properties, the M2 population plays a protective role in nerves; therefore, regulating macrophage polarization can be an important factor in improving stroke [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Lee

Jung

et al. 2020

IJMS

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Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C–C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

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“…13,15,28 However, the detailed mechanism by which elevated CCL2 is involved in BBB compromise after ICH has not been clearly identified. To clarify the potential mechanism by which CCL2 contributes to BBB disruption, the colocation of CCR2 and p-p38 MAPK was detected by triple immunofluorescence staining, and our F I G U R E 6 Colocation of the CCL2 receptor and p-p38 MAPK in vivo.…”

Section: Discussionmentioning

confidence: 99%

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

Guo

Lin

et al. 2019

FASEB j.

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Intracerebral hemorrhage (ICH) remains a devastating type of stroke that lacks an effective treatment. Recent evidence has demonstrated that CCL2 is involved in the blood‐brain barrier (BBB) disruption and propagermanium (PG) as a CCL2 receptor inhibitor is neuroprotective in ischemic stroke. However, whether PG therapy exert effective role in acute ICH still unclear. In this study, our goal was to investigate the potential role of CCL2 and the effects of PG in ICH. Differentially expressed RNAs including CCL2 were detected in human ICH. CCL2 and the activation of p‐p38 MAPK and AQP4 expression were analyzed in rats after ICH. Brain water content and BBB integrity as well as neurological function were also examined after PG administration. In addition, the mechanism by which CCL2‐mediated BBB injury was further investigated by cell coculture. Our findings showed that PG could effectively reduce brain edema and improve neurobehavioral functions. p‐p38 MAPK and AQP4 expression were significantly inhibited by PG in vivo and in vitro. To the best of our knowledge, this is the first demonstration of PG in neuroprotecting the BBB integrity by inhibition of CCL2‐CCR2‐p38 MAPK pathway following ICH, targeting CCL2 could be developed as a novel treatment for hemorrhagic stroke.

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Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia

Cited by 30 publications

References 51 publications

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke

Chemokine CCL2 contributes to BBB disruption via the p38 MAPK signaling pathway following acute intracerebral hemorrhage

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