Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats

Zhang, Yixin; Xu, Ningbo; Ding, Yan; Zhang, Yiting; Li, Qian; Flores, Jerry; Haghighiabyaneh, Mina; Doycheva, Desislava; Tang, Jiping; Zhang, Junyi

doi:10.1016/j.bbi.2018.02.015

Cited by 69 publications

(77 citation statements)

References 55 publications

(100 reference statements)

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“…Similar to M1 microglia, besides from ischemic stroke, M2 microglia activation occurs in numerous other types of neurological disease; for example, in both spinal cord injury and intracerebral hemorrhage mouse models, M2 microglia were identified to be activated, which released anti-inflammatory cytokines downstream of caMP response element-binding protein (creB)-associated signaling pathways (56,57). in neonatal germinal matrix hemorrhage rats, Rh-Chemerin promoted the accumulation and proliferation of M2 microglia in periventricular regions and suppressed the inflammatory response through nuclear factor erythroid 2-related factor 2 (nrf2)-associated signaling pathways (58). Previous studies demonstrated that M2 microglia activation can also promote brain tissue repair in other neurological diseases (56)(57)(58).…”

Section: Microgliamentioning

confidence: 99%

“…in neonatal germinal matrix hemorrhage rats, Rh-Chemerin promoted the accumulation and proliferation of M2 microglia in periventricular regions and suppressed the inflammatory response through nuclear factor erythroid 2-related factor 2 (nrf2)-associated signaling pathways (58). Previous studies demonstrated that M2 microglia activation can also promote brain tissue repair in other neurological diseases (56)(57)(58).…”

Section: Microgliamentioning

confidence: 99%

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Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. as the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. in response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. it has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. in addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified. Contents 1. introduction 2. Microglia 3. Modulatory mechanisms of microglia polarization 4. autophagy 5. conclusions

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Section: Microgliamentioning

confidence: 99%

Section: Microgliamentioning

confidence: 99%

Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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“…[47][48][49] Other studies have suggested that chemerin may play an anti-inflammatory role. 14,50,51) The underlying mechanisms of the function of C9 in cognition and AD are still unclear. We hypothesize that it is closely related to the inflammation status in the brain.…”

Section: V) On Locomotor Behaviour In Micementioning

confidence: 99%

Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ<sub>1–42</sub>-Induced Object Memory Impairment in Mice

Lei

Xue

et al. 2020

Biological & Pharmaceutical Bulletin

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Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid β 1-42 (Aβ 1-42) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aβ 1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aβ 1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aβ 1-42. Meanwhile, C9 also significantly inhibited Aβ 1-42-induced increases in the levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aβ 1-42-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.

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“…Intracerebroventricular drug administration was performed as previously described (15). Briefly, rats were placed in a stereotaxic apparatus under 2.5% isoflurane stereotactic anesthesia.…”

Section: Gmh Model and Experimental Protocolmentioning

confidence: 99%

Rh-relaxin-2 Attenuates Degranulation of mast cells by Inhibiting NF-κB through PI3K-AKT/TNFAIP3 Pathway in an Experimental Germinal Matrix Hemorrhage Rat Model

Zhao

Chen

et al. 2020

Preprint

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Background: Mast cells play an important role in early immune reactions in the brain by inducing degranulation and releasing inflammatory mediators. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a GMH rat model. Methods: One hundred and sixty-four P7 rat pups were subjected to germinal matrix hemorrhage (GMH) by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 hours prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 hour and 12 hours after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injections. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and Toluidine staining. Results: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6 and TNF-α. However, knockdown of RXFP1 and PI3K abolished the protective effects of rh-relaxin-2. Conclusions: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

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Chemerin suppresses neuroinflammation and improves neurological recovery via CaMKK2/AMPK/Nrf2 pathway after germinal matrix hemorrhage in neonatal rats

Cited by 69 publications

References 55 publications

Modulators of microglia activation and polarization in ischemic stroke (Review)

Modulators of microglia activation and polarization in ischemic stroke (Review)

Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ<sub>1–42</sub>-Induced Object Memory Impairment in Mice

Rh-relaxin-2 Attenuates Degranulation of mast cells by Inhibiting NF-κB through PI3K-AKT/TNFAIP3 Pathway in an Experimental Germinal Matrix Hemorrhage Rat Model

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