Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat

Lee, Ki Mo; Bang, Ji Hye; Han, Jung‐Soo; Kim, Bu Yeo; Lee, In Sun; Kang, Hyung Won; Jeon, Won Kyung

doi:10.1186/1472-6882-13-334

Cited by 27 publications

(31 citation statements)

References 34 publications

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“…The increased hippocampal level of TLR4 and MyD88 induced by chronic BCCAo was not observed in BCCAo rats treated with F. mume (Figure 5 A). MAPK signaling is associated with the production of proinflammatory mediators in microglia and astrocytes [ 20 ] and is activated in the brains of rats subjected to chronic BCCAo [ 26 - 29 ]. We examined the correlation between F. mume treatment and p38 MAPK phosphorylation in the hippocampus in rats subjected to chronic BCCAo.…”

Section: Resultsmentioning

confidence: 99%

Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling

Lee

Bang

Kim

et al. 2015

BMC Complement Altern Med

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BackgroundFructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.MethodsPermanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo.ResultsOur results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo.ConclusionTaken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-015-0652-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling

Lee

Bang

Kim

et al. 2015

BMC Complement Altern Med

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“…CXCR1 and ERK/p38 MAPK inhibition decreased activation of microglia and blockade of this route also attenuated lesions to the white matter, and the cognitive impairments induced by BCAS (Lee et al, 2013; Liu et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

Wolf

Lotan

Lifschytz

et al. 2017

Front. Aging Neurosci.

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Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes.

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“…Mitogen‐activated protein kinases (MAPKs), as another major inflammatory signal, are also involved in regulating the expression of several inflammatory genes. Both in vitro and in vivo studies have shown that activation of MAPKs (ERK, JNK, and p38) is necessary for a number of the inflammatory responses to LPS [Lee et al, ; Jeong et al, ; Zhao et al, ]. For example, p38 and JNK MAPKs activities are strongly enhanced in multiple cell types including glial cells, endothelial cells, and as well as mononuclear macrophages by LPS or inflammatory cytokines through increasing their phosphorylation levels, and further accelerate inflammatory responses; moreover, TNF‐α mRNA transport from the nucleus to the cytoplasm could be blocked by ERK inhibitor [Raingeaud et al, ; Dong and Davis, ; Zhi et al, ].…”

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confidence: 99%

Anti‐Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide‐Induced TRAF6‐TAK1‐NF‐κB, P38/ERK MAPKS and Jak2‐Stat1/Stat3 Pathways

Zeng

Liao

et al. 2015

J of Cellular Biochemistry

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MC13 is a novel coumarin compound found in Murraya, an economic crop whose leaves are widely used as condiment (curry) in cuisine. The aims of the present study were to investigate the neuroprotective effects of MC13 on microglia-mediated inflammatory injury model as well as potential molecular mechanism. Cell viability and apoptosis assay demonstrated that MC13 was not toxic to neurons and significantly protected neurons from microglia-mediated inflammatory injury upon lipopolysaccharide (LPS) stimulation. Results showed that MC13 markedly inhibited LPS-induced production of various inflammatory mediators, including nitrite oxide (Griess method), TNF-α and IL-6 (ELISA assay) in a concentration-dependent manner. Mechanism study showed that MC13 could suppress the activation of NF-κB, which was the central regulator for inflammatory response, and also decreased the interaction of TGF-β-activated kinase 1 (TAK1)-binding protein (TAB2) with TAK1 and TNF receptor associated factor (TRAF6), leading to the decreased phosphorylation levels of NF-κB upstream regulators such as IκB and IκB kinase (IKK). MC13 also significantly down-regulated the phosphorylation levels of ERK and p38 MAPKs, which played key roles in microglia-mediated inflammatory response. Furthermore, MC13 inhibited Jak2-dependent Stat1/3 signaling pathway activation by blocking Jak2 phosphorylation, Stat1/3 phosphorylation, and nuclear translocation. Taken together, our results demonstrated that MC13 protected neurons from microglia-mediated neuroinflammatory injury by inhibiting TRAF6-TAK1-NF-κB, p38/ERK MAPKs, and Jak2-Stat1/3 pathways. Finally, MC13 might interact with LPS and interfere LPS-binding to cell membrane surface. These findings suggested that coumarin might act as a potential medicinal agent for treating neuroinflammation as well as inflammation-related neurodegenerative diseases.

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Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat

Cited by 27 publications

References 34 publications

Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling

Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling

Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

Anti‐Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide‐Induced TRAF6‐TAK1‐NF‐κB, P38/ERK MAPKS and Jak2‐Stat1/Stat3 Pathways

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