Activation of Ras/MEK/ERK signaling in chronic subdural hematoma outer membranes

Osuka, Koji; Watanabe, Yasuo; Usuda, Nobuteru; Atsuzawa, Kimie; Aoyama, Masahiro; Niwa, Aichi; Nakura, Takahiro; Takayasu, Misako

doi:10.1016/j.brainres.2012.10.013

Cited by 22 publications

(15 citation statements)

References 31 publications

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“…The downstream signalling pathways mediated by VEGF have been investigated and may include the mitogen-activated protein kinase (MAPK) pathways: Ras-Raf-MEK-ERK, p38 and c-Jun N-terminal kinase (JNK) [50, 51]. These signalling molecules have been identified in the endothelial cells and fibroblasts of CSDH outer membranes and play an important role in disruption of endothelial gap junctions and regulation of angiogenesis [50, 51]. Another signalling pathway which is activated by VEGF in the endothelium of outer membrane vessels is the phosphatidylinositol 3-kinase-serine/threonine kinase (PI3-Akt) pathway [52].…”

Section: Angiogenesismentioning

confidence: 99%

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

Edlmann

Giorgi-Coll

Whitfield

et al. 2017

J Neuroinflammation

453

360

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Chronic subdural haematoma (CSDH) is an encapsulated collection of blood and fluid on the surface of the brain. Historically considered a result of head trauma, recent evidence suggests there are more complex processes involved. Trauma may be absent or very minor and does not explain the progressive, chronic course of the condition. This review focuses on several key processes involved in CSDH development: angiogenesis, fibrinolysis and inflammation. The characteristic membrane surrounding the CSDH has been identified as a source of fluid exudation and haemorrhage. Angiogenic stimuli lead to the creation of fragile blood vessels within membrane walls, whilst fibrinolytic processes prevent clot formation resulting in continued haemorrhage. An abundance of inflammatory cells and markers have been identified within the membranes and subdural fluid and are likely to contribute to propagating an inflammatory response which stimulates ongoing membrane growth and fluid accumulation. Currently, the mainstay of treatment for CSDH is surgical drainage, which has associated risks of recurrence requiring repeat surgery. Understanding of the underlying pathophysiological processes has been applied to developing potential drug treatments. Ongoing research is needed to identify if these therapies are successful in controlling the inflammatory and angiogenic disease processes leading to control and resolution of CSDH.

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Section: Angiogenesismentioning

confidence: 99%

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

Edlmann

Giorgi-Coll

Whitfield

et al. 2017

J Neuroinflammation

453

360

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“…11 We have previously shown activation of the Ras/MEK/ERK signaling pathway and phosphatidylinositol-3 kinase (PI3 kinase)/Akt signaling pathway by VEGF in the endothelium of vessels within the outer membrane of CSDH. 9,12 Recently, PI3 kinase-ERK crosstalk was shown to play an important role in regulation of arterial morphogenesis. 13 VEGF regulates choroid-retinal EC proliferation and tube formation, which requires both MEK/ERK and PI3 kinase/ Akt signaling.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that the extracellular signal-regulated kinase kinase (MEK)/ ERK signaling pathway is activated by VEGF in endothelial cells (ECs) of vessels, which suggests that these molecules are involved in angiogenesis of CSDH. 9 However, expression of other MAPKs, location of this expression, and mechanisms of activation of these MAPKs have not been determined. Therefore, the present study was undertaken to determine expression of three major MAPK cascade transmitters in the outer membrane of CSDH.…”

Section: Introductionmentioning

confidence: 99%

Expression of Mitogen-Activated Protein Kinases in Chronic Subdural Hematoma Outer Membranes

Aoyama

Osuka

Usuda

et al. 2015

Journal of Neurotrauma

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Growth factors and inflammatory cytokines activate the mitogen-activated protein kinase (MAPK) cascade. Previous studies have shown that chronic subdural hematoma (CSDH) fluid contains these factors and cytokines. In this study, expression of three major MAPK cascade transmitters in the outer membrane of CSDH was assessed. Eleven patients whose outer membrane and CSDH fluid were successfully obtained during trepanation surgery were included in this study. Expression of extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, and actin was examined by Western blot and immunostaining. We examined whether CSDH fluid could activate MAPKs in cultured endothelial cells (ECs) or fibroblasts in vitro. Western blot analysis showed that p-ERK was present in all samples, whereas p-p38 and p-JNK were detected, but not in all cases. Immunostaining showed that all three p-MAPKs were expressed in vascular endothelium. However, only p-ERK was expressed in fibroblasts. Expression of p-extracellular signal-regulated kinase kinase (MEK) and p-ERK in ECs and fibroblasts was significantly induced immediately after treatment with CSDH fluid, whereas p-p38 and p-JNK expression was significantly induced in ECs 60 min after treatment, but not in fibroblasts. Activation of MEK was significantly inhibited by treatment with antibodies directed against interleukin-6 and vascular endothelial growth factor in ECs, but not in fibroblasts. Inflammatory cytokines and growth factors in CSDH fluids might activate major MAPKs in ECs, which might be associated with neovascularization in the outer membrane of CSDH. These MAPK pathways could become novel targets for treatment of CSDHs.

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“…Initial surgical intervention, or some kind of infection, may have triggered the formation of the organized membrane [16]. Several factors are reported to be correlated with the growth of chronic subdural hematoma, such as tissuetype plasminogen activator, hypoxia-inducible factor-1 alfa, vascular endothelial growth factor, cyclooxygenase-2, PI3 kinase/Akt signaling, chemokines, Ras/MEK/ERK signaling, PIGF, JAK-STAT3 signaling pathway, and an effect of corticosteroid has also been reported [15,[17][18][19][20][21][22][23][24][25]. However, to our knowledge there is no report regarding organized arachnoid cysts.…”

Section: Discussionmentioning

confidence: 99%

A case of organized arachnoid cyst with repeated hemorrhage

Kobayashi

Nagashima

Noda

et al. 2016

Clinical Case Reports

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Activation of Ras/MEK/ERK signaling in chronic subdural hematoma outer membranes

Cited by 22 publications

References 31 publications

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy

Expression of Mitogen-Activated Protein Kinases in Chronic Subdural Hematoma Outer Membranes

A case of organized arachnoid cyst with repeated hemorrhage

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