• Masahiro Aoyama, Koji Osuka, Nobuteru Usuda, Yasuo Watanabe, Reo Kawaguchi, Takahiro Nakura, and Masakazu Takayasu.
• 1 Department of Neurological Surgery, Aichi Medical University , Aichi, Japan .
• J. Neurotrauma. 2015 Jul 15;32(14):1064-70.

AbstractGrowth 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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