創傷性腦損傷又稱為頭部外傷，為最常見的意外事故傷害，其死亡率及致殘率也高踞首位，造成極大的經濟損失及社會福利負擔。前人研究證實鈉-鉀-氯共同轉運蛋白 (NKCC) 經由調控有絲分裂活化蛋白質激酶 (MAPK) 訊號傳遞路徑，於頭部外傷誘發的腦水腫中扮演著重要的角色。然而近年來發現瞬時受體電位香草酸亞型通道 (TRPV4) 與發炎、痛覺傳遞和滲透壓調節息息相關，因此本研究將探討TRPV4在頭部外傷誘發的神經損傷中所扮演的角色，以及相關訊號傳遞路徑。本研究採用改良自Marmarou等人創立之頭部外傷動物模式，將重量450克砝碼自180公分之高度垂直落下，誘發雄性大白鼠產生頭部外傷，並分別於誘發頭部外傷後零、二、四、八、十二及二十四小時後將大白鼠予以犧牲。利用西方墨點法探討不同時間點海馬迴中TRPV4通道之表現，並比較控制組、頭部外傷組、頭部外傷合併給予TRPV4抑制劑或NKCC1抑制劑組別間之腦水腫情形。實驗結果顯示，在誘發頭部外傷八小時後，海馬迴中TRPV4通道之表現量達到最高峰，此外，MEK、ERK及Akt之磷酸化亦顯著增加；誘發頭部外傷後合併投予ruthenium red (TRPV4抑制劑)或bumetanide (NKCC1抑制劑)，均可有效減少MEK、ERK及Akt之磷酸化，以及減緩腦水腫的發生。由於投予bumetanide之大白鼠，其TRPV4通道之表現會受到抑制，而投予ruthenium red卻不會影響NKCC1之表現，顯示NKCC1應位於TRPV4之上游。綜合上述結果，本研究證實頭部外傷後，促使NKCC1活化而增加TRPV4表現，透過有絲分裂活化蛋白質激酶磷酸化訊號傳遞路徑，引起嚴重的神經損傷以及腦水腫的產生。

Traumatic brain injury (TBI) is one of the most prevalent causes of mortality and morbidity all over the world and represents an enormous economical and social cost. Our previous studies have evidenced that Na+-K+-2Cl- co-transporter (NKCC) played an important role in TBI-induced brain edema via mitogen-activated protein kinases (MAPK) cascade. Transient receptor potential vanilloid type 4 (TRPV4) channel is suggested to correlate with neurogenic inflammation, pain transmission and osmosis regulation. In this study, we want to investigate the role of hippocampal TRPV4 in TBI-induced neuronal damage and the signaling pathways. TBI was induced by the calibrated weight-drop device. Sprague-Dawley rats were divided into sham and experimental group for time course studies of TBI. Hippocampal TRPV4, NKCC1, MAPK cascade and Akt expression were analyzed by Western blot. We also measured the level of brain edema among sham, TBI and TBI combined with TRPV4 antagonist or NKCC1 antagonist treatment. In the present study, we found that expression of hippoccampal TRPV4 peaked at 8 hours after TBI-treatment. The phosphorylation of extracellular signal regulated kinase (ERK), mitogen-activated protein kinase (MEK) and Akt were significantly elevated after TBI. Administration of either TRPV4 antagonist, ruthenium red or NKCC1 antagonist, bumetanide significantly attenuated the TBI-induced brain edema through decreasing the phosphorylation of MEK, ERK and Akt proteins. We also found administration of bumetanide could inhibit TRPV4 expression in hippocampus. However, administration of ruthenium red could not inhibit NKCC1 expression. This study showed that hippocampal NKCC1 activation could increase TRPV4 expression after TBI and induce severe brain edema and neuronal damage through phosphorylation of MAPK cascade and Akt.

衛生署統計室 (2010) 民國98年死因統計結果分析
陳世彬譯 (2004)美國頭痛教育委員會頭痛通訊:頭部外傷及慢性頭痛
蔡福基 (2005) 國軍高雄總醫院神經外科:Brain injury
台大醫院護理守則 (2007) Trauma nursing care
台大醫院創傷醫學部 (2007) 輕度頭部外傷注意事項

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