微膠細胞為中樞神經系統中相當於免疫系統的巨噬細胞，微膠細胞的功能對於受損後中樞神經系統組織碎片的清除與重建而言是非常重要的。丙戊酸可做為histone deacetylase的抑制劑，在臨床上被用來做為一種抗痙孿與穩定情緒的藥物以治療癲癇與躁鬱症，亦被指出對於神經系統損傷後所造成的神經病理性疼痛有治療的效果。近幾年來研究指出，活化的微膠細胞P2X4受體(P2X4R)參與神經病理性疼痛的發展與維持。實驗室先前研究發現，丙戊酸能抑制脊髓損傷造成的微膠細胞P2X4R大量表現。基於此，本篇的研究目的主要是想透過in vitro的方式，利用活化微膠細胞以模擬發炎的情況下，探討丙戊酸是否調控微膠細胞P2X4R的表現並找出可能參與的訊息傳遞途徑。在Iba-1染色實驗觀察到，丙戊酸處理之下並不影響以LPS活化微膠細胞的細胞型態。根據microarray的結果發現，以細菌內毒素脂多醣(LPS)刺激的微膠細胞，其P2X4R的表現量為其他P2X受體之冠，丙戊酸會抑制由LPS活化微膠細胞的P2X4R mRNA表現量。microarray的結果亦發現，微膠細胞以LPS處理之下，調控前發炎因子的表現，其中腫瘤壞死因子(TNF-α)的表現則被丙戊酸所抑制。文獻指出，以丙戊酸處理未受刺激的微膠細胞藉由p38 MAPK的活化而導致細胞凋亡。因此，接著探討丙戊酸抑制活化的微膠細胞P2X4R與TNF-α mRNA表現量是否透過p38 MAPK的調控。結果指出，丙戊酸處理之下會增加p38 MAPK蛋白質磷酸化的表現量。前處理p38 MAPK的抑制劑SB2035802，可回升由丙戊酸所抑制的P2X4R與TNF-α mRNA表現量。綜合以上結果指出，丙戊酸藉由p38 MAPK的活化造成P2X4R與TNF-α mRNA表現量下降。

Microglia, the resident macrophages in the central nervous system (CNS), play the important role in neuropathogenesis and tissue debris removal after CNS injury. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is clinically prescribed as anti-seizure drugs to epilepsy, bipolar disorders and in other neurological condition such as neuropathic pain. Recently, a great deal of attention has been focused on the relation between neuropathic pain and microglia activated through purinergic P2X4 receptors. P2X4R action is involved in microglia activation and microglia-associated induction of neuropathic pain. Accordingly, we attempted to examine whether VPA affect P2X4R expression in activated microglia. Immunostaining indicated that VPA treatment had no effect the on cell morphology in endotoxin lipopolysaccharide(LPS)-activated microglia. Through gene expression microarray, we found that among P2 purinergic receptors a P2X isotype, P2X4R, is exclusively expressed in microglia activated by LPS. We found that LPS-induced increase in P2X4R mRNA expression was blocked by exposure to VPA. The results from the comparative gene microarray analysis also showed that a set of proinflammatory mediators, such as tumor necrosis factor alpha (TNF-α) increased in microglia by LPS stimulation was reduced by treatment with VPA. We also found that exposure to VPA induced the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in LPS- activated microglia. Preteatment with the inhibitor of p38 MAPK, SB203580, significantly blocked VPA-induced inhibition of P2X4R and TNF-α mRNA expression in LPS-activated microglia. Thus, given the fact that VPA exerts the effect on the reduction of P2X4R and TNF-α mRNA expression in LPS-activated microglia through the p38 MAPK-dependent signal pathway.

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