脊髓損傷會導致神經細胞死亡，並會在損傷中心引起嚴重的免疫反應，使得感覺與運動功能喪失。微膠質細胞是中樞神經系統的免疫細胞，負責清除細胞碎片並且在中樞神經系統受傷後扮演對組織重組有幫助性的角色。在活化之後，微膠質細胞在受傷的中樞神經系統中也參與了發炎反應的產生。丙戊酸(valproic acid; VPA)是組蛋白去乙醯酶的抑制物，也是一種臨床上常見的抗癲癇藥物。近來發現VPA 會經由調節膠細胞對發炎環境的反應而有神經保護功能以及抗發炎作用。在此篇研究中，我們利用離體實驗以及活體實驗探討VPA 在脊髓損傷後所扮演的角色。處理0.1 到1.0 mM濃度的VPA 並不會對由新生小鼠皮質組織所培養的初代微膠質細胞產生細胞毒性。然而0.5 與1.0 mM 濃度的VPA 會降低P2X4 與P2X7 受體mRNA 的表現。我們進一步發現，經由VPA 處理後的微膠質細胞，吞噬能力在處理P2X7 受體的增效劑BzATP後會有增加的現象。另外，經由活體實驗，我們發現連續三天注入VPA 能改善實驗老鼠在重度脊髓損傷後的後肢行動能力。GAP-43 的免疫螢光染色則是顯示處理VPA會在損傷的脊髓中增加表現GAP-43 的神經纖維。此外，我們觀察到在受傷的脊髓中，P2X4 與P2X7 受體mRNA 的表現會上升；然而，連續三天處理VPA 會在脊髓損傷後第十四天顯著地降低P2X4 與P2X7受體mRNA 的表現。既然受傷脊髓組織的組蛋白H3 乙醯化會在處理VPA 後增加，於是我們利用蛋白質體分析方式檢測脊髓組織在處理VPA 後的蛋白質表現。由結果得知，熱休克蛋白與抗氧化酶(過氧化氫酶與錳超氧化物歧化酶)在接受VPA 處理的受傷脊髓組織中表現量會增加。總而言之，我們推論VPA 可能透過抗發炎與抗氧化作用而在受傷的脊髓組織中有神經保護功能。此外，VPA 可能會經由降低P2X7 受體在受傷脊髓組織中的表現，進而促進微膠質細胞的吞噬作用並有效地移除組織碎片。此篇研究指出VPA 是一種有潛力的脊髓損傷治療劑。

Spinal cord injury (SCI) results in the neural cell death and severe inflammation in the lesion center and subsequently causes the loss of sensation and locomotion. Microglia, the immune cells of the central nervous system (CNS), are responsible for the removal of cell debris and play a constructive role in tissue remodeling after the injury to the CNS. However, upon activation, these cells are also involved in the induction of inflammation in the injured CNS. Valproic acid (VPA) acts as a histone deacetylase (HDAC) inhibitor and a common anti-seizure drug clinically used for the treatment of bipolar disorder. This compound has recently been found to have europrotective and anti-inflammatory activity by the regulation of glial response to inflamed environment. In this study, in vitro and in vivo experiments were performed to investigate the role that VPA treatment plays after SCI. Treatment with VPA at the region of 0.1-1.0 mM caused no cytotoxicity in cultured microglia isolated from neonatal rat cortical tissues. However, VPA at 0.5 and 1.0 mM reduced the mRNA expressions of microglial P2X4R and P2X7R, two subtypes of P2X receptor which relates with microglial activation in the inflamed condition. Furthermore, we found that the phagocytotic activity of VPA-primed microglia was enhanced after exposure to the P2X7R agonist, BzATP. Through in vivo study, we reported here that the infusion of VPA for 3 days improved the hindlimb locomotion in the rats with severe SCI. Immunofluorescence staining for GAP-43 showed that VPA treatment increased GAP-43+ neuronal fibers in the injured spinal cord when compared to observed in the PBS-treated control group. Moreover, we found that P2X4R and P2X7R mRNA levels were upregulated in the injured spinal cord, whereas a 3-day infusion with VPA significantly reduced P2X4R and P2X7R mRNA levels at 14 day after SCI. Since the level of acetylated histone H3 were increased in VPA-treated spinal cord, the proteomic analysis was performed to examinethe profile of the differential protein expression in VPA-infused spinal cord tissue. Together with the observations by western blotting, we found that the expression levels of heat shock proteins and antioxidant enzymes (catalase and MnSOD) were upregulated in the injured spinal cord tissues receiving VPA. Collectively, we concluded that VPA has the neuroprotective role in the injured spinal cord tissues possibly through its anti-inflammatory and anti-oxidative activity. Moreover, VPA may enhance microglial phagocytosis to effectively remove tissue debris via the downregulation of P2X7R expression in the injured spinal cord. Our findings indicated that VPA may act as the potent therapeutic agent for treatment of SCI.

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