抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制研究

The effect of quetiapine on the cell cycle of oligodendrocytes and its mechanism

目的探讨抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制。方法采用血小板源性生长因子(PDGF)10 ng/ml、喹硫平10μmol/L及两者混合物处理少突胶质前体细胞(OPCs)48 h,比较各组细胞周期、细胞周期退出指数及细胞分化情况。检测喹硫平干预后小鼠前额皮质8个细胞周期相关mRNA相对表达量。通过RNA干扰下调p21的表达,并分析其对细胞增殖和分化的影响。结果PDGF可诱导G0/G1期细胞百分比下降(P<0.05),S期和G2期细胞百分比升高(P<0.05);喹硫平可抑制PDGF诱导的S期或G2期细胞百分比升高,并阻止G0/G1期细胞百分比降低(P<0.05)。PDGF抑制细胞周期退出(P<0.05);喹硫平促进细胞周期退出(P<0.05),并阻断PDGF对细胞周期退出的影响(P<0.05)。喹硫平可提高OPCs细胞的成熟率,降低低分化细胞数(P<0.05)。喹硫平干预后p21表达升高(P<0.05);下调p21可增加S期细胞百分比,降低G2期细胞百分比(P<0.05),增加溴脱氧尿苷阳性细胞数(P<0.05),减少髓鞘碱性蛋白阳性细胞(P<0.05)。结论喹硫平可能通过调节少突胶质细胞的细胞周期来调节细胞分化。

Objective To investigate the effect of antipsychotic quetiapine on the cell cycle of oligodendrocytes and its mechanism.Methods The oligodendrocyte precursor cells(OPCs)were treated with platelet-derived growth factor(PDGF,10 ng/ml),quetiapine(10μmol/L)or a mixture of the two for 48 h.Cell cycle,cell cycle exit index and cell differentiation were compared under different treatments.The relative mRNA expression levels of 8 cell cycle-related molecules in mice prefrontal cortex after intervention with quetiapine were measured.The effect of down-regulation of p21 by RNA interference on cell proliferation and differentiation was examined.Results PDGF induced a significant decrease in the percentage of cells in G0/G1 phase(P<0.05)and a significant increase in the percentage of cells in S phase and G2 phase(P<0.05).Quetiapine inhibited the percentage increase of cells in S or G2 phase and prevented the percentage decrease of cells in G0/G1 phase induced by PDGF(P<0.05).Treatment with PDGF inhibited cell cycle exit(P<0.05),while quetiapine promoted cell cycle exit and blocked the influence of PDGF on cell cycle exit(P<0.05).Quetiapine increased the maturation rate of OPCs and reduced the number of poorly-differentiated cells(P<0.05).The expression of p21 was significantly increased after quetiapine intervention(P<0.05).Down-regulation of p21 increased the percentage of S-phase cells(P<0.05),decreased the percentage of G2-phase cells(P<0.05),increased the number of bromodeoxyuridine positive cells(P<0.05),and decreased the number of myelin basic protein-positive cells(P<0.05).Conclusions Quetiapine may involve in the differentiation of oligodendrocytes by regulating the cell cycle.