Objective To investigate the effect of escitalopram on different brain derived neurotrophic factor (BDNF)transcripts and DNA methylation in adult chronic unpredictable mild stress (CUMS) rat hippocampus.Methods The depression model was established with 3-week CUMS.Fifty-six Sprague-Dawley rats were divided into CUMS + water,CUMS + escitalopram,control + water and control +escitalopram group.The depressive-like behaviors were evaluated using a sucrose preference test.Then,the hippocampus BDNF transcripts and DNA methylation of BDNF promoter Ⅳ were detected.Results (1) Sucrose preference test showed that,the sucrose preference was significantly lower in CUMS + water group [ (34±21)％,(63±21)％ ] (post hoc test,P＜0.05) but not in CUMS + escitlopram group[ (58±19)％,(80±14)％ ] (post hoc test,P＞0.05) in comparison with control + water group [ (67±15)％,(80±15)％ ].(2) As to hippocampal BDNF transcripts expression,the expression of exon Ⅳ was the main part of the total BDNF mRNA.Compared with the control + water group [ (6.14±0.87) × 10-3,(6.82±0.35) × 10-3 ],exon Ⅳ and Ⅸ transcripts expression was significantly decreased in the CUMS + water group[ (4.64±0.65) × 10-3,(5.73 ±0.79) × 10-3] (post hoc test,P＜0.05) but not in CUMS +escitlopram group[ (5.69±0.18) × 10-3,(6.91±0.98) × 10-3] (post hoc test,P＜0.05).(3) As to DNA methylation levels,none of the four groups were found methyled in the fourth promoter of BDNF.No significant difference of DNA methylation was found between groups.Conclusions Escitlopram could block the decrease of total hippocampal BDNF transcripts in CUMS adult rats,which mainly due to the increase of the exon Ⅳ transcripts,and the DNA methylation mechanism might not be involved in this process.%目的 探讨艾司西酞普兰对成年慢性应激大鼠海马脑源性神经营养因子(BDNF)基因不同外显子表达及DNA甲基化的影响.方法 以慢性不可预测温和应激(chronic unpredictablemild stress,CUMS)建立应激抑郁模型并予艾司西酞普兰干预.56只雄性Sprague-Dawley大鼠随机分为CUMS+水组、CUMS+药组、对照+水组及对照+药组,每组14只,以蔗糖水偏好试验评估大鼠抑郁样行为；模型建立第3周后分别检测上述各组大鼠海马BDNF基因第Ⅰ、Ⅱ、Ⅳ、Ⅵ外显子mRNA及BDNF总mRNA(第Ⅸ外显子)表达和第Ⅳ启动子区DNA甲基化水平.结果 (1)蔗糖水偏好试验:模型建立第2,3周,CUMS+水组[(34±21)％,(63±21)％]蔗糖水偏好均低于对照+水组[(67±15)％,(80±15)％],差异均有统计学意义(事后检验,P均＜0.05)；而CUMS+药组[(58士19)％,(80±14)％]与对照+水组间的差异均无统计学意义(事后检验,P均＞0.05).(2)BDNF外显子表达:模型建立第3周,第Ⅳ外显子mRNA为BDNF总mRNA(第Ⅸ外显子)表达中的最主要者.CUMS+水组BDNF第Ⅳ及Ⅸ外显子mRNA水平[(4.64±0.65)×10-3,(5.73±0.79) ×10-3]均低于对照+水组[ (6.14±0.87)×10-3,(6.82±0.35)×10-3],差异均有统计学意义(事后检验,P均＜0.05)；而CUMS+药组[(5.69±0.18)×10-3,(6.91±0.98)×10-3]与对照+水组间的差异均无统计学意义(事后检验,P均＞0.05).(3)DNA甲基化:各组大鼠海马BDNF第Ⅳ启动子区DNA均未发生甲基化.结论 艾司西酞普兰主要调节BDNF第Ⅳ外显子转录阻止CUMS成年大鼠海马的该基因表达下降,艾司西酞普兰第Ⅳ启动子区DNA甲基化无影响.
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