MK-801对皮质酮诱导抑郁样行为大鼠海马mBDNF和proBDNF表达的影响

MK-801 changes the expression of mBDNF and proBDNF in the hippocampus of rats with corticosterone-induced depression-like behavior

目的N-甲基-D-天冬氨酸(NMDA)受体拮抗剂通过脑源性神经营养因子(BDNF)发挥抗抑郁作用。然而,NMDA受体拮抗剂调控BDNF表达的机制尚不清楚。方法口服皮质酮(CORT)诱导大鼠抑郁样行为。采用高架十字迷宫实验、蔗糖偏好实验、旷场实验和强迫游泳实验观察动物的抑郁样行为,采用蛋白免疫印迹方法检测动物背侧和腹侧海马DG脑区成熟BDNF(mBDNF)和前体BDNF(proBDNF)的表达。结果慢性给予CORT诱发大鼠抑郁样行为。NMDA受体拮抗剂地佐环平(MK-801)可减轻动物抑郁样行为,增加大鼠背侧和腹侧海马DG脑区中mBDNF的表达,同时降低proBDNF的表达(P<0.05)。组蛋白去乙酰化酶拮抗剂辛二酰苯胺异羟肟酸(SAHA)能够减轻动物抑郁样行为,增加海马脑区的mBDNF表达,降低proBDNF的表达(P<0.05)。然而,预先给予MK-801后,SAHA对大鼠抑郁样行为、海马DG脑区的mBDNF和proBDNF表达都无显著的影响。结论MK-801可通过组蛋白乙酰化改变大鼠海马DG区mBDNF和proBDNF的表达,发挥抗抑郁作用,这将为抗抑郁治疗提供新靶点。

Objective N-methyl-D-aspartate(NMDA)receptor antagonist produces antidepressant effects through the brain-derived neurotrophic factor(BDNF).However,the mechanism of NMDA regulation of BDNF expression by receptor antagonist is unclear.Methods Corticosterone(CORT)was orally administrated to induce depressive-like behaviors in rats.Using elevated plus maze test,sucrose preference test,open field test,and forced swimming test to observe the depressive-like behaviors.Western blot was applied to analyze the expression of mature BDNF(mBDNF)and precursor(proBDNF)in the dorsal and ventral hippocampus dentate gyrus(DG).ResultsChronic administration of CORT induced depressive-like behaviors in rats.Acute administration of NMDA receptorantagonist dizocilpine(MK-801)alleviated the depressive-like behaviors(P<0.05).MK-801 increased the expression of mBDNF and decreased the expression of proBDNF in the dorsal and ventral hippocampus DG of rats(P<0.05).Furthermore,administration of deacetylases antagonist suberoylanilide hydroxamic acid(SAHA)increased the mBDNF expression,decreased the proBDNF expression,and alleviated depressive-like behaviors in CORT-treated rats(P<0.05).However,SAHA treatment after MK-801 showed no significant changes in the expression of mBDNF and proBDNF in the hippocampus DG of CORT-treated rats.Conclusions MK-801 can change the expression of mBDNF and proBDNF in the hippocampus DG through histone acetylation to play antidepressant effects,which suggest a potential target for antidepressant therapy.