AICAR对氯胺酮抗抑郁作用的影响

Effect of AICAR on the antidepressant effect of ketamine

目的观察腺苷酸活化蛋白激酶(AMPK)激动剂AICAR对氯胺酮抗抑郁作用的影响,并探讨其作用机制。方法健康成年雄性Wistar大鼠24只,随机均分为四组。大鼠强迫游泳15min,建立急性抑郁大鼠模型。24h后,四组大鼠腹腔分别注射等容量生理盐水(S组和K组)和AICAR10mg/kg(A组和AK组);30min后腹腔再分别注射等容量生理盐水(S组和A组)和氯胺酮10mg/kg(K组和AK组)。给药完毕后30min,大鼠强迫游泳6min,记录后5min大鼠强迫游泳的不动时间。ELISA法检测大鼠海马脑源性神经营养因子(BDNF)和活性调节细胞骨架蛋白(Arc)的表达。Westernblot法检测大鼠海马雷帕霉素靶蛋白(mTOR)和磷酸化mTOR(p-mTOR)的表达水平。结果与S组比较,K组和AK组大鼠强迫游泳不动时间缩短,且AK组大鼠不动时间较K组缩短(P<0.05)。与S组比较,其他三组BDNF及Arc含量升高,且AK组含量最高(P<0.05),而A组和K组蛋白表达差异无统计学意义。与S组比较,K组和AK组p-mTOR的表达水平升高(P<0.01),K组与AK组比较差异无统计学意义。mTOR四组差异无统计学意义。结论大鼠腹腔给予氯胺酮可产生抗抑郁作用,且与大鼠海马组织BDNF、Arc及p-mTOR表达上调有关。大鼠腹腔预先给予AICAR能增强氯胺酮的抗抑郁作用,这可能与其能增加大鼠海马组织BDNF和Arc表达有关。

Objective Observe the effect of the agonist of AMP-activated protein kinases （AMPK）, 5-aminoimidazole-4-carboxamide-l-13-d-ribofuranoside （AICAR）, on the antidepressant effect of ketamine, and to explore the possible mechanism. Methods Twenty-four Wistar rats, equally randomized into four groups： saline group （group S）, ketamine group （group K）, AICAR group （group A）, AICAR and ketamine group （group AK）. The rats were forced to swim for 15 minutes, to establish the acute depression model. After 24 hours, the rats were peritoneal injected with the same volume of saline （group S and K） or AICAR 10 mg/kg （group A and AK） separately 30 minutes later,the rats were peritoneal injected with the same volume of saline （group S and A） or ketamine 10 mg/kg （group K and AK） separately, 30 minutes after the drug administration, the rats were forced to swim for 6 minutes, and recorded the immobility time of rats in the late 5 minutes. The expressions of brain-derived neurotrophic factor （BDNF） and activity regulated cytoskeletal- associated protein （Arc） were detected by ELISA. The expressions of mammalian target of rapamycin （roTOR） and p-mTOR were detected by Western blot. Results Compared with group S, the immobility time in group K and group AK was reduced significantly, and the immobility time in group AK was shorter than in group K （P〈0. 05）. Compared with group S, the expressions of BDNF and Arc in the other three groups were higher （P〈0.01）, and the expressions of BDNF and Are in group AK were higher than in group A and group K （P〈0.05）, the differences between group A and group K had no statistical meaning. Compared with group S, the expressions of p-roTOR in group K and group AK were higher （P^0. 05）, while the differences between group K and group AK had no statistical meaning. The differences among the four groups about roTOR expressions had no statistical meaning. Conclusion Ketamine can exert antidepressant effect, this may attribute to the increased expressions of BDNF, Arc and p-mTOR in the hippocampus of rat. The rats pretreated with AICAR can strengthen the antidepressant effect of ketamine, this may be related with the increased expressions of BDNF and Are in the hippocampus of rat.