基于cAMP-CREB-BDNF信号通路探讨交泰丸抗抑郁的作用机制
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摘要
[目的]基于cAMP-CREB-BDNF信号通路探讨交泰丸抗抑郁作用机制。[方法]采用慢性温和不可预知性应激刺激建立大鼠抑郁症模型。酶联免疫吸附实验(ELISA法)检测大鼠海马组织中环磷酸腺苷(cAMP)、磷酸化环磷腺苷效应元件结合蛋白(p-CREB)、脑源性神经营养因子(BDNF)的含量和磷酸二酯酶-4(PDE4)的活性以及血浆中cAMP含量的变化,逆转录PCR法(RT-PCR)测定海马、皮质中的BDNF mRNA的含量。免疫组织化学分析大鼠海马组织CA1和CA3区中p-CREB阳性细胞的表达数量变化。[结果]与空白组相比,模型组的大鼠血浆及海马中cAMP含量明显降低,海马组织中CREB、BDNF含量降低,海马组织中PDE4活性增强,大鼠海马、皮质和下丘脑中BDNF mRNA表达含量减少,交泰丸逆转了以上改变。[结论]交泰丸可以通过调节cAMP-CREB-BDNF信号通路发挥抗抑郁作用。
[Objective] The antidepressant mechanism of Jiaotai pill was discussed based on cAMP-CREB-BDNF signal pathway.[Methods] The rat model of depression was established by chronic mild unpredictable stress stimulation. Enzyme linked immunosorbent assay(ELISA) was used to detect the content of cyclic adenosine monophosphate(cAMP), phosphorylated cAMP-response element binding protein(p-CREB), brain derived neurotrophic factor(BDNF) and activity of phosphodiesterase(PDE4) in the hippocampus of rats, and the content of cAMP in plasma of rats. The content of BDNF mRNA in the hippocampus and cortex was measured by reverse transcriptase PCR(RT-PCR). The expression of P-CREB positive cells in the CA1 and CA3 regions of the hippocampus of rats was analyzed by immunohistochemistry. [Results] Compared with the blank group, the content of cAMP in rat plasma and hippocampus was significantly decreased, the content of CREB and BDNF in the hippocampus decreased, PDE4 activity in the hippocampus is enhanced and the expression of BDNF mRNA in the hippocampus, cortex and hypothalamus of rats decreased in model group. Jiaotai pills and positive drugs reversed the above changes. [Conclusion] Jiaotai pill can achieve antidepressant effect by regulating the cAMP-CREBBDNF signaling pathway.
[Objective] The antidepressant mechanism of Jiaotai pill was discussed based on cAMP-CREB-BDNF signal pathway.[Methods] The rat model of depression was established by chronic mild unpredictable stress stimulation. Enzyme linked immunosorbent assay(ELISA) was used to detect the content of cyclic adenosine monophosphate(cAMP), phosphorylated cAMP-response element binding protein(p-CREB), brain derived neurotrophic factor(BDNF) and activity of phosphodiesterase(PDE4) in the hippocampus of rats, and the content of cAMP in plasma of rats. The content of BDNF mRNA in the hippocampus and cortex was measured by reverse transcriptase PCR(RT-PCR). The expression of P-CREB positive cells in the CA1 and CA3 regions of the hippocampus of rats was analyzed by immunohistochemistry. [Results] Compared with the blank group, the content of cAMP in rat plasma and hippocampus was significantly decreased, the content of CREB and BDNF in the hippocampus decreased, PDE4 activity in the hippocampus is enhanced and the expression of BDNF mRNA in the hippocampus, cortex and hypothalamus of rats decreased in model group. Jiaotai pills and positive drugs reversed the above changes. [Conclusion] Jiaotai pill can achieve antidepressant effect by regulating the cAMP-CREBBDNF signaling pathway.
引文
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[2]Cui YH,Yang Y,Ni ZY,et al.Astroglial kin 4.1 in the lateral habenala drives hearonal bursts in depression[J].Nature,2016.doi:10.1038/natnre25752.
[3]Kulkarni SK,Dhir A.Current investigational drugs for major depression[J].Expert Opin Investig Drugs,2009,18(6):767-788.
[4]Fisar Z,HroudováJ.Intracellular signalling pathways and mood disorders[J].Folia Biol:praha,2010,56(4):135-148.
[5]Goldberg ND,Haddox MK,Nicol SE,et al.Biologic regulation through opposing influences of cyclic GMP and cyclic AMP:the Yin Yang hypothesis[J].Adv Cyclic Nucleotide Res,1975,(5):307-330.
[6]印会河,张伯讷.中医基础理论[M].北京:人民卫生出版社,1989:27-29.
[7]于春泉,王怡,高杉,等.交泰丸不同配比抗抑郁作用的实验研究[J].中国实验方剂学杂志,2012,18(6):225-228.
[8]于泽胜,潘晔,宋彦奇,等.交泰丸对利血平诱导小鼠抑制模型的影响[J].天津中医药,2016,33(12):740-744.
[9]张敏,于春泉.交泰丸抗抑郁作用的研究进展[J].天津中医药,2012,29(1):101-104.
[10]Zhe Q,Sulei W,Weiwei T,et al.Effects of Jiaotaiwan on depressive-like behavior in mice after lipopolysaccharide administration[J].Metab Brain Dis,2017,32(2):415-426.
[11]Kulkarni SK,Dhir A.On the mechanism of antidepressant-like action of berberine chloride[J].Eur J Pharmacol,2008,589:163-172.
[12]Peng WH,Lo KL,Lee YH.Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice[J].Life Sci,2007,81:933-938.
[13]Sohrabi R,Pazgoohan N,Seresht HR,et al.Repeated systemic administration of the cinnamon essential oil possesses anti-anxiety and anti-depressant activities in mice[J].Iranian Journal of Basic Medical Sciences,2017,20(6):708.
[14]杨帅,潘晔,宋彦奇,等.交泰丸对抑郁大鼠行为学及脑内单胺类神经递质的影响[J].中草药,2016,47(23):4218-4223.
[15]Gao S,Cui YL,Yu CQ,et al.Tetrandrine exerts antidepressant-like effects in animal models:role of brain-derived neurotrophic factor[J].Behavioural Brain Research,2013,238(1):79-85.
[16]Willner P.Validity,reliability and utility of the chronic mild stress model of depression:a 10-year review and evaluation[J].Psychopharmacology,1997,134(4):319.
[17]Cryan JF,Holmes A.The ascent of mouse:advances in modelling human depression and anxiety[J].Nature Reviews Drug Discovery,2005,4(9):775-790.
[18]Li YF,Huang Y,Amsdell SL,et al.Antidepressant-and anxiolyticlike effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding rotein-mediated neurogenesis in the hippocampus[J].Neuropsychopharmacology,2009,34(11):2404-2419.
[19]Bach ME,Barad M,Son H,et al.Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway[J].Proceedings of the National Academy of Sciences of the United States of America,1999,96(9):5280.
[20]Ernfors P,Bengzon J,Kokaia Z,et al.Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis[J].Neuron,1991,7(1):165-176.
[21]Fujimaki K,Morinobu S,Duman RS.Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus[J].Neuropsychopharmacology,2000,22(1):42-51.