罗布麻叶总黄酮抗抑郁作用及其机制研究
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摘要
抑郁症,是一种常见的精神障碍性疾病,影响着世界将近21%的人口。主要症状表现为情绪低落,悲观厌世,兴致减低或缺失,意志减退,食欲不振,睡眠障碍,缺乏主动性,严重者甚至出现自杀念头等。世界卫生组织报道到2020年抑郁症将成为危害人类健康的世界第二大疾病。因此,对于抑郁症的发病机制和治疗方面的研究越来越受到科研工作者的重视。但其发病机制尚不十分清楚,主要认为与单胺类神经递质、神经营养因子、信号转导通路等因素密切相关。目前,抗抑郁药物主要是合成药,但是合成药物普遍存在抗抑郁谱窄、存在耐药性、副作用大的弊端。因此开发安全、高效、低毒的天然抗抑郁药物成为了该领域的研究热点。罗布麻是我国的传统中药和常用中药,本研究提取它的主要有效成分之一罗布麻叶总黄酮,在评价其抗抑郁活性的基础上,对其抗抑郁作用及机制进行研究,为新型抗抑郁药物的开发及应用提供一定的理论和实验依据。
1.罗布麻叶总黄酮抗抑郁作用的活性评价
采用经典抑郁动物模型小鼠悬尾、小鼠强迫游泳、大鼠强迫游泳实验,小鼠开野实验评价罗布麻叶总黄酮的抗抑郁活性。结果表明罗布麻叶总黄酮具有明确的抗抑郁作用。
2.罗布麻叶总黄酮对抑郁大鼠脑内单胺类神经递质及其代谢产物含量的影响
利用HPLC-MS/MS联用方法测定罗布麻叶总黄酮对抑郁大鼠脑内去甲肾上腺素(NE)、5-羟色胺(5-HT)和多巴胺(DA)及其代谢产物5-吲哚乙酸(5-HIAA)、高香草酸(HVA)和3,4-二羟基苯乙酸(DOPAC)含量的影响。结果表明,抑郁模型大鼠脑内NE, DA及其代谢产物DOPAC、HVA,5-HT、5-HIAA的含量较正常组明显降低,罗布麻叶总黄酮处理后大鼠脑内NE、DA、HVA、DOPAC的含量较抑郁组明显升高,与氟西汀组结果相似,但对5-HT及其代谢产物5-HIAA含量作用不明显,与氟西汀结果相反,氟西汀显著增加了5-HT/5-HIAA含量。该结果证实了抑郁症发病的神经递质假说,同时发现罗布麻叶总黄酮可以逆转抑郁大鼠脑内单胺类物质(NE、DA)及其代谢产物(HVA、DOPAC)的降低。
3.罗布麻叶总黄酮抗抑郁作用参与单胺能系统可能机制的研究
研究选择相关NE、5-HT、DA受体阻断剂(5-HT1A→Way100635、5-HT2→赛庚啶、5-HT2A→酮舍林、a1-NE受体阻断剂→哌唑嗪、α2-NE受体阻断剂→哌唑嗪、αβ-NE受体阻断剂→普萘洛尔、D1→SCH23390、D2→舒必利,采用小鼠悬尾实验,来进一步探讨罗布麻叶总黄酮的抗抑郁机制。结果表明,5-HT2A、5-HT2受体阻断剂酮舍林(5 mg/kg)、赛庚啶(3mg/kg);α1、α2、αβ-NE受体阻断剂哌唑嗪(1 mg/kg)、哌唑嗪(1 mg/kg)、普萘洛尔(2 mg/kg);D1、D2受体阻断剂SCH23390 (0.05 mg/kg)、舒必利(50 mg/kg)与罗布麻叶总黄酮50 mg/kg联合连续灌胃给药10天后与罗布麻叶总黄酮50 mg/kg单独给药相比,能明显延长悬尾小鼠累计不动时间(p<0.05),表明罗布麻叶总黄酮的抗抑郁活性与去甲肾上腺素能系统(α1、α2、αβ-去甲肾上腺素受体)、5-羟色胺能系统(5-HT2A、5-HT2受体)、多巴胺能系统(D1、D2受体)有关。
4.罗布麻叶总黄酮神经保护作用机制的研究
采用高浓度皮质酮处理PC12细胞以模拟抑郁症病人脑神经元损伤状态,运用MTT法、Ca2+离子浓度([Ca2+]i)检测法、LDH检测法、流式细胞术法考察罗布麻叶总黄酮对皮质酮损伤的PC12细胞的保护作用。结果表明,罗布麻叶总黄酮预先处理后,与皮质酮诱导的PC12细胞损伤组相比,PC12细胞的存活率显著上升,在100μg/mL时达到78%；其LDH释放量、细胞内[Ca2+]i均显著降低(P<0.01),同时细胞S期显著延长(P<0.01),表明罗布麻叶总黄酮对皮质酮诱导损伤的PC12细胞具有神经保护作用,这种神经保护作用可能通过减少细胞内LDH的漏出、降低胞内Ca2+超载、促进细胞增殖实现的。
5.罗布麻叶总黄酮抗抑郁相关基因BDNF、CREB表达水平的研究
研究通过Real-time RT-PCR从基因水平对各组药物处理后的PC12细胞中BDNF、CREB表达水平进行检测发现,皮质酮(0.01 mmol·L-1)处理后的PC12细胞中BDNF、CREB基因的表达量最低,罗布麻叶总黄酮(25,50 and 100μg/mL)处理48小时候后,其表达量显著增加,在100μg/mL时较用药前增加了近10倍。研究结果表明,抑郁症的发病机制可能与脑中BDNF、CREB基因表达降低密切相关,罗布麻叶总黄酮的抗抑郁机制可能是通过(AC-cAMP-CREB)信号通路促进BDNF、CREB的基因表达而发挥的。
本研究在评价了罗布麻叶总黄酮的抗抑郁作用的基础上,揭示了罗布麻叶总黄酮抗抑郁作用与提高抑郁大鼠脑内单胺类神经递质NE、DA及其代谢产物HVA、DOPAC含量有关；并首次证实其抗抑郁活性与去甲肾上腺素能系统(α1、α2、αβ-去甲肾上腺素受体)、5-羟色胺能系统(5-HT2A、5-HT2受体)、多巴胺能系统(D1、D2受体)有关；在此基础上,进一步阐明了其抗抑郁作用的神经保护作用机制可能是通过减少LDH的漏出、降低胞内Ca2+超载、促进细胞增殖实现的,同时推测抑郁症的发病机制可能与脑中BDNF、CREB基因表达降低密切相关,罗布麻叶总黄酮的抗抑郁机制可能是通过(AC-cAMP-CREB)信号通路促进BDNF、CREB的基因表达而发挥的。研究结果为进一步探讨抑郁症的发病机制打下了基础,也利用天然抗抑郁药物治疗抑郁症提供了新思路。
Depression is a prevalent psychiatric disorder which affects 21% of the world population. The symptoms of depression are intense feelings of sadness, loss of interest or pleasure, hopelessness, and despair, disturbed in sleeppatterns and appetite, as well as the inability to experience pleasure in usual activities, as its worst, can lead to suicide thoughts. The World Health Organization (WHO) report has predicted that major depression will become the second cause of illness induced disability by the year 2020. Consequently, more and more researchers have paid attention to pathogenesy and therapy of depression, however, the mechanism of antidepressants is still far from clearly understood. Indeed, studies have been proposed as possible mechanisms that depression is closely related to monoamine neurotransmitters, neurotrophic factors, signal transduction and other factors. The majority of Antidepressant drugs currently used has lead too much concern shortage, such as narrow-spectrum antidepressant, drug resistance, side effect and so on. From this perspective, we need to development new type of antidepressant drugs, while the naturally medications have higher antidepressant curative effect and fewer adverse effect. Apocynum venetum (AV) L. (Apocynaceae) is a traditional drug has been the subject of intensive research in China. In the present study, we extracted the major active component of Apocynum venetum-flavonoid, investigated its antidepressant effect, and corresponding mechanisms based on antidepressant-like effect.The present study will prescribe clinical application to provide the certain theories and experiments according to develop new natural mediciations.
1. Evaluated the antidepressant-like effect of AV-extract
In this study, the classical animal models of depression including the tail suspention and force swimming of the mouse, and open-field test were applied to evaluate the antidepressant-like effect of AV-extract.The results showed that AV-extract showed a clear antidepressant-like effect in variety of animal models of depression.
2. Influence of AV-extract on monoamine neurotransmitters and its metabolites in rat brain tissue
The LC-MS/MS detection was applied to investigate the variation of norepinephrine (NE), 5-hydroxytryptamine (5-HT), dopamine (DA) and its metabolites 5-hydroxyindole-3-acetic acid (5-HIAA),3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in rats brain tissue. The results showed that the concentration of NE、DA、HVA、DOPAC、5-HT、5-HIAA in depression rats'brain were degraded compared with the control group. While the content of NE、DA、HVA、DOPAC in AV-extract group were higher than depression group, the results were similar to fluoxetine group. However, the AV-extract have no effect on 5-HT/5-HIAA contrast to fluoxetine which can increased levels of 5-HT and/or 5-HIAA in rat brain regions.These results confirmed the neurotransmitter hypothesis of depression, as well as we found that AV-extract colud reversed the variation of NE、DA、HVA、DOPAC in rat brain tissue.
3. Involvement of monoaminergic systems in the antidepressant-like effect of AV-extract
To further search for the neurotransmitter mechanism of antidepression of AV-extract, additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of AV-extract in mice were also assessed. The anti-immobility effect of AV-extract (50 mg/kg, p.o.) was completely prevented by the pretreatment of mice with ketanserin (5 mg/kg, i.g., a serotonin 5-HT2A receptor antagonist), cyproheptadine (3 mg/kg, i.g., a serotonin 5-HT2 receptor antagonist), prazosin(1 mg/kg, i.g., anα1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.g., anα2-adrenoceptor antagonist) or propranolol (2 mg/kg, i.g.,αβ-adrenoceptor antagonist) SCH23390 (0.05 mg/kg, i.g.. a dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.g., a dopamine D2 receptor antagonist). On the other hand, the pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a serotonin 5-HT1A receptor antagonist), did not block the antidepressant-like effect of AV-extract in the TST. Taken together, the data demonstrated that AV-extract produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic (5-HT2A and 5-HT2 receptors), noradrenergic (α1-adrenoceptor, a2-adrenoceptor, aβ-adrenoceptor) and dopaminergic (D1 and D2 receptors) systems.
4. The mechanism of neuroprotective effect of AV-extract
Neuroprotective effect of AV extract was studied in corticosterone-induced neurotoxicity, using PC 12 cells as a suitable vitro model of depression to illustrate elementarily the pharmacologieal mechanism of antidepressant activity of AV extract. Cell viability was quantitated by 3-(4,5-Dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay. The release amount of lactic dehydrogenase (LDH) and intracellular Ca2+concentration was measured using kit, cell period change was tested by flow cytometry. The results showed that AV extract (25, 50 and 100μg/mL) increased the survival rate of PC 12 cells, especially in 100mg/kg arrived to 78%, but decreased LDH release and Ca2+concentration significantly (P<0.01), S period of the cells reduced significantly with the corresponding corticosteron-treated PC 12 cells. These results suggest AV extract could generate a neuroprotective effect on corticosterone-induced neurotoxicity in PC 12 cells, pointing to a possible action pathway of AV extract in vivo by decreasing decreased LDH release and Ca2+concentration to promote cell proliferation.
5. Study on the expression of antidepressant effect associate-gene CREB and BDNF of AV-extract
Taqman quantitative testing technique was used to test the expression of the BDNF and CREB of PC 12 cells in the presence of corticosterone (0.01 mmol·L-1) and flavonoid extract from Apocynum venetum leaves (25,50 and 100μg/ml) for 48 h. The result showed that the expression level of BDNF、CREB was reduced significantly after treatmented by corticosterone, but was elevated significantly by Apocynum venetum treatment which was up-regulated approximately 10 times corresponding to corticosterone treated. The result showed that the possible mechanism of Apocynum venetum maybe related to elevation the expression of BDNF、CREB through the signal path AC-cAMP-CREB.
In conclusion, the study presented herein on the basis of evaluating the antidepressant effect of AV-extract demonstrated that the possible mechanism of these effect may be related to reduce the concentration of NE、DA、HVA、DOPAC, and for the first time the study investigated the antidepressant-like effect of AV-extract mediated by an interaction with the serotonergic (5-HT2A and 5-HT2 receptors), noradrenergic (α1-adrenoceptor,α2-adrenoceptor, aβ-adrenoceptor) and dopaminergic (D1 and D2 receptors)systems. Further works clarified that the antidepressant mechanism of neuroprotection may be achieved by decreasing LDH release and Ca2+ concentration to promote cell proliferation, and then speculated that the possible mechanism of Apocynum venetum antidepressant maybe related to elevating the expression of BDNF、CREB through the signal path AC-cAMP-CREB. The results presented here would be helpful to further study the pathogenesis of depression, and also provided a new idea for the use of natural anti-depressant medication to cure depression.
1.罗布麻叶总黄酮抗抑郁作用的活性评价
采用经典抑郁动物模型小鼠悬尾、小鼠强迫游泳、大鼠强迫游泳实验,小鼠开野实验评价罗布麻叶总黄酮的抗抑郁活性。结果表明罗布麻叶总黄酮具有明确的抗抑郁作用。
2.罗布麻叶总黄酮对抑郁大鼠脑内单胺类神经递质及其代谢产物含量的影响
利用HPLC-MS/MS联用方法测定罗布麻叶总黄酮对抑郁大鼠脑内去甲肾上腺素(NE)、5-羟色胺(5-HT)和多巴胺(DA)及其代谢产物5-吲哚乙酸(5-HIAA)、高香草酸(HVA)和3,4-二羟基苯乙酸(DOPAC)含量的影响。结果表明,抑郁模型大鼠脑内NE, DA及其代谢产物DOPAC、HVA,5-HT、5-HIAA的含量较正常组明显降低,罗布麻叶总黄酮处理后大鼠脑内NE、DA、HVA、DOPAC的含量较抑郁组明显升高,与氟西汀组结果相似,但对5-HT及其代谢产物5-HIAA含量作用不明显,与氟西汀结果相反,氟西汀显著增加了5-HT/5-HIAA含量。该结果证实了抑郁症发病的神经递质假说,同时发现罗布麻叶总黄酮可以逆转抑郁大鼠脑内单胺类物质(NE、DA)及其代谢产物(HVA、DOPAC)的降低。
3.罗布麻叶总黄酮抗抑郁作用参与单胺能系统可能机制的研究
研究选择相关NE、5-HT、DA受体阻断剂(5-HT1A→Way100635、5-HT2→赛庚啶、5-HT2A→酮舍林、a1-NE受体阻断剂→哌唑嗪、α2-NE受体阻断剂→哌唑嗪、αβ-NE受体阻断剂→普萘洛尔、D1→SCH23390、D2→舒必利,采用小鼠悬尾实验,来进一步探讨罗布麻叶总黄酮的抗抑郁机制。结果表明,5-HT2A、5-HT2受体阻断剂酮舍林(5 mg/kg)、赛庚啶(3mg/kg);α1、α2、αβ-NE受体阻断剂哌唑嗪(1 mg/kg)、哌唑嗪(1 mg/kg)、普萘洛尔(2 mg/kg);D1、D2受体阻断剂SCH23390 (0.05 mg/kg)、舒必利(50 mg/kg)与罗布麻叶总黄酮50 mg/kg联合连续灌胃给药10天后与罗布麻叶总黄酮50 mg/kg单独给药相比,能明显延长悬尾小鼠累计不动时间(p<0.05),表明罗布麻叶总黄酮的抗抑郁活性与去甲肾上腺素能系统(α1、α2、αβ-去甲肾上腺素受体)、5-羟色胺能系统(5-HT2A、5-HT2受体)、多巴胺能系统(D1、D2受体)有关。
4.罗布麻叶总黄酮神经保护作用机制的研究
采用高浓度皮质酮处理PC12细胞以模拟抑郁症病人脑神经元损伤状态,运用MTT法、Ca2+离子浓度([Ca2+]i)检测法、LDH检测法、流式细胞术法考察罗布麻叶总黄酮对皮质酮损伤的PC12细胞的保护作用。结果表明,罗布麻叶总黄酮预先处理后,与皮质酮诱导的PC12细胞损伤组相比,PC12细胞的存活率显著上升,在100μg/mL时达到78%；其LDH释放量、细胞内[Ca2+]i均显著降低(P<0.01),同时细胞S期显著延长(P<0.01),表明罗布麻叶总黄酮对皮质酮诱导损伤的PC12细胞具有神经保护作用,这种神经保护作用可能通过减少细胞内LDH的漏出、降低胞内Ca2+超载、促进细胞增殖实现的。
5.罗布麻叶总黄酮抗抑郁相关基因BDNF、CREB表达水平的研究
研究通过Real-time RT-PCR从基因水平对各组药物处理后的PC12细胞中BDNF、CREB表达水平进行检测发现,皮质酮(0.01 mmol·L-1)处理后的PC12细胞中BDNF、CREB基因的表达量最低,罗布麻叶总黄酮(25,50 and 100μg/mL)处理48小时候后,其表达量显著增加,在100μg/mL时较用药前增加了近10倍。研究结果表明,抑郁症的发病机制可能与脑中BDNF、CREB基因表达降低密切相关,罗布麻叶总黄酮的抗抑郁机制可能是通过(AC-cAMP-CREB)信号通路促进BDNF、CREB的基因表达而发挥的。
本研究在评价了罗布麻叶总黄酮的抗抑郁作用的基础上,揭示了罗布麻叶总黄酮抗抑郁作用与提高抑郁大鼠脑内单胺类神经递质NE、DA及其代谢产物HVA、DOPAC含量有关；并首次证实其抗抑郁活性与去甲肾上腺素能系统(α1、α2、αβ-去甲肾上腺素受体)、5-羟色胺能系统(5-HT2A、5-HT2受体)、多巴胺能系统(D1、D2受体)有关；在此基础上,进一步阐明了其抗抑郁作用的神经保护作用机制可能是通过减少LDH的漏出、降低胞内Ca2+超载、促进细胞增殖实现的,同时推测抑郁症的发病机制可能与脑中BDNF、CREB基因表达降低密切相关,罗布麻叶总黄酮的抗抑郁机制可能是通过(AC-cAMP-CREB)信号通路促进BDNF、CREB的基因表达而发挥的。研究结果为进一步探讨抑郁症的发病机制打下了基础,也利用天然抗抑郁药物治疗抑郁症提供了新思路。
Depression is a prevalent psychiatric disorder which affects 21% of the world population. The symptoms of depression are intense feelings of sadness, loss of interest or pleasure, hopelessness, and despair, disturbed in sleeppatterns and appetite, as well as the inability to experience pleasure in usual activities, as its worst, can lead to suicide thoughts. The World Health Organization (WHO) report has predicted that major depression will become the second cause of illness induced disability by the year 2020. Consequently, more and more researchers have paid attention to pathogenesy and therapy of depression, however, the mechanism of antidepressants is still far from clearly understood. Indeed, studies have been proposed as possible mechanisms that depression is closely related to monoamine neurotransmitters, neurotrophic factors, signal transduction and other factors. The majority of Antidepressant drugs currently used has lead too much concern shortage, such as narrow-spectrum antidepressant, drug resistance, side effect and so on. From this perspective, we need to development new type of antidepressant drugs, while the naturally medications have higher antidepressant curative effect and fewer adverse effect. Apocynum venetum (AV) L. (Apocynaceae) is a traditional drug has been the subject of intensive research in China. In the present study, we extracted the major active component of Apocynum venetum-flavonoid, investigated its antidepressant effect, and corresponding mechanisms based on antidepressant-like effect.The present study will prescribe clinical application to provide the certain theories and experiments according to develop new natural mediciations.
1. Evaluated the antidepressant-like effect of AV-extract
In this study, the classical animal models of depression including the tail suspention and force swimming of the mouse, and open-field test were applied to evaluate the antidepressant-like effect of AV-extract.The results showed that AV-extract showed a clear antidepressant-like effect in variety of animal models of depression.
2. Influence of AV-extract on monoamine neurotransmitters and its metabolites in rat brain tissue
The LC-MS/MS detection was applied to investigate the variation of norepinephrine (NE), 5-hydroxytryptamine (5-HT), dopamine (DA) and its metabolites 5-hydroxyindole-3-acetic acid (5-HIAA),3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in rats brain tissue. The results showed that the concentration of NE、DA、HVA、DOPAC、5-HT、5-HIAA in depression rats'brain were degraded compared with the control group. While the content of NE、DA、HVA、DOPAC in AV-extract group were higher than depression group, the results were similar to fluoxetine group. However, the AV-extract have no effect on 5-HT/5-HIAA contrast to fluoxetine which can increased levels of 5-HT and/or 5-HIAA in rat brain regions.These results confirmed the neurotransmitter hypothesis of depression, as well as we found that AV-extract colud reversed the variation of NE、DA、HVA、DOPAC in rat brain tissue.
3. Involvement of monoaminergic systems in the antidepressant-like effect of AV-extract
To further search for the neurotransmitter mechanism of antidepression of AV-extract, additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of AV-extract in mice were also assessed. The anti-immobility effect of AV-extract (50 mg/kg, p.o.) was completely prevented by the pretreatment of mice with ketanserin (5 mg/kg, i.g., a serotonin 5-HT2A receptor antagonist), cyproheptadine (3 mg/kg, i.g., a serotonin 5-HT2 receptor antagonist), prazosin(1 mg/kg, i.g., anα1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.g., anα2-adrenoceptor antagonist) or propranolol (2 mg/kg, i.g.,αβ-adrenoceptor antagonist) SCH23390 (0.05 mg/kg, i.g.. a dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.g., a dopamine D2 receptor antagonist). On the other hand, the pretreatment of mice with WAY 100635 (0.1 mg/kg, s.c., a serotonin 5-HT1A receptor antagonist), did not block the antidepressant-like effect of AV-extract in the TST. Taken together, the data demonstrated that AV-extract produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic (5-HT2A and 5-HT2 receptors), noradrenergic (α1-adrenoceptor, a2-adrenoceptor, aβ-adrenoceptor) and dopaminergic (D1 and D2 receptors) systems.
4. The mechanism of neuroprotective effect of AV-extract
Neuroprotective effect of AV extract was studied in corticosterone-induced neurotoxicity, using PC 12 cells as a suitable vitro model of depression to illustrate elementarily the pharmacologieal mechanism of antidepressant activity of AV extract. Cell viability was quantitated by 3-(4,5-Dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay. The release amount of lactic dehydrogenase (LDH) and intracellular Ca2+concentration was measured using kit, cell period change was tested by flow cytometry. The results showed that AV extract (25, 50 and 100μg/mL) increased the survival rate of PC 12 cells, especially in 100mg/kg arrived to 78%, but decreased LDH release and Ca2+concentration significantly (P<0.01), S period of the cells reduced significantly with the corresponding corticosteron-treated PC 12 cells. These results suggest AV extract could generate a neuroprotective effect on corticosterone-induced neurotoxicity in PC 12 cells, pointing to a possible action pathway of AV extract in vivo by decreasing decreased LDH release and Ca2+concentration to promote cell proliferation.
5. Study on the expression of antidepressant effect associate-gene CREB and BDNF of AV-extract
Taqman quantitative testing technique was used to test the expression of the BDNF and CREB of PC 12 cells in the presence of corticosterone (0.01 mmol·L-1) and flavonoid extract from Apocynum venetum leaves (25,50 and 100μg/ml) for 48 h. The result showed that the expression level of BDNF、CREB was reduced significantly after treatmented by corticosterone, but was elevated significantly by Apocynum venetum treatment which was up-regulated approximately 10 times corresponding to corticosterone treated. The result showed that the possible mechanism of Apocynum venetum maybe related to elevation the expression of BDNF、CREB through the signal path AC-cAMP-CREB.
In conclusion, the study presented herein on the basis of evaluating the antidepressant effect of AV-extract demonstrated that the possible mechanism of these effect may be related to reduce the concentration of NE、DA、HVA、DOPAC, and for the first time the study investigated the antidepressant-like effect of AV-extract mediated by an interaction with the serotonergic (5-HT2A and 5-HT2 receptors), noradrenergic (α1-adrenoceptor,α2-adrenoceptor, aβ-adrenoceptor) and dopaminergic (D1 and D2 receptors)systems. Further works clarified that the antidepressant mechanism of neuroprotection may be achieved by decreasing LDH release and Ca2+ concentration to promote cell proliferation, and then speculated that the possible mechanism of Apocynum venetum antidepressant maybe related to elevating the expression of BDNF、CREB through the signal path AC-cAMP-CREB. The results presented here would be helpful to further study the pathogenesis of depression, and also provided a new idea for the use of natural anti-depressant medication to cure depression.
引文
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