知母总皂苷及萨尔萨皂苷元的抗抑郁作用及其机制研究
|
摘要
抑郁症是一种以情感病态变化为主的精神障碍性疾病，呈慢性、反复发作以及高自杀率，对个人、家庭和社会有许多负面的影响。近年来其发病率正在迅速攀升。目前临床上使用的抗抑郁药物多存在有效率低、易产生耐药性以及副作用较多等缺点，因此许多患者开始寻求植物药进行治疗。
知母总皂苷(total timosaponin，TT)是从中药知母中提取分离的皂苷类活性物质，主要含有知母皂苷A-Ⅰ、A-Ⅲ、知母皂苷B以及知母皂苷E等，具有促进神经再生、抗氧化损伤、抗应激以及抗老年痴呆等药理作用。而萨尔萨皂苷元(sarsasapogenin)是知母总皂苷中最为主要的苷元，并且很可能是其主要的生物活性基团。本课题运用体内外相结合的方法，采用多种动物模型以及细胞模型，从整体、器官、细胞水平研究了TT以及萨尔萨皂苷元的抗抑郁作用，并对其可能的作用机制进行了探讨。
药理诱导实验结果显示，TT多次给药能够拮抗利血平反应，明显加强育亨宾的致死作用以及5—羟色氨酸诱导的甩头行为，这些结果提示TT可能具有提高脑内去甲肾上腺素(NE)能和5—羟色胺(5-HT)能神经功能的作用。
小鼠强迫游泳实验以及悬尾实验结果显示，TT在12.5～50mg／kg剂量范围内，在不影响小鼠活动能力的前提下，能够显著缩短小鼠的不动时间。在获得性无助模型中，TT能够显著减少应激动物逃避反应失败次数。在慢性温和应激模型中，TT能够显著对抗慢性应激导致的小鼠蔗糖水摄取量减少，改善小鼠自主活动能力以及学习记忆能力的降低。以上实验结果提示，TT对于实验性抑郁动物模型具有良好的抗抑郁活性。
慢性温和应激实验结果显示，长期慢性温和应激可导致模型动物HPA轴功能亢进，海马神经元损伤。给予TT治疗3周，可明显缓解应激导致的HPA轴功能亢进，降低血浆中促肾上腺释放激素、皮质醇的含量，改善肾上腺的异常增生。TT还能够明显的改善应激动物海马神经元数量的减少以及形态学的改变。此外，TT能够显著改善慢性应激导致的机体抗氧化应激能力下降，并且提高脑组织脑源性神经生长因子(BDNF)的含量。皮质酮诱导PC12细胞损伤模型实验结果显示，TT0.05～5mg／L可显著对抗0.2mM皮质酮诱导的细胞损伤，该保护作用可能与降低细胞内钙离子超载、提高细胞抗氧化能力有关。上述结果提示，知母总皂苷的抗抑郁机制主要是通过改善慢性应激导致的神经元损伤而发挥作用。该神经元保护作用一方面是通过抑制慢性应激引起的HPA轴功能亢进、降低皮质激素水平实现的，另一方面是通过提高脑内BDNF含量以及改善高浓度皮质酮诱导的细胞内Ca~(2+)超载以及SOD活性下降而发挥作用。
为了进一步寻找知母总皂苷的活性成分，本研究通过酸解、提取、硅胶柱分离、重结晶等实验步骤从知母中提取分离得到萨尔萨皂苷元白色针状晶体，纯度达到98％以上。小鼠强迫游泳实验结果显示，萨尔萨皂苷元在12.5～50mg／kg剂量范围内，在不影响小鼠活动能力的前提下，能够显著缩短小鼠的不动时间，也具有较好的抗抑郁作用。该结果显示，萨尔萨皂苷元是知母总皂苷中具有抗抑郁作用的活性基团，当其与糖基相联后可提高其抗抑郁活性，进一步纯化分离知母总皂苷中的皂苷类活性成分或以萨尔萨皂苷元为母核进行糖基化结构改造，可能会得到抗抑郁活性更好的化合物。此外，在脑内单胺递质含量测定实验中，慢性给予萨尔萨皂苷元可明显升高海马以及下丘脑内5-HT以及NE神经递质水平，而该作用可能主要是通过抑制A型单胺氧化酶的活性实现的。
综上所述，知母总皂苷以及萨尔萨皂苷元具有良好的抗抑郁活性，其作用机制涉及调节神经生化功能、神经内分泌功能以及改善神经元损伤等多个环节。萨尔萨皂苷元及其糖苷类衍生物很可能会被开发成具有良好市场前景的抗抑郁药物。
Depression is an affective disorder associated with high rates of chronicity, relapse and recurrence; psychosocial and physical impairment; and a high suicide rate, which has mufti-negative to individuals, families and society. The incidence of depression is rapidly increasing during these years. Nonetheless, many currently available antidepressants have low rates of response and remission. Moreover, contemporary antidepressants can produce many unwanted side effects. Therefore, research for new antidepressants with greater effectiveness from herbs is desirable.
Total timosaponin (TT) is a mixture of total saponins extracted from the rhizome of Anemarrhena asphodeloides Bunge, containing a high level of steroid saponins such as timosaponin A-I, A-III, B and E, which exhibits a variety of pharmacological effects such as the promotion of neurogenesis activity, antioxidative action, antistress action and improving cognitive impairment. Sarsasapogenin is a major bioactive group of total timosaponin. Our dissertation studied the antidepressant effects of TT and sarsasapogenin with various animal models and their possible mechanisms in celluar and molecular levels.
TT can distinctly antagonized the syndrome induced by reserpine, increase the head-twitch response induced by 5-HTP, and enhanced the toxicity induced by yohimbine. The research results indicated the mechanisms of its antidepressant effects may be related with the reinforcement of NE and 5-HT nerves system.
Our results showed that TT treatment at 12.5 to 50 mg/kg (p.o.) for 14 days significantly reduced the duration of immobility in the forced swimming test and tail suspension test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. TT siginificantly decreased the number of escape deficits in the LH test. After a three-week treatment, TT markedly enhanced the locomotor activity and increased consumption of sucrose solution in chronic mild stressed (CMS) mice. The research results indicated TT had antidepressant effects in depression mouse models.
Abnormally high corticosteroid levels have been associated with both psychiatric problems and neuronal damage. The research results demonstrated that CMS activied the hypothalamic-pituitary-adrenal (HPA) axis and induced hippocampal neuronal damage. After a three-week treatment, TT markedly decreased the enhanced plasma corticosterone and adrenocorticotrophic hormone levels, and decreased the hyperplasy of adrenal gland. TT can also improve hippocampal neuronal density and morphologic changes induced by CMS. Furthermore, TT ameliorated the decreacing of anti-oxidative stress capability and brain-derived neurotrophic factor (BDNF) levels. The research results of corticosterone induced PC12 cells damage model demonstrated TT (0.05, 0.5, 5 mg/L) could improve the morphological change induced by corticosterone, markedly increase the survival rate and decrease the LDH activity. In the fura-2/AM labeling assay, TT attenuated Cort-induced intracellular Ca~(2+) overloading in PC12 cells. Furthermore, TT improved the decreaced of anti-oxidative stress capability. In summary, the mechanisms of its antidepressant effects may be related with the protection of neuronal damage induced by stress. At least a couple of factors seem to be involved in the neuronal protecting effects of TT. Firstly, TT can inhibit stress-induced the activation of the HPA axis and decrease the adrenal cortex hormone levels. Secondly, TT can increase BDNF levels and improve Cort-induced intracellular Ca~(2+) overloading and superoxide dismutase activity breakdown.
To search the antidepressant active component of TT, we extracted sarsasapogenin form Anernarrhema asphodeloides Bunge by acid-degradation analysis, extraction, gel silica collumn separation, and re-crystallization methods. The extracted production is white needl crystal, and the purity of sarsasapogenin is more than 98%. Our results showed that sarsasapogenin treatment at 12.5 to 50 mg/kg (p.o.) for 14 days significantly reduced the duration of immobility in the forced swimming test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. The results indicated sarsasapogenin is a major active component of TT. If some monosaccharides side chains were introduced at its 3rd position, we can possibly fine the new derivate of sarsasapogenin with more potent antidepressant activity. Furthermore, in the monoamine assay, chronic sarsasapogenin administration significantly elevated the NE and 5-HT level in hypothalamus and hippocampus. According to the present results, it is possible that the MAO inhibition contributes, at least in part, to the enhancement of NE and 5-HT levels in mouse brain.
In conclusion, our study indicated that TT and sarsasapogenin have distinctive antidepressant effects in several of animal models. The mechanisms of its antidepressant effects may be related with the adjustment of neurobiochemist function, neuroendocrine function and improvation of neuronal damage. This study could be of interest in the study of the potential therapeutic of TT and sarsasapogenin on depression treatment.
知母总皂苷(total timosaponin，TT)是从中药知母中提取分离的皂苷类活性物质，主要含有知母皂苷A-Ⅰ、A-Ⅲ、知母皂苷B以及知母皂苷E等，具有促进神经再生、抗氧化损伤、抗应激以及抗老年痴呆等药理作用。而萨尔萨皂苷元(sarsasapogenin)是知母总皂苷中最为主要的苷元，并且很可能是其主要的生物活性基团。本课题运用体内外相结合的方法，采用多种动物模型以及细胞模型，从整体、器官、细胞水平研究了TT以及萨尔萨皂苷元的抗抑郁作用，并对其可能的作用机制进行了探讨。
药理诱导实验结果显示，TT多次给药能够拮抗利血平反应，明显加强育亨宾的致死作用以及5—羟色氨酸诱导的甩头行为，这些结果提示TT可能具有提高脑内去甲肾上腺素(NE)能和5—羟色胺(5-HT)能神经功能的作用。
小鼠强迫游泳实验以及悬尾实验结果显示，TT在12.5～50mg／kg剂量范围内，在不影响小鼠活动能力的前提下，能够显著缩短小鼠的不动时间。在获得性无助模型中，TT能够显著减少应激动物逃避反应失败次数。在慢性温和应激模型中，TT能够显著对抗慢性应激导致的小鼠蔗糖水摄取量减少，改善小鼠自主活动能力以及学习记忆能力的降低。以上实验结果提示，TT对于实验性抑郁动物模型具有良好的抗抑郁活性。
慢性温和应激实验结果显示，长期慢性温和应激可导致模型动物HPA轴功能亢进，海马神经元损伤。给予TT治疗3周，可明显缓解应激导致的HPA轴功能亢进，降低血浆中促肾上腺释放激素、皮质醇的含量，改善肾上腺的异常增生。TT还能够明显的改善应激动物海马神经元数量的减少以及形态学的改变。此外，TT能够显著改善慢性应激导致的机体抗氧化应激能力下降，并且提高脑组织脑源性神经生长因子(BDNF)的含量。皮质酮诱导PC12细胞损伤模型实验结果显示，TT0.05～5mg／L可显著对抗0.2mM皮质酮诱导的细胞损伤，该保护作用可能与降低细胞内钙离子超载、提高细胞抗氧化能力有关。上述结果提示，知母总皂苷的抗抑郁机制主要是通过改善慢性应激导致的神经元损伤而发挥作用。该神经元保护作用一方面是通过抑制慢性应激引起的HPA轴功能亢进、降低皮质激素水平实现的，另一方面是通过提高脑内BDNF含量以及改善高浓度皮质酮诱导的细胞内Ca~(2+)超载以及SOD活性下降而发挥作用。
为了进一步寻找知母总皂苷的活性成分，本研究通过酸解、提取、硅胶柱分离、重结晶等实验步骤从知母中提取分离得到萨尔萨皂苷元白色针状晶体，纯度达到98％以上。小鼠强迫游泳实验结果显示，萨尔萨皂苷元在12.5～50mg／kg剂量范围内，在不影响小鼠活动能力的前提下，能够显著缩短小鼠的不动时间，也具有较好的抗抑郁作用。该结果显示，萨尔萨皂苷元是知母总皂苷中具有抗抑郁作用的活性基团，当其与糖基相联后可提高其抗抑郁活性，进一步纯化分离知母总皂苷中的皂苷类活性成分或以萨尔萨皂苷元为母核进行糖基化结构改造，可能会得到抗抑郁活性更好的化合物。此外，在脑内单胺递质含量测定实验中，慢性给予萨尔萨皂苷元可明显升高海马以及下丘脑内5-HT以及NE神经递质水平，而该作用可能主要是通过抑制A型单胺氧化酶的活性实现的。
综上所述，知母总皂苷以及萨尔萨皂苷元具有良好的抗抑郁活性，其作用机制涉及调节神经生化功能、神经内分泌功能以及改善神经元损伤等多个环节。萨尔萨皂苷元及其糖苷类衍生物很可能会被开发成具有良好市场前景的抗抑郁药物。
Depression is an affective disorder associated with high rates of chronicity, relapse and recurrence; psychosocial and physical impairment; and a high suicide rate, which has mufti-negative to individuals, families and society. The incidence of depression is rapidly increasing during these years. Nonetheless, many currently available antidepressants have low rates of response and remission. Moreover, contemporary antidepressants can produce many unwanted side effects. Therefore, research for new antidepressants with greater effectiveness from herbs is desirable.
Total timosaponin (TT) is a mixture of total saponins extracted from the rhizome of Anemarrhena asphodeloides Bunge, containing a high level of steroid saponins such as timosaponin A-I, A-III, B and E, which exhibits a variety of pharmacological effects such as the promotion of neurogenesis activity, antioxidative action, antistress action and improving cognitive impairment. Sarsasapogenin is a major bioactive group of total timosaponin. Our dissertation studied the antidepressant effects of TT and sarsasapogenin with various animal models and their possible mechanisms in celluar and molecular levels.
TT can distinctly antagonized the syndrome induced by reserpine, increase the head-twitch response induced by 5-HTP, and enhanced the toxicity induced by yohimbine. The research results indicated the mechanisms of its antidepressant effects may be related with the reinforcement of NE and 5-HT nerves system.
Our results showed that TT treatment at 12.5 to 50 mg/kg (p.o.) for 14 days significantly reduced the duration of immobility in the forced swimming test and tail suspension test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. TT siginificantly decreased the number of escape deficits in the LH test. After a three-week treatment, TT markedly enhanced the locomotor activity and increased consumption of sucrose solution in chronic mild stressed (CMS) mice. The research results indicated TT had antidepressant effects in depression mouse models.
Abnormally high corticosteroid levels have been associated with both psychiatric problems and neuronal damage. The research results demonstrated that CMS activied the hypothalamic-pituitary-adrenal (HPA) axis and induced hippocampal neuronal damage. After a three-week treatment, TT markedly decreased the enhanced plasma corticosterone and adrenocorticotrophic hormone levels, and decreased the hyperplasy of adrenal gland. TT can also improve hippocampal neuronal density and morphologic changes induced by CMS. Furthermore, TT ameliorated the decreacing of anti-oxidative stress capability and brain-derived neurotrophic factor (BDNF) levels. The research results of corticosterone induced PC12 cells damage model demonstrated TT (0.05, 0.5, 5 mg/L) could improve the morphological change induced by corticosterone, markedly increase the survival rate and decrease the LDH activity. In the fura-2/AM labeling assay, TT attenuated Cort-induced intracellular Ca~(2+) overloading in PC12 cells. Furthermore, TT improved the decreaced of anti-oxidative stress capability. In summary, the mechanisms of its antidepressant effects may be related with the protection of neuronal damage induced by stress. At least a couple of factors seem to be involved in the neuronal protecting effects of TT. Firstly, TT can inhibit stress-induced the activation of the HPA axis and decrease the adrenal cortex hormone levels. Secondly, TT can increase BDNF levels and improve Cort-induced intracellular Ca~(2+) overloading and superoxide dismutase activity breakdown.
To search the antidepressant active component of TT, we extracted sarsasapogenin form Anernarrhema asphodeloides Bunge by acid-degradation analysis, extraction, gel silica collumn separation, and re-crystallization methods. The extracted production is white needl crystal, and the purity of sarsasapogenin is more than 98%. Our results showed that sarsasapogenin treatment at 12.5 to 50 mg/kg (p.o.) for 14 days significantly reduced the duration of immobility in the forced swimming test, and produced no overt locomotor activity change in the open-field test, indicating an antidepressant activity. The results indicated sarsasapogenin is a major active component of TT. If some monosaccharides side chains were introduced at its 3rd position, we can possibly fine the new derivate of sarsasapogenin with more potent antidepressant activity. Furthermore, in the monoamine assay, chronic sarsasapogenin administration significantly elevated the NE and 5-HT level in hypothalamus and hippocampus. According to the present results, it is possible that the MAO inhibition contributes, at least in part, to the enhancement of NE and 5-HT levels in mouse brain.
In conclusion, our study indicated that TT and sarsasapogenin have distinctive antidepressant effects in several of animal models. The mechanisms of its antidepressant effects may be related with the adjustment of neurobiochemist function, neuroendocrine function and improvation of neuronal damage. This study could be of interest in the study of the potential therapeutic of TT and sarsasapogenin on depression treatment.
引文
[1] Murray C J, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global burden of disease study. Lancet, 1997, 349(9063): 436-42.
[2] Lecrubier Y. The burden of depression and anxiety in general medicine. J Clin Psychiatry, 2001, 62(suppl 8): 4-9.
[3] Leonard BE. Neuropharmacology of antidepressants that modify central noradrenergic and serotonergic function: a short review. Hum Psychoharmacol, 1999, 14(2): 75-81.
[4] Song C. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments. Hum Psychopharmacol, 2000, 15(3): 199-211.
[5] Hyman SE, Nestler EJ. The molecular foundations of psychiatry. Washington, DC: American Psychiatric Press, 1993.
[6] Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry, 2000, 61(supple 6): 4-6.
[7] 易正辉，方贻儒，王祖承．抑郁症神经生化和神经电生理学研究进展．中国新药与临床杂志，2005，24(9)：676-9．
[8] 代英杰，范骏，孟昭义．抑郁症的神经生化特征及进展．中国临床康复，2003，7(30)：4126-7．
[9] Jay TM, Rocher C, Hotte M, et al. Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: importance for psychiatric diseases. Neurotox Res, 2004, 6(3): 233-44.
[10] Bender BG, Lerner JA, Ikle D, et al. Psychological change associated with theophylline treatment of asthmatic children: a 6-month study. Pediatr Pulmonol, 1991, 11(3): 233-42.
[11] Murphy BE, Dhar V, Ghadirian AM, et al. Response to steroid suppression in major depression resistant to antidepressant therapy. J Clin Psychopharmacol, 1991, 11(2): 121-6.
[12] Coplan JD, Smith EL, Altemus M, et al. Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates. Biol Psychiatry, 2001, 50(3): 200-4.
[13] Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci USA, 1996, 93(4): 1619-23.
[14] Arborelius L, Owens M J, Plotsky PM, et al. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol, 1999, 160(1): 1-12.
[15] Raadsheer FC, Hoogendijk W J, Stam FC, et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular depressed patients. Neuroendocrinology, 1994, 60(4): 436-44.
[16] Hauger RL, Shelat SG, Redei EE. Decreased corticotropin-releasing factor receptor expression and adrenocorticotropic hormone responsiveness in anterior pituitary cells of Wistar-Kyoto rats. J Neuroendocrinol, 2002, 14(2): 126-34.
[17] Rubin RT, Phillips JJ, McCracken JT, et al. Adrenal gland volume in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function. Biol Psychiatry, 1996, 40(2): 89-97.
[18] Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry, 2001,49(5): 391-404.
[19] Pepin MC, Pothier F, Barden N. Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol, 1992, 42(6): 991-5.
[20] Cotter PA, Mulligan OF, Landau S, et al. Vasoconstrictor response to topical beclomethasone in major depression. Psychoneuroendecrinology, 2002,27(4): 475-87.
[21] Hofmann PJ, Nutzinger DO, Kotter MR, et al. The hypothalamic-pituitury-thyroid axis in agoraphobia, panic disorder, major depression and normal controls. J Affect Disord, 2001, 66(1): 75-7.
[22] Esel E, Turan T, Kula M, et al. Effects of electroconvulsive therapy on hypothalamic-pituitury-thyroid axis activity in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 2002,26(6): 1171-5.
[23] Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA, 2001, 98(22): 12796-801.
[24] Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA, 1996, 93(9): 3908-13.
[25] Abraham I, Juhasz G, Kekesi KA, et al. Corticosterone peak is responsible for stress-induced elevation of glutamate in the hippocampus. Stress, 1998, 2(3): 171-81.
[26] Moghaddam B, Bolinao ML, Stein-Behrens B, et al. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res, 1994,655(1-2): 251-4.
[27] Sheline YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy woman with recurrent major depression. J Neurosci, 1999, 19(12): 5034-43.
[28] Duman RS, Malberg J, Nakagawa S, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry, 2000,48(8): 732-9.
[29] Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science, 1995, 268(5208): 239-47.
[30] Duman RS, Vaidya VA, Nibuya M, et al. Stress, antidepressant treatments, and neurotrophic factors: molecular and cellular mechanisms. The Neuroscientist, 1995, 1(6): 351-60.
[31] Barad M, Bortchouladze R, Winder DG, et al. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-term potentiation and improves memory. Proc Natl Acad Sci USA, 1998, 95(25): 15020-5.
[32] Nagakura A, Niimura M, Takeo S. Effects of a phosphodiesterase Ⅳ inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br J Pharmacol, 2002, 135: 1783-93.
[33] DeVane CL. Pharmacogenetics and metabolism of newer antidepressants. J Clin Psychiatry, 1994, 55(suppl): 38-45.
[34] Hellbom E. Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment. Med Hypotheses, 2006, 66(4): 689-90.
[35] Nierenberg AA. Do some antidepressants work faster than others? J Clin Psychiatry, 2001, 62(suppl 5): 22-5.
[36] de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry, 1996, 57(suppl 4): 19-25.
[37] Moller H J, Volz HP. Drug treatment of depression in 1990s: An overviews of achievements and future possibilities. Drugs, 1996, 52(5): 625-38.
[38] Slattery DA, Hudson AL, Nutt DJ. Invited review: the evolution of antidepressant mechanisms. Fundam Clin Pharmacol, 2004, 18(1): 1-21.
[39] Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypes and emotion. Biol psychiatry, 1999(11), 46: 1480-508.
[40] Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatry Res, 2000, 34(3): 171-81.
[41] Bellanoff JK, Flores BH, Kalezhan M, et al. Rapid reversal of psychotic depression using mifepristone. J Clin Psychophamacol, 2001, 21 (5): 516-21.
[42] Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol, 1999, 375(1-3): 31-40.
[43] Di Carlo G, Bomelli F, Ernst E, et al. St John's wort: Prozac from the plant kingdom. Trends Pharmacol Sci, 2001, 22(6): 292-7.
[44] Clement K, Covertson CR, Johnson MJ, et al. St. John's wort and the treatment of mild to moderate depression: a systematic review. Holist Nurs Pract, 2006, 20(4): 197-203.
[45] Hemmeter U, Annen B, Bischof R, et al. Polysomnographic effects of adjuvant ginkgo biloba therapy in patients with major depression medicated with trimipramine. Pharmacopsychiatry, 2001, 34(2): 50-9.
[46] Satyan KS, Jaiswal AK, Ghosal S, et al. Effect of Ginkgolic acid conjugates on the brain monoamines and metabolites in rodents. Biog amines, 1997, 3(2): 143-51.
[47] Xu Y, Ku BS, Yao HY, et al. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[48] Li S, Wang C, Wang M, et al. Antidepressant like effects of piperine in chronic mild stress treated mice and its possible echanisms. Life Sci, 2007, doi: 10. 1016/j. lfs. 2006. 12. 027.
[49] 张仲启，黄世杰，袁莉，等．巴戟天寡糖对鼠强迫游泳和获得性无助抑郁模型的影响．中国药理 学与毒理学杂志，2001，15(4)：262-5．
[50] 陈瑶，韩婷，芮耀诚，等．积雪草总苷对实验性抑郁症大鼠血清皮质酮和单胺类神经递质的影响．中药材，2005，28(6)：492-6．
[51] 边际，徐绥绪．知母化学及药理研究进展．沈阳药科大学学报，1993，10(2)：141-6．
[52] 倪梁红，秦民坚．知母资源化学及药理研究进展．中国野生植物资源，2005，24(4)：16-20．
[53] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[54] 胡雅儿，孙启祥，夏宗勤．ZMS对大鼠脑内NGF和BDNF的影响．中国药理学通报，2003，19(2)：149-51．
[55] 陈勤，夏宗勤，胡雅儿．知母皂苷元对拟痴呆大鼠β2淀粉样肽沉积及胆碱能系统功能的影响．中国药理学通报，2002，18(4)：390-3．
[56] 欧阳石，孙莉莎．徐江平知母总皂苷对大鼠脑皮质乙酰胆碱酯酶的抑制作用．中国药学杂志，2006，41(19)：1472-4．
[57] 邓云，马百平，徐秋萍，等．甾体皂苷化合物对局灶性脑缺血大鼠的保护作用．军事医学科学院院刊，2004，28(2)：108-10．
[58] 邓云，马百平，徐秋萍，等．甾体皂苷化合物抑制血栓形成作用的研究．军事医学科学院院刊，2004，28(3)：215-7．
[59] 邓云，马百平，徐秋萍，等．知母有效成分对拟痴呆模型大鼠学习记忆的影响及机制．中国药理学通报，2005，21(7)：830-3．
[60] 邓云，马百平，徐秋萍，等．知母有效成分体内外给药对血小板聚集的抑制作用．中国药理学通报，2005，21(12)：1460-2．
[61] 吴非，钟雷，程玉芳，等．知母总皂苷对脑缺血再灌注损伤的保护机制．中国临床康复，2006，10(31)：22-4．
[62] Oh JK, Hyun SY, Oh HR, et al. Effects of Anemarrhena asphodeloides on focal ischemic brain injury induced by middle cerebral artery occlusion in rats. Biol Pharm Bull, 2007, 30(1): 38-43.
[63] 陈锐群，余竹元，张夏英，等．知母皂甙元是Na~+，K~+-ATP酶的抑制剂．生物化学与生物物理学报，1982，14(2)：159．
[64] Nian H, Qin LP, Chen WS, et al. Protective effect of steroidal saponins from rhizome of Anemarrhena asphodeloides on ovadectomy-induced bone loss in rats. Acta Pharmacol Sin. 2006, 27(6): 728-34.
[65] 杨茗，季晖，戴胜军，等．知母皂苷元对维A酸致小鼠骨质疏松的防治作用．中国天然药物，2006，4(3)：219-23．
[66] Niwa A, Takeda O, Ishimaru M, et al. Screening test for platelet aggregation inhibitor in natural products. The active principle of Anemarrhenae Rhizoma. Yakugaku Zasshi, 1988, 108(6): 555-61.
[67] Kaname N, Zhang J, Meng Z, et al. Effect of timosaponin E1 and E2 on superoxide generation induced by various stimuli in human neutrophils and on platelet aggregation in human blood. Clin Chim Acta, 2000, 295(1-2): 129-40.
[68] Zhang JY, Meng ZY, Zhang MY, et al. Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clinica Chimica Acta, 1999, 289(1-2): 79-88.
[69] 李春梅，高永林，李敏，等．知母皂苷对小鼠血糖的影响．中药药理与临床，2005，21(4)：22-3．
[70] Xiao SZ, Xu ME, Ge YK, et al. Inhibitory effects of saponins from Anemarrhena asphodeloides Bunge on the growth of vascular smooth muscle cells. Biomed Environ Sci, 2006, 19(3): 185-91.
[71] 李泽松，李德良，黄坚，等．心血管相关基因芯片的制备及其在知母皂苷作用机理研究中的应用．药学学报，2003，38(7)：496-500．
[72] 梅田纯代．知母中的抗应激活性成分．国外医学中医中药分册，2003，25(6)：372．
[1] 中华人民共和国卫生部药典委员会．中华人民共和国药典一部，广东科技出版社，1995，182．
[2] 何薇，曾祖平．知母皂苷及其苷元抗衰老作用的研究进展．北京中医，2006，25(6)：376-8．
[3] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[4] Oh JK, Hyun SY, Oh HR, et al. Effects of Anemarrhena asphodeloides on focal ischemic brain injury induced by middle cerebral artery occlusion in rats. Biol Pharm Bull, 2007, 30(1): 38-43.
[5] O′Neil MF, Moore NA. Animal models of depression: are there any? Hum Psychopharmacol, 2003, 18(4): 239-54.
[6] Cryan JF, Slattery DA. Animal models of mood disorders: Recent developments. Curr Opin Psychiatry, 2007, 20(1): 1-7.
[7] 郑丽芳，明亮．抑郁症动物模型的研究与应用．安徽医药，200，9(11)：801-4．
[8] 李晓秋，许晶．抑郁动物模型的研究进展．中华精神科杂志，2002，35(3)：184-6．
[9] Bourin M, Poncelet M, Chermat R, et al. The value of the reserpine test in psychopharmacology. Arzneimittelforschung, 1983, 33(8): 1173-6.
[10] Porsolt RD. Animal models of depression: utility for transgenic research. Rev Neurosci, 2000, 11(1): 53-8.
[11] Joop S de G, Henk van R, Hemmie HG, et al. A set of behavioural tests predicting antidepressant activity. Drug Develop Res, 1985, 5(4): 291-301.
[12] Goodwin GM, Green AR, Johnson P. 5-HT2 receptor characteristics in frontal codex and mediated head-twitch behaviour following antidepressant treatment to mice. Br J Pharmacol, 1984, 83(1): 235-42.
[13] Porsolt RD, Bertin A, Jalfre M. Behavioural despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn, 1977, 229: 327-36.
[14] 张中启．国内昆明种小鼠和Wistar大鼠适合作强迫性游泳抑郁模型动物．中国药理学通报，2001，17(5)：592-3．
[15] Xu Y, Ku BS, Yao HY, et al. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[16] 李崧，王澈，李巍，等．胡椒碱及其衍生物3，4-次甲二氧桂皮酰哌啶的抗抑郁作用．沈阳药科大学学报，2006，23(6)：392-6．
[17] Steru L, Chermat R, Thierry B, et al. The tail suspension test: a new methods for screening antidepressants in mice. Psychopharmacology, 1985, 85: 367-70.
[18] Vaugeois JM, Passera G, Zuccaro F, et al. Individual differences in response to imipramine in the mouse tail suspension test. Psychopharmacology, 1997, 134(4): 387-91.
[19] Seligman ME, Beagly G. Learned helplessness in the rat. J Comp Physiol Psychol, 1975, 88(2): 534-41.
[20] Itoh T, Tokumura M, Abe K. Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol, 2004, 498: 135-42.
[21] Li S, Wang C, Wang MW, et al. Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Behav, 2006, 83(2): 186-93.
[22] Willner P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl), 1997, 134(4), 319-29.
[23] Willner P, Towell A, Sampson D, et al. Reduction of sucrose preference by chronic unpredictable mild stress and its restoration by a tdcyclic antidepressant. Psychopharmacology (Berl), 1987, 93: 358-64.
[24] 张均田．学习、记忆的行为学研究方法．／／张均田，张庆柱．神经药理学研究技术与方法．第1版．北京：人民卫生出版社，2005：297．
[25] Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci, 2001, 2: 343-51.
[26] Borsini F, Volterra G, Meli A. Does the behavioral "despair" test measure "despair"? Physiol Behav, 1986, 38(3): 385-6.
[27] Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressants activity? Psychopharmacology, 1988, 94(2): 147-60.
[28] Takamori K, Yoshida S, Okuyama S. Availability of learned helplesness test as a model of depression compared to a forced swimming test in rats. Pharmacology, 2001, 63(3): 147-53.
[29] Vollmayr B, Henn FA. Learned helplessness in the rat: improvements in validity and reliability. Brain Res Brain Res Protoc, 2001, 8: 1-7.
[30] Foy MR, Stanton ME, Levine S, et al. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol, 1987, 48(1): 138-49.
[31] Pavlides C, Watanabe Y, McEwen BS. Effects of glucocorticoids on hippocampal long-term potentiation. Hippocampus, 3(2): 183-92.
[32] Maroun M, Richter-Levin G. Exposure to acute stress blocks the induction of Long-Term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci, 2003, 23(11): 4406-9.
[1] Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA, 2001,98(22): 12796-801.
[2] Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA, 1996,93(9): 3908-13.
[3] Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord, 2002, 4(2): 117-28.
[4] Magarinos AM, Verdugo JMG, McEwen B. Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci USA, 1997,94(25): 14002-8.
[5] Sousa N, Lukoyanov NV, Madeira MD, et al. Erratum to reorganization of the morphology of hippcampal neuritis and synapse after stress induced damage correlates with behavioral improvement. Neuroscience, 2000,97(2): 253-66.
[6] Joels M, Karst H, Alfarez D, et al. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress, 2004, 7(4): 221-31.
[7] Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry, 2002, 17(suppl 3): 306-10.
[8] Dinan TG, Scott LV. Anatomy of melancholia: focus on hypothalamic-pituitary-adrenal axis overactivity and the role of vasopressin. J Anat. 2005,207(3): 259-64.
[9] Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry, 2000,15(48): 713-4.
[10] Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry, 2000, 57(10): 925-35.
[11] Nair A, Vaidya VA. Cyclic AMP response element binding protein and brain-derived neurotrophic factor: molecules that modulate our mood? J Biosci, 2006, 31(3): 423-34.
[12] Kuipers SD, Bramham CR. Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel, 2006, 9(5): 580-6.
[13] Maberg J, Eisch AJ, Nestler EJ, et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 2000,20(4): 9104-10.
[14] Robert M, Sapolsky RM. Depression, antidepressant, and the shrinking hippocampus. Proc Natl Acad Sci USA, 2001, 98(22): 12320-2.
[15] Li YF, Luo ZP. Depression: damage of neurons and down-regulation of neurogenesis. Acta Pharm Sin, 2004, 39(11): 949-53.
[16] Xia X, Pan Y, Zhang WY, et al. Ethanolic extracts from Curcuma longa attenuates behavioral, immune, and neuroendocrine alterations in a rat chronic mild stress model. Biol Pharm Bull, 2006, 29(5): 938-44.
[17] 李丽萍，华金双，兰敬昀，等．针刺百会和太冲穴对慢性应激抑郁模型大鼠细胞因子的影响．针灸临床杂志，2006，22(9)：49-50．
[18] Zhang YM, Yang Q, Xu CT, et al. Effects of chronic stress on morphology and structure of hippocampal pyramidal neurons in rats. Prog Biochem Biophy, 2002, 29(5): 719-23.
[19] 程燕，明亮，周兰兰，等．白僵菌代谢物对慢性应激抑郁大鼠的抗氧化作用．中国行为医学科学，2005，14(5)：396-7．
[20] 胡雅儿，孙启祥，夏宗勤．ZMS对老年大鼠脑内NGF和BDNF的影响．中国药理学通报，2003，9(2)：149-51．
[21] Zhu SW, Pham TM, Aberg E, et al. Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running. Behav Brain Res, 2006, 167(1): 1-8.
[22] 李云峰，罗质璞．丁螺环酮对皮质酮所致PC12细胞损伤的保护作用．中国药理学与毒理学杂志，2001，15(5)：333-6．
[23] Li YF, Gong ZH, Yang M, et al. Inhibition of the oligosaccharides extracted from Morinda officinalis, a Chinese traditional herbal medicine, on the corticosterone induced apoptosis in PC12 cells. Life Sci, 2003, 72: 933-42.
[24] Li YF, Liu YQ, H WC, et al. Cytoprotective effect is one of common action pathways for antidepressants. Acta Pharmacol Sin, 2003, 24(10): 996-1000.
[25] Mosmann T. Rapid colorimetic assay for celluar growth an dsurvival: Application to proliferation and cytotoxicity assay. J Immunol Methods, 1983, 65: 55-63.
[26] 陈金明，陈思聪，钟纪根，等．粉防己碱对大鼠心肌细胞电压依赖性钙通道的作用．中国药理学通报，1996，12(3)：226-8．
[27] Shang YZ, Qin BW, Cheng JJ, et al. Prevention of oxidative injury by flavonoids from stems and leaves of Scutellaria baicalensis Georgi in PC 12 cells. Phytother Res, 2006, 20(1): 53-7.
[28] Kumar A, Brar R, Wang P, et al. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol, 1999, 276: 265-76.
[29] Muscat R, Papp M, Willner P. Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology, 1992, 109(4): 433-8.
[30] Bhargava A, Meijer OC, Dallman MF, et al. Plasma Membrane Calcium Pump Isoform 1 Gene Expression Is Repressed by Corticosterone and Stress in Rat Hippocampus. TJ Neurosci, 2000, 20(9): 3129-38.
[31] Holslay BA. Stress, hypereortisolism and corticosteroid receptors in depression: implications for therapy. J Afect Disord, 2001, 6(2): 77-91.
[32] Sheliner YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci, 1999, 19: 5034-43.
[33] Heuser I. The hypothalamic-pituitary-adrenal system in depression. Pharmacopsychiatry, 1998, 31 (1): 10.
[34] Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of intedeukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord, 1995, 34(4): 301-9.
[35] Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab, 77: 1690-4.
[36] Maes M, Bosmans E, Meltzer HY, et al. Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression. Am J Psychiatry, 1993, 150: 1189-93.
[37] Lohr JB, John A, Browing BA. Free radical involvement in neuropsychiatric illness. Psychopharmacol Bull, 1995, 31: 159-65.
[38] 郭华，周东丰，杨长虹，等．抑郁症病人细胞免疫和血超氧化物歧化酶含量的研究．中国神经精神疾病杂志，1998，24(2)：73-5．
[39] Willner P. The validity of animal models of depression. Psychopharmacology, 1984, 83: 1-15.
[40] Saarelainen T, Hendolin P, Lucas G, et al. Activation of the trkB neurotrophin receptor is induced by antidepressant-induced behavioral effects. J Neurosci, 2003, 23: 349-57.
[41] Lawrence MS, Sapolsky RM. Glucocorticoids accelerate ATP loss following metabolic insult in cultured hippocampal neurons. Brain Res, 1994, 646(2): 303-6.
[42] Virgin CE, Ha TPT, Packan D. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: inplication for glucocorticoid neurotoxicity. J Neurochem, 1991, 57: 1422-8.
[43] Reagan LP, McEwen BS. Controversies surrounding glucocorticoids-mediated cell death in the hippocampal. J Chem Neuroanatomy, 1997, 13(3): 149-67.
[44] Sun D, Gilboe DD. Ischemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat. J Neurochem, 1994, 62(5): 1921-8.
[45] Schinder AF, Closon EC, Spitzer NC, et al. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci, 1996, 16(19): 6125-33.
[1] 廖洪利，王伟新，赵福胜，等．知母化学成分研究进展．药学实践杂志，2005，23(1)：12-4．
[2] Meng ZY, Zhang JY, Xu SX, et al. Steroidal saponins from Anemarrhena asphodeloides and their effects on superoxide generation. Planta Med, 1999, 65(7): 661-3.
[3] 王卫东，程祖珏，邵卫中，等．知母皂苷对体外培养成年大鼠海马神经前体细胞增殖的影响．江西医药，2004，39(2)：96-8．
[4] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[5] Yi NY, Hu YE, Xia ZQ. ZMS, mechanism in treating senile dementia, in: J. R. Heys, D. G. Melillo (Eds.), Synthesis and Applications of Isotopically Labelled Compounds, John Wiley and Sons, Chichester, 1998: 315-20.
[6] 陈勤，夏宗勤，胡雅儿．知母皂苷元对拟痴呆大鼠β2淀粉样肽沉积及胆碱能系统功能的影响．中国药理学通报，2002，18(4)：390-3．
[7] 狄维，王林，彭涛，等．知母菝葜皂苷元3-位糖基化衍生物的合成．中国药物化学杂志，2003，13(6)：324-8．
[8] 任爱农，季锡忠．知母中菝葜皂苷元含量测定方法探讨．中成药，2000，22(2)：171-2．
[9] 李崧，王澈，李巍，等．胡椒碱及其衍生物3，4-次甲二氧桂皮酰哌啶的抗抑郁作用．沈阳药科大学学报，2006，23(6)：392-6．
[10] Porsolt RD, Bertin A, Jalfre M. Behavioural despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn, 1977, 229: 327-36.
[11] Xu Y, Ku BS, Yao HY, et al. The effects ofcurcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[12] 屈志炜，刘云，张均田．用高效液相色谱电化学检测器测定大小鼠脑内单胺类物质的研究．中国医学科学院学报，1987，9(5)：371-5．
[13] Zhang LK, Niu XY, Yu YW. Simultaneous determination of monoamines and their main metabolites in rat brain using high performance liquid chromatography with electrochemical detection. Acta Pharm Sin, 1987, 22(8): 591-6.
[14] 张均田主编．现代药理实验方法(上册)．北京：北京医科大学中国协和医科大学联合大学出版社．1998：616-9．
[15] Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with folin phenol reagent. J Biol Chem, 1951, 193: 265-75.
[16] Schurr A, Livne A. Different inhibition of mitochondrial monoamine oxidase from brain by hashish components. Biochemical Pharmacology, 1976, 25: 1201-3.
[17] Yu ZF, Kong LD, Chen Y. Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol, 2002, 83(1-2): 161-5.
[18] 陈卫平，廖新华．知母皂苷元生产工艺研究．江西中医学院学报，2005，17(6)：50-1．
[19] 韩丽萍，赵树进，李俭洪．大孔树脂法提取知母总皂苷．中药材，2004，27：288-9．
[20] Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressants activity? Psychopharmacology, 1988, 94(2): 147-60.
[21] 刘美正，郭忠武．皂苷研究新进展．天然产物研究与开发，1997，9(2)：81-5．
[22] 刘美正，郭忠武，惠永正．皂苷研究—糖链的作用．有机化学，1997，17(4)：307-18．
[23] Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry, 2000, 61(supple 6): 4-6.
[24] Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci, 2001, 26(1): 37-43.
[25] Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry, 2007, 12(4): 331-59.
[26] Dar A, Khatoon S. Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut. Pharmacol Biochem Behav, 2000, 65: 1-6.
[2] Lecrubier Y. The burden of depression and anxiety in general medicine. J Clin Psychiatry, 2001, 62(suppl 8): 4-9.
[3] Leonard BE. Neuropharmacology of antidepressants that modify central noradrenergic and serotonergic function: a short review. Hum Psychoharmacol, 1999, 14(2): 75-81.
[4] Song C. The interaction between cytokines and neurotransmitters in depression and stress: possible mechanism of antidepressant treatments. Hum Psychopharmacol, 2000, 15(3): 199-211.
[5] Hyman SE, Nestler EJ. The molecular foundations of psychiatry. Washington, DC: American Psychiatric Press, 1993.
[6] Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry, 2000, 61(supple 6): 4-6.
[7] 易正辉，方贻儒，王祖承．抑郁症神经生化和神经电生理学研究进展．中国新药与临床杂志，2005，24(9)：676-9．
[8] 代英杰，范骏，孟昭义．抑郁症的神经生化特征及进展．中国临床康复，2003，7(30)：4126-7．
[9] Jay TM, Rocher C, Hotte M, et al. Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: importance for psychiatric diseases. Neurotox Res, 2004, 6(3): 233-44.
[10] Bender BG, Lerner JA, Ikle D, et al. Psychological change associated with theophylline treatment of asthmatic children: a 6-month study. Pediatr Pulmonol, 1991, 11(3): 233-42.
[11] Murphy BE, Dhar V, Ghadirian AM, et al. Response to steroid suppression in major depression resistant to antidepressant therapy. J Clin Psychopharmacol, 1991, 11(2): 121-6.
[12] Coplan JD, Smith EL, Altemus M, et al. Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentrations in adult primates. Biol Psychiatry, 2001, 50(3): 200-4.
[13] Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci USA, 1996, 93(4): 1619-23.
[14] Arborelius L, Owens M J, Plotsky PM, et al. The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol, 1999, 160(1): 1-12.
[15] Raadsheer FC, Hoogendijk W J, Stam FC, et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular depressed patients. Neuroendocrinology, 1994, 60(4): 436-44.
[16] Hauger RL, Shelat SG, Redei EE. Decreased corticotropin-releasing factor receptor expression and adrenocorticotropic hormone responsiveness in anterior pituitary cells of Wistar-Kyoto rats. J Neuroendocrinol, 2002, 14(2): 126-34.
[17] Rubin RT, Phillips JJ, McCracken JT, et al. Adrenal gland volume in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function. Biol Psychiatry, 1996, 40(2): 89-97.
[18] Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry, 2001,49(5): 391-404.
[19] Pepin MC, Pothier F, Barden N. Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Mol Pharmacol, 1992, 42(6): 991-5.
[20] Cotter PA, Mulligan OF, Landau S, et al. Vasoconstrictor response to topical beclomethasone in major depression. Psychoneuroendecrinology, 2002,27(4): 475-87.
[21] Hofmann PJ, Nutzinger DO, Kotter MR, et al. The hypothalamic-pituitury-thyroid axis in agoraphobia, panic disorder, major depression and normal controls. J Affect Disord, 2001, 66(1): 75-7.
[22] Esel E, Turan T, Kula M, et al. Effects of electroconvulsive therapy on hypothalamic-pituitury-thyroid axis activity in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 2002,26(6): 1171-5.
[23] Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA, 2001, 98(22): 12796-801.
[24] Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA, 1996, 93(9): 3908-13.
[25] Abraham I, Juhasz G, Kekesi KA, et al. Corticosterone peak is responsible for stress-induced elevation of glutamate in the hippocampus. Stress, 1998, 2(3): 171-81.
[26] Moghaddam B, Bolinao ML, Stein-Behrens B, et al. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Res, 1994,655(1-2): 251-4.
[27] Sheline YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy woman with recurrent major depression. J Neurosci, 1999, 19(12): 5034-43.
[28] Duman RS, Malberg J, Nakagawa S, et al. Neuronal plasticity and survival in mood disorders. Biol Psychiatry, 2000,48(8): 732-9.
[29] Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science, 1995, 268(5208): 239-47.
[30] Duman RS, Vaidya VA, Nibuya M, et al. Stress, antidepressant treatments, and neurotrophic factors: molecular and cellular mechanisms. The Neuroscientist, 1995, 1(6): 351-60.
[31] Barad M, Bortchouladze R, Winder DG, et al. Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-term potentiation and improves memory. Proc Natl Acad Sci USA, 1998, 95(25): 15020-5.
[32] Nagakura A, Niimura M, Takeo S. Effects of a phosphodiesterase Ⅳ inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br J Pharmacol, 2002, 135: 1783-93.
[33] DeVane CL. Pharmacogenetics and metabolism of newer antidepressants. J Clin Psychiatry, 1994, 55(suppl): 38-45.
[34] Hellbom E. Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment. Med Hypotheses, 2006, 66(4): 689-90.
[35] Nierenberg AA. Do some antidepressants work faster than others? J Clin Psychiatry, 2001, 62(suppl 5): 22-5.
[36] de Boer T. The pharmacologic profile of mirtazapine. J Clin Psychiatry, 1996, 57(suppl 4): 19-25.
[37] Moller H J, Volz HP. Drug treatment of depression in 1990s: An overviews of achievements and future possibilities. Drugs, 1996, 52(5): 625-38.
[38] Slattery DA, Hudson AL, Nutt DJ. Invited review: the evolution of antidepressant mechanisms. Fundam Clin Pharmacol, 2004, 18(1): 1-21.
[39] Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypes and emotion. Biol psychiatry, 1999(11), 46: 1480-508.
[40] Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatry Res, 2000, 34(3): 171-81.
[41] Bellanoff JK, Flores BH, Kalezhan M, et al. Rapid reversal of psychotic depression using mifepristone. J Clin Psychophamacol, 2001, 21 (5): 516-21.
[42] Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol, 1999, 375(1-3): 31-40.
[43] Di Carlo G, Bomelli F, Ernst E, et al. St John's wort: Prozac from the plant kingdom. Trends Pharmacol Sci, 2001, 22(6): 292-7.
[44] Clement K, Covertson CR, Johnson MJ, et al. St. John's wort and the treatment of mild to moderate depression: a systematic review. Holist Nurs Pract, 2006, 20(4): 197-203.
[45] Hemmeter U, Annen B, Bischof R, et al. Polysomnographic effects of adjuvant ginkgo biloba therapy in patients with major depression medicated with trimipramine. Pharmacopsychiatry, 2001, 34(2): 50-9.
[46] Satyan KS, Jaiswal AK, Ghosal S, et al. Effect of Ginkgolic acid conjugates on the brain monoamines and metabolites in rodents. Biog amines, 1997, 3(2): 143-51.
[47] Xu Y, Ku BS, Yao HY, et al. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[48] Li S, Wang C, Wang M, et al. Antidepressant like effects of piperine in chronic mild stress treated mice and its possible echanisms. Life Sci, 2007, doi: 10. 1016/j. lfs. 2006. 12. 027.
[49] 张仲启，黄世杰，袁莉，等．巴戟天寡糖对鼠强迫游泳和获得性无助抑郁模型的影响．中国药理 学与毒理学杂志，2001，15(4)：262-5．
[50] 陈瑶，韩婷，芮耀诚，等．积雪草总苷对实验性抑郁症大鼠血清皮质酮和单胺类神经递质的影响．中药材，2005，28(6)：492-6．
[51] 边际，徐绥绪．知母化学及药理研究进展．沈阳药科大学学报，1993，10(2)：141-6．
[52] 倪梁红，秦民坚．知母资源化学及药理研究进展．中国野生植物资源，2005，24(4)：16-20．
[53] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[54] 胡雅儿，孙启祥，夏宗勤．ZMS对大鼠脑内NGF和BDNF的影响．中国药理学通报，2003，19(2)：149-51．
[55] 陈勤，夏宗勤，胡雅儿．知母皂苷元对拟痴呆大鼠β2淀粉样肽沉积及胆碱能系统功能的影响．中国药理学通报，2002，18(4)：390-3．
[56] 欧阳石，孙莉莎．徐江平知母总皂苷对大鼠脑皮质乙酰胆碱酯酶的抑制作用．中国药学杂志，2006，41(19)：1472-4．
[57] 邓云，马百平，徐秋萍，等．甾体皂苷化合物对局灶性脑缺血大鼠的保护作用．军事医学科学院院刊，2004，28(2)：108-10．
[58] 邓云，马百平，徐秋萍，等．甾体皂苷化合物抑制血栓形成作用的研究．军事医学科学院院刊，2004，28(3)：215-7．
[59] 邓云，马百平，徐秋萍，等．知母有效成分对拟痴呆模型大鼠学习记忆的影响及机制．中国药理学通报，2005，21(7)：830-3．
[60] 邓云，马百平，徐秋萍，等．知母有效成分体内外给药对血小板聚集的抑制作用．中国药理学通报，2005，21(12)：1460-2．
[61] 吴非，钟雷，程玉芳，等．知母总皂苷对脑缺血再灌注损伤的保护机制．中国临床康复，2006，10(31)：22-4．
[62] Oh JK, Hyun SY, Oh HR, et al. Effects of Anemarrhena asphodeloides on focal ischemic brain injury induced by middle cerebral artery occlusion in rats. Biol Pharm Bull, 2007, 30(1): 38-43.
[63] 陈锐群，余竹元，张夏英，等．知母皂甙元是Na~+，K~+-ATP酶的抑制剂．生物化学与生物物理学报，1982，14(2)：159．
[64] Nian H, Qin LP, Chen WS, et al. Protective effect of steroidal saponins from rhizome of Anemarrhena asphodeloides on ovadectomy-induced bone loss in rats. Acta Pharmacol Sin. 2006, 27(6): 728-34.
[65] 杨茗，季晖，戴胜军，等．知母皂苷元对维A酸致小鼠骨质疏松的防治作用．中国天然药物，2006，4(3)：219-23．
[66] Niwa A, Takeda O, Ishimaru M, et al. Screening test for platelet aggregation inhibitor in natural products. The active principle of Anemarrhenae Rhizoma. Yakugaku Zasshi, 1988, 108(6): 555-61.
[67] Kaname N, Zhang J, Meng Z, et al. Effect of timosaponin E1 and E2 on superoxide generation induced by various stimuli in human neutrophils and on platelet aggregation in human blood. Clin Chim Acta, 2000, 295(1-2): 129-40.
[68] Zhang JY, Meng ZY, Zhang MY, et al. Effect of six steroidal saponins isolated from anemarrhenae rhizoma on platelet aggregation and hemolysis in human blood. Clinica Chimica Acta, 1999, 289(1-2): 79-88.
[69] 李春梅，高永林，李敏，等．知母皂苷对小鼠血糖的影响．中药药理与临床，2005，21(4)：22-3．
[70] Xiao SZ, Xu ME, Ge YK, et al. Inhibitory effects of saponins from Anemarrhena asphodeloides Bunge on the growth of vascular smooth muscle cells. Biomed Environ Sci, 2006, 19(3): 185-91.
[71] 李泽松，李德良，黄坚，等．心血管相关基因芯片的制备及其在知母皂苷作用机理研究中的应用．药学学报，2003，38(7)：496-500．
[72] 梅田纯代．知母中的抗应激活性成分．国外医学中医中药分册，2003，25(6)：372．
[1] 中华人民共和国卫生部药典委员会．中华人民共和国药典一部，广东科技出版社，1995，182．
[2] 何薇，曾祖平．知母皂苷及其苷元抗衰老作用的研究进展．北京中医，2006，25(6)：376-8．
[3] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[4] Oh JK, Hyun SY, Oh HR, et al. Effects of Anemarrhena asphodeloides on focal ischemic brain injury induced by middle cerebral artery occlusion in rats. Biol Pharm Bull, 2007, 30(1): 38-43.
[5] O′Neil MF, Moore NA. Animal models of depression: are there any? Hum Psychopharmacol, 2003, 18(4): 239-54.
[6] Cryan JF, Slattery DA. Animal models of mood disorders: Recent developments. Curr Opin Psychiatry, 2007, 20(1): 1-7.
[7] 郑丽芳，明亮．抑郁症动物模型的研究与应用．安徽医药，200，9(11)：801-4．
[8] 李晓秋，许晶．抑郁动物模型的研究进展．中华精神科杂志，2002，35(3)：184-6．
[9] Bourin M, Poncelet M, Chermat R, et al. The value of the reserpine test in psychopharmacology. Arzneimittelforschung, 1983, 33(8): 1173-6.
[10] Porsolt RD. Animal models of depression: utility for transgenic research. Rev Neurosci, 2000, 11(1): 53-8.
[11] Joop S de G, Henk van R, Hemmie HG, et al. A set of behavioural tests predicting antidepressant activity. Drug Develop Res, 1985, 5(4): 291-301.
[12] Goodwin GM, Green AR, Johnson P. 5-HT2 receptor characteristics in frontal codex and mediated head-twitch behaviour following antidepressant treatment to mice. Br J Pharmacol, 1984, 83(1): 235-42.
[13] Porsolt RD, Bertin A, Jalfre M. Behavioural despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn, 1977, 229: 327-36.
[14] 张中启．国内昆明种小鼠和Wistar大鼠适合作强迫性游泳抑郁模型动物．中国药理学通报，2001，17(5)：592-3．
[15] Xu Y, Ku BS, Yao HY, et al. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[16] 李崧，王澈，李巍，等．胡椒碱及其衍生物3，4-次甲二氧桂皮酰哌啶的抗抑郁作用．沈阳药科大学学报，2006，23(6)：392-6．
[17] Steru L, Chermat R, Thierry B, et al. The tail suspension test: a new methods for screening antidepressants in mice. Psychopharmacology, 1985, 85: 367-70.
[18] Vaugeois JM, Passera G, Zuccaro F, et al. Individual differences in response to imipramine in the mouse tail suspension test. Psychopharmacology, 1997, 134(4): 387-91.
[19] Seligman ME, Beagly G. Learned helplessness in the rat. J Comp Physiol Psychol, 1975, 88(2): 534-41.
[20] Itoh T, Tokumura M, Abe K. Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol, 2004, 498: 135-42.
[21] Li S, Wang C, Wang MW, et al. Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Behav, 2006, 83(2): 186-93.
[22] Willner P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl), 1997, 134(4), 319-29.
[23] Willner P, Towell A, Sampson D, et al. Reduction of sucrose preference by chronic unpredictable mild stress and its restoration by a tdcyclic antidepressant. Psychopharmacology (Berl), 1987, 93: 358-64.
[24] 张均田．学习、记忆的行为学研究方法．／／张均田，张庆柱．神经药理学研究技术与方法．第1版．北京：人民卫生出版社，2005：297．
[25] Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci, 2001, 2: 343-51.
[26] Borsini F, Volterra G, Meli A. Does the behavioral "despair" test measure "despair"? Physiol Behav, 1986, 38(3): 385-6.
[27] Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressants activity? Psychopharmacology, 1988, 94(2): 147-60.
[28] Takamori K, Yoshida S, Okuyama S. Availability of learned helplesness test as a model of depression compared to a forced swimming test in rats. Pharmacology, 2001, 63(3): 147-53.
[29] Vollmayr B, Henn FA. Learned helplessness in the rat: improvements in validity and reliability. Brain Res Brain Res Protoc, 2001, 8: 1-7.
[30] Foy MR, Stanton ME, Levine S, et al. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol, 1987, 48(1): 138-49.
[31] Pavlides C, Watanabe Y, McEwen BS. Effects of glucocorticoids on hippocampal long-term potentiation. Hippocampus, 3(2): 183-92.
[32] Maroun M, Richter-Levin G. Exposure to acute stress blocks the induction of Long-Term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci, 2003, 23(11): 4406-9.
[1] Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA, 2001,98(22): 12796-801.
[2] Sheline YI, Wang PW, Gado MH, et al. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA, 1996,93(9): 3908-13.
[3] Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord, 2002, 4(2): 117-28.
[4] Magarinos AM, Verdugo JMG, McEwen B. Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci USA, 1997,94(25): 14002-8.
[5] Sousa N, Lukoyanov NV, Madeira MD, et al. Erratum to reorganization of the morphology of hippcampal neuritis and synapse after stress induced damage correlates with behavioral improvement. Neuroscience, 2000,97(2): 253-66.
[6] Joels M, Karst H, Alfarez D, et al. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress, 2004, 7(4): 221-31.
[7] Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry, 2002, 17(suppl 3): 306-10.
[8] Dinan TG, Scott LV. Anatomy of melancholia: focus on hypothalamic-pituitary-adrenal axis overactivity and the role of vasopressin. J Anat. 2005,207(3): 259-64.
[9] Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry, 2000,15(48): 713-4.
[10] Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry, 2000, 57(10): 925-35.
[11] Nair A, Vaidya VA. Cyclic AMP response element binding protein and brain-derived neurotrophic factor: molecules that modulate our mood? J Biosci, 2006, 31(3): 423-34.
[12] Kuipers SD, Bramham CR. Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy. Curr Opin Drug Discov Devel, 2006, 9(5): 580-6.
[13] Maberg J, Eisch AJ, Nestler EJ, et al. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 2000,20(4): 9104-10.
[14] Robert M, Sapolsky RM. Depression, antidepressant, and the shrinking hippocampus. Proc Natl Acad Sci USA, 2001, 98(22): 12320-2.
[15] Li YF, Luo ZP. Depression: damage of neurons and down-regulation of neurogenesis. Acta Pharm Sin, 2004, 39(11): 949-53.
[16] Xia X, Pan Y, Zhang WY, et al. Ethanolic extracts from Curcuma longa attenuates behavioral, immune, and neuroendocrine alterations in a rat chronic mild stress model. Biol Pharm Bull, 2006, 29(5): 938-44.
[17] 李丽萍，华金双，兰敬昀，等．针刺百会和太冲穴对慢性应激抑郁模型大鼠细胞因子的影响．针灸临床杂志，2006，22(9)：49-50．
[18] Zhang YM, Yang Q, Xu CT, et al. Effects of chronic stress on morphology and structure of hippocampal pyramidal neurons in rats. Prog Biochem Biophy, 2002, 29(5): 719-23.
[19] 程燕，明亮，周兰兰，等．白僵菌代谢物对慢性应激抑郁大鼠的抗氧化作用．中国行为医学科学，2005，14(5)：396-7．
[20] 胡雅儿，孙启祥，夏宗勤．ZMS对老年大鼠脑内NGF和BDNF的影响．中国药理学通报，2003，9(2)：149-51．
[21] Zhu SW, Pham TM, Aberg E, et al. Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running. Behav Brain Res, 2006, 167(1): 1-8.
[22] 李云峰，罗质璞．丁螺环酮对皮质酮所致PC12细胞损伤的保护作用．中国药理学与毒理学杂志，2001，15(5)：333-6．
[23] Li YF, Gong ZH, Yang M, et al. Inhibition of the oligosaccharides extracted from Morinda officinalis, a Chinese traditional herbal medicine, on the corticosterone induced apoptosis in PC12 cells. Life Sci, 2003, 72: 933-42.
[24] Li YF, Liu YQ, H WC, et al. Cytoprotective effect is one of common action pathways for antidepressants. Acta Pharmacol Sin, 2003, 24(10): 996-1000.
[25] Mosmann T. Rapid colorimetic assay for celluar growth an dsurvival: Application to proliferation and cytotoxicity assay. J Immunol Methods, 1983, 65: 55-63.
[26] 陈金明，陈思聪，钟纪根，等．粉防己碱对大鼠心肌细胞电压依赖性钙通道的作用．中国药理学通报，1996，12(3)：226-8．
[27] Shang YZ, Qin BW, Cheng JJ, et al. Prevention of oxidative injury by flavonoids from stems and leaves of Scutellaria baicalensis Georgi in PC 12 cells. Phytother Res, 2006, 20(1): 53-7.
[28] Kumar A, Brar R, Wang P, et al. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol, 1999, 276: 265-76.
[29] Muscat R, Papp M, Willner P. Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology, 1992, 109(4): 433-8.
[30] Bhargava A, Meijer OC, Dallman MF, et al. Plasma Membrane Calcium Pump Isoform 1 Gene Expression Is Repressed by Corticosterone and Stress in Rat Hippocampus. TJ Neurosci, 2000, 20(9): 3129-38.
[31] Holslay BA. Stress, hypereortisolism and corticosteroid receptors in depression: implications for therapy. J Afect Disord, 2001, 6(2): 77-91.
[32] Sheliner YI, Sanghavi M, Mintun MA, et al. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci, 1999, 19: 5034-43.
[33] Heuser I. The hypothalamic-pituitary-adrenal system in depression. Pharmacopsychiatry, 1998, 31 (1): 10.
[34] Maes M, Meltzer HY, Bosmans E, et al. Increased plasma concentrations of intedeukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord, 1995, 34(4): 301-9.
[35] Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab, 77: 1690-4.
[36] Maes M, Bosmans E, Meltzer HY, et al. Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression. Am J Psychiatry, 1993, 150: 1189-93.
[37] Lohr JB, John A, Browing BA. Free radical involvement in neuropsychiatric illness. Psychopharmacol Bull, 1995, 31: 159-65.
[38] 郭华，周东丰，杨长虹，等．抑郁症病人细胞免疫和血超氧化物歧化酶含量的研究．中国神经精神疾病杂志，1998，24(2)：73-5．
[39] Willner P. The validity of animal models of depression. Psychopharmacology, 1984, 83: 1-15.
[40] Saarelainen T, Hendolin P, Lucas G, et al. Activation of the trkB neurotrophin receptor is induced by antidepressant-induced behavioral effects. J Neurosci, 2003, 23: 349-57.
[41] Lawrence MS, Sapolsky RM. Glucocorticoids accelerate ATP loss following metabolic insult in cultured hippocampal neurons. Brain Res, 1994, 646(2): 303-6.
[42] Virgin CE, Ha TPT, Packan D. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: inplication for glucocorticoid neurotoxicity. J Neurochem, 1991, 57: 1422-8.
[43] Reagan LP, McEwen BS. Controversies surrounding glucocorticoids-mediated cell death in the hippocampal. J Chem Neuroanatomy, 1997, 13(3): 149-67.
[44] Sun D, Gilboe DD. Ischemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat. J Neurochem, 1994, 62(5): 1921-8.
[45] Schinder AF, Closon EC, Spitzer NC, et al. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci, 1996, 16(19): 6125-33.
[1] 廖洪利，王伟新，赵福胜，等．知母化学成分研究进展．药学实践杂志，2005，23(1)：12-4．
[2] Meng ZY, Zhang JY, Xu SX, et al. Steroidal saponins from Anemarrhena asphodeloides and their effects on superoxide generation. Planta Med, 1999, 65(7): 661-3.
[3] 王卫东，程祖珏，邵卫中，等．知母皂苷对体外培养成年大鼠海马神经前体细胞增殖的影响．江西医药，2004，39(2)：96-8．
[4] Hu YE, Xia ZQ, Sun QX, et al. A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models. Brain Res, 2005, 1660(1-2): 26-39.
[5] Yi NY, Hu YE, Xia ZQ. ZMS, mechanism in treating senile dementia, in: J. R. Heys, D. G. Melillo (Eds.), Synthesis and Applications of Isotopically Labelled Compounds, John Wiley and Sons, Chichester, 1998: 315-20.
[6] 陈勤，夏宗勤，胡雅儿．知母皂苷元对拟痴呆大鼠β2淀粉样肽沉积及胆碱能系统功能的影响．中国药理学通报，2002，18(4)：390-3．
[7] 狄维，王林，彭涛，等．知母菝葜皂苷元3-位糖基化衍生物的合成．中国药物化学杂志，2003，13(6)：324-8．
[8] 任爱农，季锡忠．知母中菝葜皂苷元含量测定方法探讨．中成药，2000，22(2)：171-2．
[9] 李崧，王澈，李巍，等．胡椒碱及其衍生物3，4-次甲二氧桂皮酰哌啶的抗抑郁作用．沈阳药科大学学报，2006，23(6)：392-6．
[10] Porsolt RD, Bertin A, Jalfre M. Behavioural despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn, 1977, 229: 327-36.
[11] Xu Y, Ku BS, Yao HY, et al. The effects ofcurcumin on depressive-like behaviors in mice. Eur J Pharmacol, 2005, 518(1): 40-6.
[12] 屈志炜，刘云，张均田．用高效液相色谱电化学检测器测定大小鼠脑内单胺类物质的研究．中国医学科学院学报，1987，9(5)：371-5．
[13] Zhang LK, Niu XY, Yu YW. Simultaneous determination of monoamines and their main metabolites in rat brain using high performance liquid chromatography with electrochemical detection. Acta Pharm Sin, 1987, 22(8): 591-6.
[14] 张均田主编．现代药理实验方法(上册)．北京：北京医科大学中国协和医科大学联合大学出版社．1998：616-9．
[15] Lowry OH, Rosebrough NJ, Farr AL, et al. Protein measurement with folin phenol reagent. J Biol Chem, 1951, 193: 265-75.
[16] Schurr A, Livne A. Different inhibition of mitochondrial monoamine oxidase from brain by hashish components. Biochemical Pharmacology, 1976, 25: 1201-3.
[17] Yu ZF, Kong LD, Chen Y. Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol, 2002, 83(1-2): 161-5.
[18] 陈卫平，廖新华．知母皂苷元生产工艺研究．江西中医学院学报，2005，17(6)：50-1．
[19] 韩丽萍，赵树进，李俭洪．大孔树脂法提取知母总皂苷．中药材，2004，27：288-9．
[20] Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressants activity? Psychopharmacology, 1988, 94(2): 147-60.
[21] 刘美正，郭忠武．皂苷研究新进展．天然产物研究与开发，1997，9(2)：81-5．
[22] 刘美正，郭忠武，惠永正．皂苷研究—糖链的作用．有机化学，1997，17(4)：307-18．
[23] Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry, 2000, 61(supple 6): 4-6.
[24] Blier P, Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J Psychiatry Neurosci, 2001, 26(1): 37-43.
[25] Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry, 2007, 12(4): 331-59.
[26] Dar A, Khatoon S. Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut. Pharmacol Biochem Behav, 2000, 65: 1-6.