甘露散治疗更年期综合征的药理学研究
摘要
本文对甘露散(GLS)治疗更年期综合征相关症状进行了试验研究，并对其机理进行了初步探讨。
试验结果表明：
1．GLS对潮热模型动物抑制热量的产生，抑制微循环，降低体温，具有治疗作用。
2．GLS能够改善东莨菪碱所致小鼠的记忆获得障碍和乙醇所致记忆再现障碍。
3．GLS能增强戊巴比妥钠催眠作用和拮抗兴奋剂戊四唑诱导的中枢兴奋惊厥作用。
4．GLS可以改善悬尾小鼠与强迫游泳小鼠的绝望抑郁状态。
5．GLS可以降低期待性焦虑小鼠体温，表现抗焦虑作用。
6．GLS对去势雌性大鼠与高脂饮食胖肥大鼠具有很好的减肥、降血脂作用。
7．GLS对去势雌性大鼠具有一定的抗骨质流失作用。
8．GLS能够增加阴虚小鼠体重、增加免疫器官重量，表明具有抗阴虚，增强免疫作用。
9．GLS可降低更年期小鼠血清MDA与升高SOD，提示抗氧化防衰老作用。
10．GLS对性未成熟小鼠阴道上皮角化细胞与子宫没有作用，GLS没有雌激素活性。
综上所述，甘露散对潮热、记忆减退、抑郁、焦虑、睡眠障碍、高血脂、肥胖等更年期综合征相关症状具有改善作用，其作用机理与雌激素作用无关，属对症治疗药物。更年期综合征也是一种衰老有关的疾病，GLS的抗氧化与增强免疫作用对防衰老有一定积极意义。
Objective: Effects and mechanism of GanLuSan (GLS) on climacteric syndrome were investigated in this paper. Results as following:1. GLS inhibit microcirculation, decrease activity of ATP enzyme and lower body temperature in pyretic model. Suggest it can influence hot flash of climacteric syndrome positively.2. GLS improve acquisition impairment of memory induced by scopolamine and reappearance impairment of memory induced by alcohol in mice.3. GLS can influence sleepness positively by augmenting effect of barbital on sleepness and antagonizing picrotoxin on seizures in mice.4. GLS improve depression state in tail suspension test and forced swimming test in mice.5. GLS shows anti-anxiety effect by lowering body temperature in hyperthermia of mice in test of anticipatory anxiety6. GLS lower body weight and body fat and serum CHO、TG in OVX rats and feeding fat rats.7. GLS can inhibit bone loss by increasing dry bone index and bone ash index of femur bone in OVX rats.8. GLS improve YIN weak mice by inceasing body weight、thymus and spleen weight.9. GLS shows antioxidant and antisenile effect by decreasing serum MDA level, and inceasing SOD activity,10. GLS shows no estrogen activity on uterine or virginal in premature mice.Conclusion: GLS has some positive effects on climacteric syndrome related syndromes such as hot flash, depression, anxiety,fat,hypercholesterolemia,bone loss. No estrogen activity is related to these action. Since CS is related to aging process, Antioxidant effect of GLS may contribute to its action at some extent.
试验结果表明：
1．GLS对潮热模型动物抑制热量的产生，抑制微循环，降低体温，具有治疗作用。
2．GLS能够改善东莨菪碱所致小鼠的记忆获得障碍和乙醇所致记忆再现障碍。
3．GLS能增强戊巴比妥钠催眠作用和拮抗兴奋剂戊四唑诱导的中枢兴奋惊厥作用。
4．GLS可以改善悬尾小鼠与强迫游泳小鼠的绝望抑郁状态。
5．GLS可以降低期待性焦虑小鼠体温，表现抗焦虑作用。
6．GLS对去势雌性大鼠与高脂饮食胖肥大鼠具有很好的减肥、降血脂作用。
7．GLS对去势雌性大鼠具有一定的抗骨质流失作用。
8．GLS能够增加阴虚小鼠体重、增加免疫器官重量，表明具有抗阴虚，增强免疫作用。
9．GLS可降低更年期小鼠血清MDA与升高SOD，提示抗氧化防衰老作用。
10．GLS对性未成熟小鼠阴道上皮角化细胞与子宫没有作用，GLS没有雌激素活性。
综上所述，甘露散对潮热、记忆减退、抑郁、焦虑、睡眠障碍、高血脂、肥胖等更年期综合征相关症状具有改善作用，其作用机理与雌激素作用无关，属对症治疗药物。更年期综合征也是一种衰老有关的疾病，GLS的抗氧化与增强免疫作用对防衰老有一定积极意义。
Objective: Effects and mechanism of GanLuSan (GLS) on climacteric syndrome were investigated in this paper. Results as following:1. GLS inhibit microcirculation, decrease activity of ATP enzyme and lower body temperature in pyretic model. Suggest it can influence hot flash of climacteric syndrome positively.2. GLS improve acquisition impairment of memory induced by scopolamine and reappearance impairment of memory induced by alcohol in mice.3. GLS can influence sleepness positively by augmenting effect of barbital on sleepness and antagonizing picrotoxin on seizures in mice.4. GLS improve depression state in tail suspension test and forced swimming test in mice.5. GLS shows anti-anxiety effect by lowering body temperature in hyperthermia of mice in test of anticipatory anxiety6. GLS lower body weight and body fat and serum CHO、TG in OVX rats and feeding fat rats.7. GLS can inhibit bone loss by increasing dry bone index and bone ash index of femur bone in OVX rats.8. GLS improve YIN weak mice by inceasing body weight、thymus and spleen weight.9. GLS shows antioxidant and antisenile effect by decreasing serum MDA level, and inceasing SOD activity,10. GLS shows no estrogen activity on uterine or virginal in premature mice.Conclusion: GLS has some positive effects on climacteric syndrome related syndromes such as hot flash, depression, anxiety,fat,hypercholesterolemia,bone loss. No estrogen activity is related to these action. Since CS is related to aging process, Antioxidant effect of GLS may contribute to its action at some extent.
引文
[1] 王淑贞．妇产科理论与实践．第一版，上海：上海科技出版社，1993；474．
[2] 田秦杰 妇女绝经后相关问题的处理 案头参考 2004，2(3) 47—50
[3] 陈慧侬．更年期综合征与肾衰血瘀的关系．广西中医药，1992；15(6)：28—29．
[4] 罗元恺，等．以补肾为主治疗更年期综合征临床研究．中国医药学报，1990；5(2)：23—25．2
[5] 杨菁 程丹 更年期综合征的药物治疗 世界临床药物 2004，25(4)244—249
[6] Writing Group for the women's Health Initiative Investigation. Risks and Benefits of Estrogen Plus Progrestin in healthy postmenopausal women. Principal Results from th women's initiative randomized controlled trial. JAMA. 2002; 288: 321-333
[7] 崔拱斌主编．大豆生物活性物质研究应用进展(论文集)．北京：华文出版社，74—82
[8] 张玉梅，滕燕平 大豆异黄酮抗高脂型大鼠主动脉血管壁粥样硬化斑块形成研究 中国预防医学杂志 2003，4(1)1—4
[9] Beck V. Rohr U, Jungbauer A Phytoestrogens derived from red clover: An alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol. 2005 Apr; 94(5): 499-518. Epub 2005 Mar 231
[10] Clarker R, Hilakivi-Clarker L, Estrogens, phytoestrogens, and breast cancer. Adv Exp Med Biol. 1996; 401: 63-85.
[11] Stimulatory influence of soy protein isolate on breast secretion in pre-and postmenopausal women. Cancer Epidemiol Biomarkers Prey. 1996 Oct; 5(10): 785-94.
[12] Hemandez BY, Reports: plasma and dietary phytoestrogens and risk of premalignant lesions of the cervix. Nutr Cancer. 2004; 49(2): 109-24.
[13] Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro. Int J Gynecol Cancer. 2004 Sep-Oct; 14(5): 882-8.
[14] 徐叔云，等 药理实验方法学．第2版．北京：人民卫生出版社 1994：641-686，1299-1360。
[15] 李仪奎．中药药理实验方法学．上海：上海科技出版社，1991．139
[16] 张钧田．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出版社，1998：1061-1062
[17] 刘利民等，高脂饮料致大鼠肥胖的实验研究，北京医科大学学报，1991，23(5)，359
[18] 陈小野 实用中医证候动物模型学[M] 北京：中国协和医科大学北京医科大学联合出版社，1993：301
[19] 王加真 中年妇女易发潮热的危险因素 现代中西医结合杂志 2004 Jul，13(13)1788-1789
[20] Burger HG The endocrinology of the menopause[J] Maturitas 1996, 23(2): 129-136
[21] Overliel, Moen MH, Holte A et al. Androgens and estrogens inrelation to hot flashes during
[22] Freedman RR. Hot flashes revisited. Menopause 2000, 7(1): 3-4the menopausal transition. Maturi-tus 2002, 41(1): 69 —77
[23] 李连香，陈亚琼，GnRH受体和5—HT受体与更年期大鼠潮热的关系 解剖学杂志 2004，27(4)380-383
[24] Berendsen HH. The role ofserotonin in hot flushes,.Maturitas, 2000, 36, 155-164
[25] 叶雪清，葛杏林主编．更年期综合征——神经内分泌免疫网络的变化．西安：陕西科学技术出版社，1996：57
[26] 张均田．近年国内关于学习与记忆药理学研究概况．药学学报 1986；21(8)：638
[27] Porsolt RD, Lepichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatment. Nature, 1977, 266: 730—732
[28] Kimura M, et al. The obesityin bilateral ovariectomized rats is related to a decrease in the expressionof ieptin receptors in the brain. Biochem BioPhys Res Comnlun, 2002, 290(4): 1349
[29] Liang YQ, et al. Estrogen receptor beta is involved in the anorectic action of estrogen. In J obes relate MetabDisord. 2002, 26(8): 1103
[30] Duda RJ Jr, O'Brien IF, Katzmann JA, et al. Concurrent assays of circulating bone Gla-protein and bone alkaline phosphatase: effects of sex, age, and metabolic bone disease. J Clin Endocrinol Metab, 1988, 66: 951-957
[31] Basedovsky H O.Clin Exp Immunol 1977; 27: 1
[32] 王秀杰 黄连的药理研究及现代应用 中国药师 2003，6(6)370
[33] 周长征 黄连与吴茱萸药对的研究 山东中医杂志，2003，22(4)232-234
[34] 李盛青，黄兆胜．黄耀权 黄连与吴茱萸不同比例组成的方剂的不同药理作用研究 广州中医药大学学报 2002，19(1)48—51
[35] 蔡钢 黄连阿胶汤在妇科临床中的运用 石河子医学院学报 1997，19(1)
[36] 朱俊程 黄连阿胶汤治疗顽固性失眠64例 国医论坛 1999，14(3)8
[37] 陈敏 吴茱萸汤在妇科临床的应用 四川中医 1995年第8期
[38] Li H, Miyahara T, Tezuka Y, Tran QL, Seto H, Kadota S. Effect of berberine on bone mineral density in SAMP6 as a senile osteoporosis model. Biol Pharm Bull. 2003 Jan; 26(1): 110-1.
[39] 罗来源 中国药理学报，1986，7(5)407—409
[40] Weijia Kong, Jing Wei, Parveen Abid Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins Nature Medicine vol 10 2004, December
[41] Peng WH, Wu CR, Chen CS, Chen CF Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: interaction with drugs acting at 5-HT receptors. Life Sci. 2004 Oct 1; 75(20): 2451-62.
[42] 阎晓红等。中国药理学通报。1991，7(5)：381—384
[43] 侯羽飞等。药学学报。1988，23(11)：801～805
[44] Kim DK, Lee KT, Baek NI, Acetylcholinesterase inhibitors from the aerial parts of Corydalis speciosa. Arch Pharm Res. 2004 Nov; 27(11): 1127-31
[45] 句海松等。中国药理学报。1990，11(6)：539—541
[46] 胡长平，李元建吴茱萸碱与吴茱萸次碱的药理学研究进展 中国药理学通报 2003，19(10)：1084—7
[47] Y Kobayashi/Y Nakano/M Kizaki/K Hoshikuma/Y Yokoo/T Kamiya, Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med, Oct 2001
[48] Pearce LV, Petukhov PA, Szabo T, Evodiamine functions as an agonist for the vanilloid receptor TRPV1. Org Biomol Chem. 2004 Aug 21; 2(16): 2281-6. Epub 2004 Jul 27.
[49] Park CH, Kim SH, Choi W, Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med. 2001 Oct; 67(7): 628-33
[50] J Yamahara/T Yamada/T Kitani/Y Naitoh/H Fujimura, Antianoxic action and active constituents of evodiae fructus. Chem Pharm Bull (Tokyo), Jul 1989
[51] Lee YJ, Kim JS, Kang SS, Suh YH. Novel anticholinesterase and antiamnesic activities of dehydroevodiamine, a constituent of Evodia rutaecarpa. Planta Med. 1996 Oct; 62(5): 405-9.
[52] Chang CP, Chang JY, Wang FY, Tseng J, Chang JG. The effect of Evodia rutaecarpa extract on cytokine secretion by human mononuclear cells in vitro. Am J Chin Med. 1995; 23(2): 173-80.
[53] Hu CP, Xiao L, Deng HW, Li YJ. The cardioprotection of rutaecarpine is mediated by endogenous caicitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts Pianta Med. 2002 Aug; 68(8): 705-9..
[54] Fei XF, Wang BX, Li T J, Tashiro S, Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. Cancer Sci. 2003 Jan; 94(1): 92-8.
[2] 田秦杰 妇女绝经后相关问题的处理 案头参考 2004，2(3) 47—50
[3] 陈慧侬．更年期综合征与肾衰血瘀的关系．广西中医药，1992；15(6)：28—29．
[4] 罗元恺，等．以补肾为主治疗更年期综合征临床研究．中国医药学报，1990；5(2)：23—25．2
[5] 杨菁 程丹 更年期综合征的药物治疗 世界临床药物 2004，25(4)244—249
[6] Writing Group for the women's Health Initiative Investigation. Risks and Benefits of Estrogen Plus Progrestin in healthy postmenopausal women. Principal Results from th women's initiative randomized controlled trial. JAMA. 2002; 288: 321-333
[7] 崔拱斌主编．大豆生物活性物质研究应用进展(论文集)．北京：华文出版社，74—82
[8] 张玉梅，滕燕平 大豆异黄酮抗高脂型大鼠主动脉血管壁粥样硬化斑块形成研究 中国预防医学杂志 2003，4(1)1—4
[9] Beck V. Rohr U, Jungbauer A Phytoestrogens derived from red clover: An alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol. 2005 Apr; 94(5): 499-518. Epub 2005 Mar 231
[10] Clarker R, Hilakivi-Clarker L, Estrogens, phytoestrogens, and breast cancer. Adv Exp Med Biol. 1996; 401: 63-85.
[11] Stimulatory influence of soy protein isolate on breast secretion in pre-and postmenopausal women. Cancer Epidemiol Biomarkers Prey. 1996 Oct; 5(10): 785-94.
[12] Hemandez BY, Reports: plasma and dietary phytoestrogens and risk of premalignant lesions of the cervix. Nutr Cancer. 2004; 49(2): 109-24.
[13] Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro. Int J Gynecol Cancer. 2004 Sep-Oct; 14(5): 882-8.
[14] 徐叔云，等 药理实验方法学．第2版．北京：人民卫生出版社 1994：641-686，1299-1360。
[15] 李仪奎．中药药理实验方法学．上海：上海科技出版社，1991．139
[16] 张钧田．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出版社，1998：1061-1062
[17] 刘利民等，高脂饮料致大鼠肥胖的实验研究，北京医科大学学报，1991，23(5)，359
[18] 陈小野 实用中医证候动物模型学[M] 北京：中国协和医科大学北京医科大学联合出版社，1993：301
[19] 王加真 中年妇女易发潮热的危险因素 现代中西医结合杂志 2004 Jul，13(13)1788-1789
[20] Burger HG The endocrinology of the menopause[J] Maturitas 1996, 23(2): 129-136
[21] Overliel, Moen MH, Holte A et al. Androgens and estrogens inrelation to hot flashes during
[22] Freedman RR. Hot flashes revisited. Menopause 2000, 7(1): 3-4the menopausal transition. Maturi-tus 2002, 41(1): 69 —77
[23] 李连香，陈亚琼，GnRH受体和5—HT受体与更年期大鼠潮热的关系 解剖学杂志 2004，27(4)380-383
[24] Berendsen HH. The role ofserotonin in hot flushes,.Maturitas, 2000, 36, 155-164
[25] 叶雪清，葛杏林主编．更年期综合征——神经内分泌免疫网络的变化．西安：陕西科学技术出版社，1996：57
[26] 张均田．近年国内关于学习与记忆药理学研究概况．药学学报 1986；21(8)：638
[27] Porsolt RD, Lepichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatment. Nature, 1977, 266: 730—732
[28] Kimura M, et al. The obesityin bilateral ovariectomized rats is related to a decrease in the expressionof ieptin receptors in the brain. Biochem BioPhys Res Comnlun, 2002, 290(4): 1349
[29] Liang YQ, et al. Estrogen receptor beta is involved in the anorectic action of estrogen. In J obes relate MetabDisord. 2002, 26(8): 1103
[30] Duda RJ Jr, O'Brien IF, Katzmann JA, et al. Concurrent assays of circulating bone Gla-protein and bone alkaline phosphatase: effects of sex, age, and metabolic bone disease. J Clin Endocrinol Metab, 1988, 66: 951-957
[31] Basedovsky H O.Clin Exp Immunol 1977; 27: 1
[32] 王秀杰 黄连的药理研究及现代应用 中国药师 2003，6(6)370
[33] 周长征 黄连与吴茱萸药对的研究 山东中医杂志，2003，22(4)232-234
[34] 李盛青，黄兆胜．黄耀权 黄连与吴茱萸不同比例组成的方剂的不同药理作用研究 广州中医药大学学报 2002，19(1)48—51
[35] 蔡钢 黄连阿胶汤在妇科临床中的运用 石河子医学院学报 1997，19(1)
[36] 朱俊程 黄连阿胶汤治疗顽固性失眠64例 国医论坛 1999，14(3)8
[37] 陈敏 吴茱萸汤在妇科临床的应用 四川中医 1995年第8期
[38] Li H, Miyahara T, Tezuka Y, Tran QL, Seto H, Kadota S. Effect of berberine on bone mineral density in SAMP6 as a senile osteoporosis model. Biol Pharm Bull. 2003 Jan; 26(1): 110-1.
[39] 罗来源 中国药理学报，1986，7(5)407—409
[40] Weijia Kong, Jing Wei, Parveen Abid Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins Nature Medicine vol 10 2004, December
[41] Peng WH, Wu CR, Chen CS, Chen CF Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: interaction with drugs acting at 5-HT receptors. Life Sci. 2004 Oct 1; 75(20): 2451-62.
[42] 阎晓红等。中国药理学通报。1991，7(5)：381—384
[43] 侯羽飞等。药学学报。1988，23(11)：801～805
[44] Kim DK, Lee KT, Baek NI, Acetylcholinesterase inhibitors from the aerial parts of Corydalis speciosa. Arch Pharm Res. 2004 Nov; 27(11): 1127-31
[45] 句海松等。中国药理学报。1990，11(6)：539—541
[46] 胡长平，李元建吴茱萸碱与吴茱萸次碱的药理学研究进展 中国药理学通报 2003，19(10)：1084—7
[47] Y Kobayashi/Y Nakano/M Kizaki/K Hoshikuma/Y Yokoo/T Kamiya, Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med, Oct 2001
[48] Pearce LV, Petukhov PA, Szabo T, Evodiamine functions as an agonist for the vanilloid receptor TRPV1. Org Biomol Chem. 2004 Aug 21; 2(16): 2281-6. Epub 2004 Jul 27.
[49] Park CH, Kim SH, Choi W, Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med. 2001 Oct; 67(7): 628-33
[50] J Yamahara/T Yamada/T Kitani/Y Naitoh/H Fujimura, Antianoxic action and active constituents of evodiae fructus. Chem Pharm Bull (Tokyo), Jul 1989
[51] Lee YJ, Kim JS, Kang SS, Suh YH. Novel anticholinesterase and antiamnesic activities of dehydroevodiamine, a constituent of Evodia rutaecarpa. Planta Med. 1996 Oct; 62(5): 405-9.
[52] Chang CP, Chang JY, Wang FY, Tseng J, Chang JG. The effect of Evodia rutaecarpa extract on cytokine secretion by human mononuclear cells in vitro. Am J Chin Med. 1995; 23(2): 173-80.
[53] Hu CP, Xiao L, Deng HW, Li YJ. The cardioprotection of rutaecarpine is mediated by endogenous caicitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts Pianta Med. 2002 Aug; 68(8): 705-9..
[54] Fei XF, Wang BX, Li T J, Tashiro S, Evodiamine, a constituent of Evodiae Fructus, induces anti-proliferating effects in tumor cells. Cancer Sci. 2003 Jan; 94(1): 92-8.