艾拉片对重复束缚应激所致勃起功能障碍小鼠的治疗作用

doi:10.5246/jcps.2021.11.076

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (11): 883-894.DOI: 10.5246/jcps.2021.11.076

艾拉片对重复束缚应激所致勃起功能障碍小鼠的治疗作用

高泽宇¹^,²^,^#, 陈君³^,⁴^,^#, 阿依努尔·热合曼³^,⁴^,⁵, 孙懿¹^,², 吴涛³, 希尔艾力·吐尔逊⁴, 蒲小平¹^,²^,^*(), 阿吉艾克拜尔·艾萨³^,^*(), 赵欣¹^,²^,^*()

1. 北京大学药学院天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学药学院分子与细胞药理学系, 北京 100191
3. 中国科学院新疆理化技术研究所干旱区植物资源与化学重点实验室, 新疆乌鲁木齐 830011
4. 中国科学院大学, 北京 100039
5. 新疆医科大学维吾尔医学院, 新疆乌鲁木齐 830011

收稿日期:2021-04-21 修回日期:2021-05-18 接受日期:2021-07-20 出版日期:2021-11-28 发布日期:2021-11-28
通讯作者: 蒲小平, 阿吉艾克拜尔·艾萨, 赵欣
作者简介:
+ Tel.: +86-10-82802648, E-mail: pxp123@bjmu.edu.cn
+ E-mail: haji@ms.xjb.ac.cn
+ E-mail: zhaoxin2010@bjmu.edu.cn
基金资助:
National Major Scientific and Technological Special Project for "Significant New Drugs Development" during the Thirteenth Five-year Plan Period, China (Grant No. 2017ZX09101003-009-006), the Major Science and Technology Projects of Xinjiang Uyghur Autonomous Region (Grant No. 2016A03005-3), the Key Laboratory of Plant Resources and Chemistry in Arid Regions, Chinese Academy of Sciences (Grant No. 2008DP173091-2017-X; 2008DP173091-2017-2), and the National Natural Science Foundation of China (Grant No. U1603128), the Research and Development of New Ethnic Medicine Varities and Their Innovative Technologies (Grant No. 2017ZX009301045).

Ela tablets improve sexual performance in mice with erectile dysfunction caused by repeated restraint stress

Zeyu Gao¹^,²^,^#, Jun Chen³^,⁴^,^#, Ayinuer Reheman³^,⁴^,⁵, Yi Sun¹^,², Tao Wu³, Xirali Tursun⁴, Xiaoping Pu¹^,²^,^*(), Haji Akber Aisa³^,^*(), Xin Zhao¹^,²^,^*()

1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
3 Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, Xinjiang, China
4 University of Chinese Academy of Sciences, Beijing 100039, China
5 College of Traditional Uyghur Medicine, Xinjiang Medical University, Urumqi 830011, Xinjiang, China

Received:2021-04-21 Revised:2021-05-18 Accepted:2021-07-20 Online:2021-11-28 Published:2021-11-28
Contact: Xiaoping Pu, Haji Akber Aisa, Xin Zhao
About author:
# Zeyu Gao and Jun Chen contributed equally to this work.

摘要/Abstract

摘要：

拉片是由经典维医方药Majun Mupakhi Ela优化提取制备得到的。该方一直用于阳痿的治疗, 但艾拉片的具体适应证和治疗机制尚不清楚。本研究拟探讨艾拉片对重复束缚应激所致勃起功能障碍(ED)小鼠的保护作用及其可能机制。每天将小鼠置于束缚盒中连续14天, 并在束缚前1小时给予艾拉片。第14日晚进行交配实验。此后, 收集血液、睾丸和阴茎样本, 测定血清睾酮水平, HE染色观察睾丸组织形态, 免疫印迹法检测磷酸二脂酶5(PDE5)在海绵体中的表达变化情况。结果表明, 艾拉片能显著缩短性唤起时间, 增加性接触次数, 维持睾丸组织的正常形态, 提高血清睾酮水平, 降低阴茎海绵体PDE5的表达。综上, 艾拉片对重复束缚应激小鼠的性能力具有保护作用, 其机制与保护睾丸组织形态、维持睾酮水平及抑制阴茎PDE5表达有关。

关键词: 艾拉片, 勃起功能障碍, 重复束缚应激

Abstract:

Ela tablets contain an optimized extract of a Chinese herbal prescription. The original prescription has been used to treat erectile dysfunction (ED), while the detailed indications and specific treatment mechanisms of Ela tablets remain unclear. In the present study, we aimed to investigate whether Ela tablets could protect mice from ED caused by repeated restraint stress and to explore the possible mechanisms. Mice were restrained daily in centrifuge tubes with venting holes for 14 consecutive days and administered Ela tablets at 1 h before restraining. On the 14^th night, mating experiments were conducted. Thereafter, blood, testicular, and penile samples were collected. Serum testosterone levels were measured using a kit. Testicular tissue morphology was observed by H&E staining. The PDE5 expression in the corpus cavernosum was measured by Western blotting analysis. The results indicated that Ela tablets significantly shortened the sexual arousal time, increased the number of sexual encounters, maintained the normal morphology of testicular tissue, increased the serum testosterone levels, and decreased the PDE5 expression in the corpus cavernosum. Our data showed that Ela tablets elicited protective effects on the sexual ability of mice exposed to repeated restraint stress. Moreover, the underlying mechanism was related to the preservation of testicular tissue morphology, maintenance of testosterone levels, and inhibition of penile PDE5 expression.

Key words: Ela tablets, Erectile dysfunction, Repeated restraint stress

Supporting:

高泽宇, 陈君, 阿依努尔·热合曼, 孙懿, 吴涛, 希尔艾力·吐尔逊, 蒲小平, 阿吉艾克拜尔·艾萨, 赵欣. 艾拉片对重复束缚应激所致勃起功能障碍小鼠的治疗作用[J]. 中国药学(英文版), 2021, 30(11): 883-894.

Zeyu Gao, Jun Chen, Ayinuer Reheman, Yi Sun, Tao Wu, Xirali Tursun, Xiaoping Pu, Haji Akber Aisa, Xin Zhao. Ela tablets improve sexual performance in mice with erectile dysfunction caused by repeated restraint stress[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(11): 883-894.

图/表 9

Table 1. Quality standard for Ela tablet production.

Figure 1. HPLC fingerprint of the 10 sample batches[8]. The compounds of fingerprint respectively are gallic acid (peak 5), salidroside (peak 8), catechin (peak 11), chlorogenic acid (peak 12), rutin (peak17), ferulic acid (peak 18), hyperoside (peak 19), luteoloside (peak 20), daidzein (peak 22), quercetin (peak 25), icariin (peak 26), apigenin (peak 27), and kaempferol (peak 29).

Table 2. Herbs used for preparing Ela tablets.

Figure 2. Workflow of the Ela tablet preparation.

Figure 3. Effects of Ela tablets on the capturing and inserting abilities of mice under repeated restraint stress. (A) Capture incubation period. (B) Captures in 20 min. (C) Insert incubation period. (D) Inserts in 20 min. C: control group; Mo: model group; S: sildenafil group; L: Ela tablet at 0.13 g/kg treatment group; M: Ela tablet at 0.26 g/kg treatment group; H: Ela tablet at 0.52 g/kg treatment group. Data are presented as mean ± SEM; n = 20. #P < 0.05, ###P < 0.001 vs. control group; *P < 0.05, **P < 0.01, ***P < 0.001 vs. model group.

Figure 4. Effects of Ela tablets on testicular tissue morphology of mice under repeated restraint stress. C: control group; Mo: model group; S: sildenafil treatment group; L: Ela tablet at 0.13 g/kg treatment group; M: Ela tablet at 0.26 g/kg treatment group; H: Ela tablet at 0.52 g/kg treatment group.

Figure 5. Effects of Ela tablets on long and short diameters of the seminiferous tubules of mice under repeated restraint stress. (A) long diameter. (B) short diameter. C: control group; Mo: model group; S: sildenafil treatment group; L: Ela tablet at 0.13 g/kg treatment group; M: Ela tablet at 0.26 g/kg treatment group; H: Ela tablet at 0.52 g/kg treatment group. Data are presented as mean ± SEM; n = 5. #P < 0.05, ##P < 0.01 vs. control group; *P < 0.05, **P < 0.01 vs. model group.

Figure 6. Effects of Ela tablets on serum testosterone levels in mice under repeated restraint stress. C: control group; Mo: model group; S: sildenafil treatment group; L: Ela tablet at 0.13 g/kg treatment group; M: Ela tablet at 0.26 g/kg treatment group; H: Ela tablet at 0.52 g/kg treatment group. Data are presented as mean and SEM; n = 10. ###P < 0.001 vs. control group; ***P < 0.001 vs. model group.

Figure 7. Effects of Ela tablets on the PDE5 expression in the corpus cavernosum of mice under repeated restraint stress. (A) PDE5 protein expression detected by Western blotting analysis. (B) Densitometric analysis is presented as the relative ratio of protein PDE5/actin using Quantity One software. C: control group; Mo: model group; L: Ela tablet at 0.13 g/kg treatment group; M: Ela tablet at 0.26 g/kg treatment group; H: Ela tablet at 0.52 g/kg treatment group. Data are presented as mean ± SEM; n = 6. ###P < 0.001 vs. control group; **P < 0.01, ***P < 0.001 vs. model group.

参考文献 31

[1]	Eren, A.E.; Ersay, A.R.; Demirci, E.; Alan, C.; Basturk, G. Diagnostic value of plasma Pentraxin3- level for diagnosis of erectile dysfunction. Urol. J. 2018, 15, 199–203.
[2]	Feldman, H.A.; Goldstein, I.; Hatzichristou, D.G.; Krane, R.J.; McKinlay, J.B. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994, 151, 54–61.
[3]	Corona, G.; Lee, D.M.; Forti, G.; O’Connor, D.B.; Maggi, M.; O’Neill, T.W.; Pendleton, N.; Bartfai, G.; Boonen, S.; Casanueva, F. F.et al. Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). J. Sex. Med. 2010, 7, 1362–1380.
[4]	Yafi, F.A.; Jenkins, L.; Albersen, M.; Corona, G.; Isidori, A.M.; Goldfarb, S.; Maggi, M.; Nelson, C.J.; Parish, S.; Salonia, A. Tan, R.; Mulhall, J.P.; Hellstrom, W.J. Erectile dysfunction. Nat. Rev. Dis. Primers. 2016, 2, 16003–16003.
[5]	Xinjiang Uygur Autonomous Region Food and Drug Administration, Ed. Urumqi, China, 1999.
[6]	AHMAT; Ouwulihan; Silafu; Nurnisa. Progress in Uyghur Pharmacy Research. Chin. J. Ethnomed. Ethnopharm. 2000, 325–326.
[7]	Reheman, A.; Gao, Z.Y.; Tursun, X.; Pu, X.P.; Wu, T.; He, F.; Zhao, X.; Aisa, H.A. Optimization of extraction technology of Majun mupakhi ela and its effect on hydrocortisone-induced kidney Yang deficiency in mice. Sci. Rep. 2019, 9, 4628.
[8]	Reheman, A.; Aisa, H.A.; Ma, Q.L.; Nijat, D.; Abdulla, R. Quality evaluation of the traditional medicine Majun mupakhi ELA via chromatographic fingerprinting coupled with UHPLC-DAD-quadrupole-orbitrap-MS and the antioxidant activity in vitro. Evid. Based Complement. Alternat. Med. 2018, 2018, 1035809.
[9]	Nan, Y.; Zhou, X.; Liu, Q.; Zhang, A.; Guan, Y.; Lin, S.; Kong, L.; Han, Y.; Wang, X. Serum metabolomics strategy for understanding pharmacological effects of ShenQi pill acting on kidney Yang deficiency syndrome. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2016, 1026, 217–226.
[10]	Tang, D.; Zhang, L.; Xiong, J.; Tan, Z. Experimental study on Yangkang capsule for prevention and treatment of impotence. Pharm. Clin. Chin. Materia Medica. 2016, 32, 176–179.
[11]	Tian, E.; Long, T.; D., Q. Establishment and applications of mating model in male rat. Chin. J. Androl. 2008, 22, 7–10.
[12]	Gajbhiye, S.V.; Jadhav, K.S.; Marathe, P.A.; Pawar, D.B. Animal models of erectile dysfunction. Indian J. Urol. 2015, 31, 15.
[13]	Davila, H.H.; Rajfer, J.; Gonzalez-Cadavid, N.F. Corporal veno-occlusive dysfunction in aging rats: evaluation by cavernosometry and cavernosography. Urology. 2004, 64, 1261–1266.
[14]	Elsakka, A. I.; Yen, T. B.; Lin, C. S.; Lue, T. F. Traumatic arteriogenic erectile dysfunction: a rat model. Int. J. Impot. Res. 2001, 13, 162–171.
[15]	Firoozi, F.; Longhurst, P.A.; White, M.D. In vivo and in vitro response of corpus cavernosum to phosphodiesterase-5 inhibition in the hypercholesterolaemic rabbit. BJU Int. 2005, 96, 164–168.
[16]	Merlin, S.L.; Brock, G.B.; Begin, L.R.; Hiou Tim, F.F.; Macramalla, A.N.; Seyam, R.M.; Shenouda, G.; Dion, S.B. New insights into the role of endothelin-1 in radiation-associated impotence. Int. J. Impot. Res. 2001, 13, 104–109.
[17]	Kimura, M.; Yan, H.; Rabbani, Z.; Satoh, T.; Baba, S.; Yin, F.F.; Polascik, T.J.; Donatucci, C.F.; Vujaskovic, Z.; Koontz, B. F. Radiation-Induced Erectile Dysfunction Using Prostate-Confined Modern Radiotherapy in a Rat Model. J. Sex. Med. 2011, 8, 2215–2226.
[18]	Azadzoi, K.M.; Master, T.A.; Siroky, M.B. Effect of chronic ischemia on constitutive and inducible nitric oxide synthase expression in erectile tissue. J. Androl. 2004, 25, 382–388.
[19]	Demir, O.; Murat, N.; Soner, B.C.; Demir, T.; Bal, E.; Can, E.T.; Gidener, S.; Esen, A.A. Acute effects of hypercholesterolemic diet on erectile responses in rats. Urol. Int. 2010, 85, 112–117.
[20]	Xie, D.; Odronic, S.I.; Wu, F.; Pippen, A.M.; Donatucci, C.F.; Annex, B.H. A Mouse Model of Hypercholesterolemia-Induced Erectile Dysfunction. J. Sex. Med. 2010, 4, 898–907.
[21]	Yang, R.; Wang, J., Y; Sun, Z.; Wang, R.; Dai, Y. Effect of caffeine on erectile function via up-regulating cavernous cyclic guanosine monophosphate in diabetic rats. J. Androl. 2008, 29, 586 –591.
[22]	Ma, Z.Q.; Hu, H.; He, T.T.; Guo, H.; Zhang, M.Y.; Chen, M.W.; Wang, Y.T. An assessment of traditional Uighur medicine in current Xinjiang region (China). Afr. J. Tradit. Complement. Altern Med. 2014, 11, 301–314.
[23]	Chinese Medical Encyclopedia Committee Chinese Medical Encyclopedia. Uyghur Medicine; Shanghai Science and Technology Press, 2005.
[24]	Makarova, M.N.; Pozharitskaya, O.N.; Shikov, A.N.; Tesakova, S.V.; Makarov, V.G.; Tikhonov, V.P. Effect of lipid-based suspension of Epimedium koreanum Nakai extract on sexual behavior in rats. J. Ethnopharmacol. 2007, 114, 412–416.
[25]	Qian, Z.Z.; Dan, Y.; Liu, Y.Z.; Peng, Y. Pharmacopoeia of the People’s Republic of China (2010 Edition): A Milestone in Development of China’s Healthcare. Chin. Herb. Med. 2010, 02, 157–160.
[26]	Chauhan, N.S.; Sharma, V.; Sharma, V.; Dixit, V.K.; Thakur, M. A review on plants used for improvement of sexual performance and virility. Biomed. Res. Int. 2014, 2014, 868062.
[27]	Ge, R.; Chen, G.; Hardy, M.P. The Role of the Leydig Cell in Spermatogenic Function. Adv. Exp. Med. Biol. 2008, 636, 255.
[28]	Gades, N.M.; Jacobson, D.J.; Mcgree, M.E.; Sauver, J.L.S.; Lieber, M.M.; Nehra, A.; Girman, C.J.; Klee, G.G.; Jacobsen, S.J. The Associations Between Serum Sex Hormones, Erectile Function, and Sex Drive: The Olmsted County Study of Urinary Symptoms and Health Status Among Men. J. Sex. Med. 2010, 5, 2209–2220.
[29]	Podlasek, C.A.; Mulhall, J.; Davies, K.; Wingard, C.J.; Hannan, J.L.; Bivalacqua, T.J.; Musicki, B.; Khera, M.; González-Cadavid, N.F. Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction. J. Sex. Med. 2016, 13, 1183–1198.
[30]	Chen, H.; Ge, R. S.; Zirkin, B.R. Leydig cells: From stem cells to aging. Mol. Cell Endocrinol. 2009, 306, 9–16.
[31]	Huang, Z.Q.; Fan, X.M.; Wang, Y.M.; Liang, Q.L.; Tong, X.L.; Bai, Y.; Li, Y.M.; Luo, G.A.; Chen, C. A new method to evaluate the dose-effect relationship of a TCM formula Gegen Qinlian Decoction: "Focus" mode of integrated biomarkers. Acta Pharmacol. Sin. 2017, 38, 1141–1149.

艾拉片对重复束缚应激所致勃起功能障碍小鼠的治疗作用

Ela tablets improve sexual performance in mice with erectile dysfunction caused by repeated restraint stress

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