The Journal of Korean Obstetrics and Gynecology (대한한방부인과학회지)

The Society of Korean Medicine Obstetrics and Gynecology (대한한방부인과학회)
권호 표지
DOI QR코드

DOI QR Code

Analgesic Effects of Gyejibokryeong-hwan Aqueous Extracts on the Rat Model of Primary Dysmenorrhea

원발성 월경통에 대한 계지복령환(桂枝茯苓丸) 열수 추출물의 진통 효과

  • Cho, Su-Yun (Dept. of Korean Obstetrics ＆) ;
  • Kim, Dong-Chul ( Gynecology, College of Korean Medicine, Daegu Haany UniversityDept. of Korean Obstetrics ＆ Gynecology, College of Korean Medicine, Daegu Haany University)
  • 조수연 (대구한의대학교 한의과대학 부인과학교실) ;
  • 김동철 (대구한의대학교 한의과대학 부인과학교실)
  • Received : 2020.07.17
  • Accepted : 2020.08.28
  • Published : 2020.08.28
Download PDF
⟨ Previous Next ⟩

Abstract

Objectives: The objective of this in vivo study is to observe the analgesic effects or improvements of Gyejibokryeong-hwan aqueous extracts (GJBRHe) on the Primary dysmenorrhea (PD) in rats as compared to those of Indomethacin (IND). Methods: The rats were administered with estradiol benzoate for 10 days and oxytocin 1 hour after the last 10th administration of estradiol benzoate to make the primary dysmenorrhea rat model. Gyejibokryeong-hwan aqueous extracts 500, 250 and 125 mg/kg were orally administrated, for 10 days once a day. Then the changes on the body weights and gains during experimental periods, uterine weights and gross inspections, abdominal writhing response for analgesic activities, uterus lipid peroxidation (malondialdehyde (MDA) levels), antioxidant defense system - glutathione (GSH) contents, activities of superoxide dismutase (SOD) and catalase (CAT), Nuclear factor-κB (NF-κB) and Cyclooxygenase (COX)-2 mRNA expressions, were monitored with uterus histopathology and immunohistochemistry for tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). The results of Gyejibokryeong-hwan aqueous extracts were compared to those of Indomethacin adminstered rats. Results: As results of estradiol benzoate and oxytocin treatment, noticeable decreases of body weights and gains, uterus GSH contents, SOD and CAT activities, increases of abdominal writhing responses, uterus lipid peroxidation (MDA level), uterus weights, NF-κB and COX-2 mRNA expressions were observed with increases of TNF-α and iNOS immunolabeled cells, inflammatory cell infiltrations, congestion and enlargement of the uterus at gross and histopathological inspections. These means classic inflammatory and oxidative stress mediated primary dysmenorrhea are relatively well induced. However, these signs were favorably and dose-dependently inhibited by administration of three different dosages of Gyejibokryeong-hwan aqueous extracts, but lesser than those of Indomethacin. Conclusions: The results obtained in this study suggest that Gyejibokryeong-hwan aqueous extracts has favorable analgesic and refinement activities dose-dependently on the estradiol benzoate and oxytocin treatment-induced primary dysmenorrhea signs.

목 적: 이 생체 내 연구의 목적은 인도메타신과 비교했을 때 쥐의 원발성 월경통에 대한 계지 복령환 열수 추출물의 진통 및 개선 효과를 관찰하는 것이다. 방 법: 랫트 PD 모델을 만들기 위해, Estradiol benzoate를 10일간 투여한 다음 마지막 10회 estradiol benzoate 투여 1시간 후 1 U/kg의 oxytocin을 투여하였다. 계지복령환 열수 추출물을 500, 250 및 125 mg/kg 용량으로 매일 1회씩 10일간 투여하였다. 이후 체중 및 실험 기간 동안의 체중 증가량, 자궁 중량 및 육안부검 소견, 진통 활성을 나타내는 abdominal writhing test, 자궁 조직 내 지질 과산화(Malondialdehyde, MDA 함량) 및 항산화 방어 시스템 - glutathione (GSH) 함량, superoxide dismutase (SOD) 및 catalase (CAT) 활성, Nuclear factor-κB (NF-κB) 및 cyclooxygenase (COX)-2 mRNA의 발현, 자궁의 조직병리학적 변화, tumor necrosis factor (TNF)-α 및 inducible nitric oxide synthase (iNOS)로 나타나는 면역조직 화학적 변화를 관찰하였다. 계지복령환 열수 추출물의 결과는 인도메타신 투여 쥐의 결과와 비교하였다. 결 과: Estradiol benzoate 및 oxytocin 투여 결과, 현저한 체중 및 증체량, 자궁 GSH 함량, SOD와 CAT 활성의 감소와 abdominal writhing 반응, 자궁 지질 과산화(MDA 함량), 자궁 중량, NF-κB 및 COX-2 mRNA 발현의 증가가 TNF-α 및 iNOS 면역반응세포와 염증세포 침윤 증가, 자궁의 충혈 및 확대와 함께 관찰되었다. 이는 전형적인 염증 및 산화 스트레스성 원발성 월경통이 잘 유도되었음을 의미한다. 한편 이러한 소견은 계지복령환 열수 추출물의 투여에 의해 용량의존적으로 현저히 억제되었으며, 인도메타신의 억제 효과보다는 낮았다. 결 론: 이 연구에서 얻은 결과는 계지복령환 열수 추출물이 estradiol benzoate 및 oxytocin으로 유도된 원발성 월경통에 용량-의존적으로 유리한 진통 및 개선 활성을 가짐을 시사한다.

Keywords

References

  1. The Society of Korean Medicine Obstetrics and Gynecology. Korean Medicine Ostetrics & Gynecology (Ha). 3rd rev. ed. Seoul: Euiseongdang Publishing Co. 2016:99-116.
  2. Korean Society of Obstetrics and Gynecology. Gynecology. 5th rev. ed. Seoul:Korea Medical Book Publisher. 2015:129-32.
  3. Osuga Y, et al. Dysmenorrhea in Japanese women. Int J Gynaecol Obstet. 2005;88(1):82-3. https://doi.org/10.1016/j.ijgo.2004.09.004
  4. Proctor M, Farquhar C. Diagnosis and management of dysmenorrhoea. BMJ. 2006;332(7550):1134-8. https://doi.org/10.1136/bmj.332.7550.1134
  5. French L. Dysmenorrhea. Am Fam Physician. 2005;71(2):285-91.
  6. Marjoribanks J, et al. Nonsteroidal antiinflammatory drugs for dysmenorrhoea. Cochrane Database Syst Rev. 2015;(7):CD001751.
  7. Pickles VR. Prostaglandins and dysmenorrhea. Historical survey. Acta Obstet Gynecol Scand Suppl. 1979;87(S87):7-12. https://doi.org/10.3109/00016347909157782
  8. Garcia Rodriguez LA, et al. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med. 1994;154(3):311-6. https://doi.org/10.1001/archinte.1994.00420030117012
  9. Ungprasert P, et al. Individual nonsteroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015;26(4):285-91. https://doi.org/10.1016/j.ejim.2015.03.008
  10. Liang CM, et al. Risk of Recurrent Peptic Ulcer Disease in Patients Receiving Cumulative Defined Daily Dose of Nonsteroidal Anti-Inflammatory Drugs. J Clin Med. 2019;8(10):E1722.
  11. Kim JB. Geum-Gwe-Yo-Ryak-Byeon-Seok (金匱要略辨釋). 2nd rev. ed. Seoul: Han-Ui-Mun-Hwa-Sa(韓醫文化社). 2010:534-7.
  12. Guk YB, et al. Bang-Je-Hak(方劑學). 2nd rev. ed. Seoul:Yeong-Rim-Sa(永林社). 1999:409-10.
  13. Jang SB, et al. The Analysis of the Experimental Research Trend of Efficacy of Gyejibokryeong-hwan. J Korean Obstet Gynecol. 2016;29(2):99-112. https://doi.org/10.15204/jkobgy.2016.29.2.099
  14. Hu C, et al. Guizhi fuling capsule, an ancient Chinese formula, attenuates endometriosis in rats via induction of apoptosis. Climacteric. 2014;17(4):410-6. https://doi.org/10.3109/13697137.2013.876618
  15. Mori T, et al. Suppression of spontaneous development of uterine adenomyosis by a Chinese herbal medicine, keishibukuryo-gan, in mice. Planta Med. 1993;59(4):308-11. https://doi.org/10.1055/s-2006-959687
  16. Liu P, et al. Effects of xiang-fu-si-wu decoction and its main components for dysmenorrhea on uterus contraction. J Ethnopharmacol. 2011;133(2):591-7. https://doi.org/10.1016/j.jep.2010.10.042
  17. Park BK, et al. Antidepressant-like effects of Gyejibokryeong-hwan in a mouse model of reserpine-induced depression. Biomed Res Int. 2018;2018:5845491. https://doi.org/10.1155/2018/5845491
  18. Kim YS, et al. Effects of Polycan, a ${\beta}$-glucan, on experimental periodontitis and alveolar bone loss in Sprague-Dawley rats. J Periodontal Res. 2012;47(6):800-10. https://doi.org/10.1111/j.1600-0765.2012.01502.x
  19. Yang L, et al. Ge-Gen Decoction attenuates oxytocin-induced uterine contraction and writhing response: potential application in primary dysmenorrhea therapy. Chin J Nat Med. 2016;14(2):124-32. https://doi.org/10.1016/S1875-5364(16)60005-5
  20. Zhan C, Yang J. Protective effects of isoliquiritigenin in transient middle cerebral artery occlusion-induced focal cerebral ischemia in rats. Pharmacol Res. 2006;53(3):303-9. https://doi.org/10.1016/j.phrs.2005.12.008
  21. Jamall IS, Smith JC. Effects of cadmium treatment on selenium-dependent and selenium-independent glutathione peroxidase activities and lipid peroxidation in the kidney and liver of rats maintained on various levels of dietary selenium. Arch Toxicol. 1985;58(2):102-5. https://doi.org/10.1007/BF00348317
  22. Lowry OH, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75. https://doi.org/10.1016/S0021-9258(19)52451-6
  23. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem. 1968;25(1):192-205. https://doi.org/10.1016/0003-2697(68)90092-4
  24. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988;34(3):497-500. https://doi.org/10.1093/clinchem/34.3.497
  25. Ibrahim BS, et al. Beneficial effects of vitamin C treatment on pregnant rats exposed to formaldehyde: Reversal of immunosuppression in the offspring. Toxicol Appl Pharmacol. 2016;300:77-81. https://doi.org/10.1016/j.taap.2016.03.010
  26. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8. https://doi.org/10.1038/nprot.2008.73
  27. Chen Y, et al. Traditional Chinese medicine for the treatment of primary dysmenorrhea: how do Yuanhu painkillers effectively treat dysmenorrhea? Phytomedicine. 2013;20(12):1095-104. https://doi.org/10.1016/j.phymed.2013.05.003
  28. Lee CW, et al. Biomolecular evidence of anti-inflammatory effects by Clematis mandshurica Ruprecht root extract in rodent cells. J Ethnopharmacol. 2014;155(2):1141-55. https://doi.org/10.1016/j.jep.2014.06.048
  29. Choi JS, et al. Blood glycemia-modulating effects of melanian snail protein hydrolysates in mice with type II diabetes. Int J Mol Med. 2017;39(6):1437-51. https://doi.org/10.3892/ijmm.2017.2967
  30. Guliaeva NV, et al. The inhibition stage of lipid peroxidation during stress. Biull Eksp Biol Med. 1988;106(12):660-3.
  31. Dikensoy E, et al. Malondialdehyde, nitric oxide and adrenomedullin levels in patients with primary dysmenorrhea. J Obstet Gynaecol Res. 2008;34(6):1049-53. https://doi.org/10.1111/j.1447-0756.2008.00802.x
  32. Liao CH, Ho CT, Lin JK. Effects of garcinol on free radical generation and NO production in embryonic rat cortical neurons and astrocytes. Biochem Biophys Res Commun. 2005;329(4):1306-14. https://doi.org/10.1016/j.bbrc.2005.02.110
  33. Surh YJ, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 2001;480(1):243-68. https://doi.org/10.1016/S0027-5107(01)00183-X
  34. Goto H, et al. Effects of Keishi-bukuryo-gan on vascular function and hemorheological factors in spontaneously diabetic (WBN/kob) rats. Phytomedicine. 2004;11(2-3):188-95. https://doi.org/10.1078/0944-7113-00336
  35. Kim BJ, et al. A water-extract of the Korean traditional formulation Geiji-Bokryung-Hwan reduces atherosclerosis and hypercholesteremia in cholesterol-fed rabbits. Int Immunopharmacol. 2003;3(5):723-34. https://doi.org/10.1016/S1567-5769(03)00073-0
  36. Li TJ, et al. Protective effects of Guizhi-Fuling-Capsules on rat brain ischemia/reperfusion injury. J Pharmacol Sci. 2007;105(1):34-40. https://doi.org/10.1254/jphs.FP0070450
  37. Yao Z, Shulan Z. Inhibition effect of Guizhi-Fuling-decoction on the invasion of human cervical cancer. J Ethnopharmacol. 2008;120(1):25-35. https://doi.org/10.1016/j.jep.2008.07.044
  38. Park WH, et al. Tumor initiation inhibition through inhibition COX-1 activity of a traditional Korean herbal prescription, Geiji-Bokryung-Hwan, in human hepatocarcinoma cells. Immunopharmacol Immunotoxicol. 2005;27(3):473-83. https://doi.org/10.1080/08923970500241311
  39. Lee MY, et al. The genotoxicity of an aqueous extract of Gyejibokryeong-hwan. BMC Complement Altern Med. 2018;18(1):21. https://doi.org/10.1186/s12906-017-2054-z
  40. Jin SE, et al. Sub-chronic toxicity of Gyejibokryeong-hwan in Sprague-Dawley rats. J Ethnopharmacol. 2018;224:441-50. https://doi.org/10.1016/j.jep.2018.06.017
  41. Cheng Y, et al. Pharmacokineticpharmacodynamic modeling to study the anti-dysmenorrhea effect of Guizhi Fuling capsule on primary dysmenorrhea rats. Phytomedicine. 2018;48:141-51. https://doi.org/10.1016/j.phymed.2018.04.041
  42. Lang L, et al. Intergrated metabonomic study of the effects of Guizhi Fuling capsule intervention on primary dysmenorrheal using RP-UPLC-MS complementary with HILIC-UPLC-MS technique. Biomed Chromatogr. 2018;32(2):e4093. https://doi.org/10.1002/bmc.4093
  43. Xiong Z, et al. An integrative urinary metabolomic study of the therapeutic effect of Guizhi Fuling capsule on primary dysmenorrheal rats based 1H NMR and UPLC-MS. J Pharm Biomed Anal. 2019;164:750-8. https://doi.org/10.1016/j.jpba.2018.11.039
  44. Sun L, et al. Traditional Chinese medicine Guizhi Fuling capsule used for therapy of dysmenorrhea via attenuating uterus contraction. J Ethnopharmacol. 2016;191:273-9. https://doi.org/10.1016/j.jep.2016.06.042
  45. Asarian L, Geary N. Modulation of appetite by gonadal steroid hormones. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1251-63. https://doi.org/10.1098/rstb.2006.1860
  46. Kaplan O, et al. Non-steroidal antiinflammatory drug modulates oxidative stress and calcium ion levels in the neutrophils of patients with primary dysmenorrhea. J Reprod Immunol. 2013;100(2):87-92. https://doi.org/10.1016/j.jri.2013.10.004
  47. Videla LA. Energy metabolism, thyroid calorigenesis, and oxidative stress: functional and cytotoxic consequences. Redox Rep. 2000;5(5):265-75. https://doi.org/10.1179/135100000101535807
  48. Messarah M, et al. Influence of thyroid dysfunction on liver lipid peroxidation and antioxidant status in experimental rats. Exp Toxicol Pathol. 2010;62(3):301-10. https://doi.org/10.1016/j.etp.2009.04.009
  49. Odabasoglu F, et al. Gastroprotective and antioxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol. 2006;103(1):59-65. https://doi.org/10.1016/j.jep.2005.06.043
  50. Cheeseman KH, Slater TF. An introduction to free radical biochemistry. Br Med Bull. 1993;49(3):481-93. https://doi.org/10.1093/oxfordjournals.bmb.a072625
  51. Isaacs A. Lymphokines and Cytokines. In: Immunology an introduction (Tizard IR editor). 4th edition. Saunders: Philadelphia. 1995:155-69.
  52. Szabo C. Alterations in nitric oxide production in various forms of circulatory shock. New Horiz. 1995;3(1):2-32.