葛根异黄酮对大鼠前列腺增生的抑制作用
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摘要
目的探讨葛根异黄酮对丙酸睾酮诱发大鼠前列腺增生的抑制作用及其可能机制。方法雄性Wistar大鼠48只按体质量随机分成6组,分别为正常对照组,模型组,葛根异黄酮高、中、低剂量组,非那雄胺阳性对照组。除正常对照组做假手术外,其他5组做去势手术,待恢复后5组大鼠均以丙酸睾酮(10 mg·kg~(-1)·d~(-1))皮下注射10 d建立前列腺增生模型,然后每2d皮下注射1次。葛根异黄酮高,中,低剂量组于造模第2天灌胃给药(40,80,160 mg·kg~(-1)·d~(-1)),阳性对照组灌胃非那雄胺(1. 0 mg·kg~(-1)·d~(-1)),正常组和模型组均给予等量生理盐水,持续给药28 d。末次给药后麻醉,分离前列腺和精囊腺组织,称量其湿重和体积,并计算前列腺和精囊腺指数;取血,测量血清中双氢睾酮(DHT)和雌二醇(E2)含量;测量前列腺组织中一氧化氮(NO)、一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)和丙二醛(MDA)水平;各组随机取前列腺组织做HE染色,光学显微镜下观察前列腺组织病理结构变化。结果与正常对照组比较,模型组大鼠前列腺和精囊腺指数明显升高、体积增大(P <0. 01),大鼠血清DHT、E2水平明显升高(P <0. 01),大鼠组织中MDA含量升高而NO水平、NOS和SOD活性明显降低(P <0. 01),HE染色显示,模型组大鼠前列腺腺腔大小不一致,有明显的扩张和增生,腔内充满粉色浓染均质状物,有乳头状突起,间质可见明显的血管扩张充血、炎性细胞浸润和纤维结缔组织增生。与模型组比较,葛根异黄酮各剂量组和阳性对照组前列腺和精囊腺指数和体积均明显降低(P <0. 05或P <0. 01),葛根异黄酮中、高剂量组大鼠血清DHT和E2水平均明显降低(P <0. 05或P <0. 01),各治疗组除葛根异黄酮低剂量组,MDA含量降低而NO、NOS以及SOD水平升高(P <0. 05或P <0. 01),HE染色葛根异黄酮低剂量组中度增生,阳性对照组和葛根异黄酮中剂量组前列腺组织轻度增生,葛根异黄酮高剂量组基本无增生。结论葛根异黄酮对丙酸睾酮所致的大鼠前列腺增生具有一定的抑制作用,尤以中、高剂量组效果明显。其机制可能与葛根异黄酮抗氧化、清除体内自由基、增加NOS的活性、提高NO水平等作用有关。
OBJECTIVE To investigate the inhibitory effect and possible mechanisms of puerariae isoflavone( PI) on prostatic hyperplasia induced by testosterone propionate. METHODS Forty-eight male Wistar rats were randomly divided into six groups according to their body weight including normal control group,model group,40,80,160 mg·kg~(-1)·d~(-1) PI group,and finasteride positive control group. In addition to the sham operation for rats in the normal control group,the rats in other five groups performed castration surgery. After the restoration,the five groups of rats were subcutaneously injected with testosterone propionate( 10 mg·kg~(-1)·d~(-1))for 10 d to establish a benign prostatic hyperplasia model and then the subcutaneous injection was maintained every 2 d. High,middle and low dose PI groups were intragastrically administered( 40,80,160 mg·kg~(-1)·d~(-1)) from the second day when the benign prostatic hyperplasia model was successfully constructed. The positive control group was given finasteride( 1. 0 mg·kg~(-1)·d~(-1)). Rats in normal and model groups were given an equal volume of saline for 28 d. After the last administration,the prostate and seminal vesicles were separated under anesthesia in rats,the wet weight and volume of the prostate and seminal vesicles were measured. The prostate and seminal vesicles index were calculated too. Rat blood was drawn and dihydrotestosterone( DHT) and estradiol( E2) in the serum were measured. Nitric oxide( NO),nitric oxide synthase( NOS),superoxide dismutase( SOD) and malondialdehyde( MDA) levelsin prostate tissues were measured. The prostate tissue in each group was randomly selected for HE staining. The pathological structure of the prostate tissue was observed under an optical microscope. RESULTS Compared with the normal control group,the prostate gland index and seminal vesicle gland index of the model group increased significantly( P < 0. 01),and the DHT and E2 levels in serum increased significantly( P < 0. 01). MDA content was increased while NO levels,NOS and SOD activities were significantly decreased( P < 0. 01). HE staining showed that the size of the prostate gland in the model group was different,there were obvious dilation,hyperplasia and papillary protrusions,and the cavity was full of pink and homogeneous density. The interstitial tissue showed obvious dilations of blood vessels,infiltration of inflammatory cells,and proliferation of fibrous connective tissues. Compared with the model group,the index and volume of prostate and seminal vesicles in the PI and positive control groups were significantly decreased( P < 0. 05 or P < 0. 01),and the levels of serum DHT and E2 in the middle and high doses PI groups were significantly lower( P < 0. 05 or P < 0. 01).In all treatment groups,MDA content was decreased and NO,NOS,and SOD levels were increased( P < 0. 05 or P < 0. 01) except the low-dose PI groups. There was moderately hyperplasia in low-dose PI group,mild prostatic hyperplasia in positive control group and middle-dose PI group,basically no hyperplasia in high-dose PI group. CONCLUSION PI has a certain inhibitory effect on prostate hyperplasia induced by testosterone propionate,especially in the medium and high dose PI groups. The mechanism may be related to the effects of pueraria isoflavone on antioxidant,free radical scavenging in vivo,increasing NOS activity and increasing NO level.
OBJECTIVE To investigate the inhibitory effect and possible mechanisms of puerariae isoflavone( PI) on prostatic hyperplasia induced by testosterone propionate. METHODS Forty-eight male Wistar rats were randomly divided into six groups according to their body weight including normal control group,model group,40,80,160 mg·kg~(-1)·d~(-1) PI group,and finasteride positive control group. In addition to the sham operation for rats in the normal control group,the rats in other five groups performed castration surgery. After the restoration,the five groups of rats were subcutaneously injected with testosterone propionate( 10 mg·kg~(-1)·d~(-1))for 10 d to establish a benign prostatic hyperplasia model and then the subcutaneous injection was maintained every 2 d. High,middle and low dose PI groups were intragastrically administered( 40,80,160 mg·kg~(-1)·d~(-1)) from the second day when the benign prostatic hyperplasia model was successfully constructed. The positive control group was given finasteride( 1. 0 mg·kg~(-1)·d~(-1)). Rats in normal and model groups were given an equal volume of saline for 28 d. After the last administration,the prostate and seminal vesicles were separated under anesthesia in rats,the wet weight and volume of the prostate and seminal vesicles were measured. The prostate and seminal vesicles index were calculated too. Rat blood was drawn and dihydrotestosterone( DHT) and estradiol( E2) in the serum were measured. Nitric oxide( NO),nitric oxide synthase( NOS),superoxide dismutase( SOD) and malondialdehyde( MDA) levelsin prostate tissues were measured. The prostate tissue in each group was randomly selected for HE staining. The pathological structure of the prostate tissue was observed under an optical microscope. RESULTS Compared with the normal control group,the prostate gland index and seminal vesicle gland index of the model group increased significantly( P < 0. 01),and the DHT and E2 levels in serum increased significantly( P < 0. 01). MDA content was increased while NO levels,NOS and SOD activities were significantly decreased( P < 0. 01). HE staining showed that the size of the prostate gland in the model group was different,there were obvious dilation,hyperplasia and papillary protrusions,and the cavity was full of pink and homogeneous density. The interstitial tissue showed obvious dilations of blood vessels,infiltration of inflammatory cells,and proliferation of fibrous connective tissues. Compared with the model group,the index and volume of prostate and seminal vesicles in the PI and positive control groups were significantly decreased( P < 0. 05 or P < 0. 01),and the levels of serum DHT and E2 in the middle and high doses PI groups were significantly lower( P < 0. 05 or P < 0. 01).In all treatment groups,MDA content was decreased and NO,NOS,and SOD levels were increased( P < 0. 05 or P < 0. 01) except the low-dose PI groups. There was moderately hyperplasia in low-dose PI group,mild prostatic hyperplasia in positive control group and middle-dose PI group,basically no hyperplasia in high-dose PI group. CONCLUSION PI has a certain inhibitory effect on prostate hyperplasia induced by testosterone propionate,especially in the medium and high dose PI groups. The mechanism may be related to the effects of pueraria isoflavone on antioxidant,free radical scavenging in vivo,increasing NOS activity and increasing NO level.
引文
[1]ZHOU J T,LI W F.Observation of curative effect of finasteride and point shenque application in the treatment of elderly male patients with benign prostatic hyperplasia[J].Clin J Tradit Chin Med(中医药临床),2017,29(11):1898-1900.
[2]WANG Y,YUAN J Q.Clinic effect of four drugs for treating benign prostatic hyperplasia[J].Chin Pharm Aff(中国药事),2003,17(8):525-526.
[3]CHENG Z H,LIU D L.A cross-sectional study on the medication compliance and its influence factors in elderly patients with benign prostatic hyperplasia[J].J Bengbu Med Coll(蚌埠医学院学报),2017,42(3):405-408.
[4]UNNIKRISHNAN R,ALMASSI N,FAREED K.Benign prostatic hyperplasia:evaluation and medical management in primary care[J].Cleve Clin J Med,2017,84(1):53-61.
[5]GAO J,CHENG J H.Research status of pueraria and pueraria isoflavone[J].Anim Husb Feed Sci(畜牧与饲料科学),2013,34(6):44-45.
[6]RONG L,LI C Z,WANG A Q,et al.Literature analysis of research progress on pueratia lobata from 2007 to 2012 in China[J].Pop Sci Technol(大众科技),2014,16(173):80-83.
[7]CHENG S Q,ZHAO L J,YU Q Y,et al.The influence of puerariae isoflavones on benign prostatic hyperplasia in emasculated rat[J].J Jilin Med Univ(吉林医药学院学报),2014,35(1):17-20.
[8]DU L F,CHEN J L.Study on the protective mechanism of flavoxate on prostatic hyperplasia in model rats[J].J China Pharm(中国药房),2016,27(31):4357-4359.
[9]ZHANG Y J,HOU J M,LUO X N,et al.Effects of yishen huoxue granules on benign prostatic hyperplasia related to caspase-3and b FGF expressions in rats caspase-3[J].Chin Tradit Pat Med(中成药),2017,39(5):906-911.
[10]DU C C,SONG L M,HU M,et al.Association between prostate volume and serum levels of androgen and estrogen[J].Chin Gen Pract(中国全科医学),2011,14(1B):159-163.
[11]XU X L,ZHAO R N,NIE L H,et al.Establishment of a model of prostate hyperplasia induced by testosterone propionate in ovariectomized rats[J].J Ningxia Med Univ(宁夏医科大学学报),2017,39(3):256-259.
[12]RIPPLE M O,HENRY W F,RAGO R P,et al.Prooxidant-antioxdant shift induced by androgen treatment of human prostate carcinoma cells[J].J Natl Cancer Lnst,1997,89(1):40-48.
[13]KOLASA A,MARCHLEWICZ M,ADLER G,et al.Expression of E.Sod,GPX5 mRNAs and immunoexpression of Cu/ZnSOD in epididymal epithelialcells of finasteridel-treated rats[J].Andrologia,2008,40(5):303-311.
[14]AO M,XIONG Y,LIU J.Pharmacological effects of huatian capsule on SOD and MDA in rat with prostatic hyperplasia[J].JChina Pharm(中国药房),2014,23(23):4-5.
[15]KANG L B.The change of nitric oxide and nitric oxide synthase in prostatic tissue in the grown and old rats[J].J Mod Med Health(现代医药卫生),2005,21(21):2885-2886.
[16]YANG A Q,REN G F,TANG L,et al.Effects of soy bean isoflavone on inhibition of benign prostatic hyperplasia and the expressions of NO and NOS of rats[J].J Hyg Res(卫生研究),2009,38(2):172-174.
[17]LIU Y Q,SHI B K,XU Z S,et al.Detection of nitric oxide synthase activity in benign prostatic hyperplasia[J].Chin J Geriatr(中华老年医学杂志),2002,21(6):458-459.
[2]WANG Y,YUAN J Q.Clinic effect of four drugs for treating benign prostatic hyperplasia[J].Chin Pharm Aff(中国药事),2003,17(8):525-526.
[3]CHENG Z H,LIU D L.A cross-sectional study on the medication compliance and its influence factors in elderly patients with benign prostatic hyperplasia[J].J Bengbu Med Coll(蚌埠医学院学报),2017,42(3):405-408.
[4]UNNIKRISHNAN R,ALMASSI N,FAREED K.Benign prostatic hyperplasia:evaluation and medical management in primary care[J].Cleve Clin J Med,2017,84(1):53-61.
[5]GAO J,CHENG J H.Research status of pueraria and pueraria isoflavone[J].Anim Husb Feed Sci(畜牧与饲料科学),2013,34(6):44-45.
[6]RONG L,LI C Z,WANG A Q,et al.Literature analysis of research progress on pueratia lobata from 2007 to 2012 in China[J].Pop Sci Technol(大众科技),2014,16(173):80-83.
[7]CHENG S Q,ZHAO L J,YU Q Y,et al.The influence of puerariae isoflavones on benign prostatic hyperplasia in emasculated rat[J].J Jilin Med Univ(吉林医药学院学报),2014,35(1):17-20.
[8]DU L F,CHEN J L.Study on the protective mechanism of flavoxate on prostatic hyperplasia in model rats[J].J China Pharm(中国药房),2016,27(31):4357-4359.
[9]ZHANG Y J,HOU J M,LUO X N,et al.Effects of yishen huoxue granules on benign prostatic hyperplasia related to caspase-3and b FGF expressions in rats caspase-3[J].Chin Tradit Pat Med(中成药),2017,39(5):906-911.
[10]DU C C,SONG L M,HU M,et al.Association between prostate volume and serum levels of androgen and estrogen[J].Chin Gen Pract(中国全科医学),2011,14(1B):159-163.
[11]XU X L,ZHAO R N,NIE L H,et al.Establishment of a model of prostate hyperplasia induced by testosterone propionate in ovariectomized rats[J].J Ningxia Med Univ(宁夏医科大学学报),2017,39(3):256-259.
[12]RIPPLE M O,HENRY W F,RAGO R P,et al.Prooxidant-antioxdant shift induced by androgen treatment of human prostate carcinoma cells[J].J Natl Cancer Lnst,1997,89(1):40-48.
[13]KOLASA A,MARCHLEWICZ M,ADLER G,et al.Expression of E.Sod,GPX5 mRNAs and immunoexpression of Cu/ZnSOD in epididymal epithelialcells of finasteridel-treated rats[J].Andrologia,2008,40(5):303-311.
[14]AO M,XIONG Y,LIU J.Pharmacological effects of huatian capsule on SOD and MDA in rat with prostatic hyperplasia[J].JChina Pharm(中国药房),2014,23(23):4-5.
[15]KANG L B.The change of nitric oxide and nitric oxide synthase in prostatic tissue in the grown and old rats[J].J Mod Med Health(现代医药卫生),2005,21(21):2885-2886.
[16]YANG A Q,REN G F,TANG L,et al.Effects of soy bean isoflavone on inhibition of benign prostatic hyperplasia and the expressions of NO and NOS of rats[J].J Hyg Res(卫生研究),2009,38(2):172-174.
[17]LIU Y Q,SHI B K,XU Z S,et al.Detection of nitric oxide synthase activity in benign prostatic hyperplasia[J].Chin J Geriatr(中华老年医学杂志),2002,21(6):458-459.
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