title: Argirein alleviates stress-induced and diabetic hypogonadism in rats via normalizing testis endothelin receptor A and connexin 43.
abstract: OBJECTIVE
  Argirein (rhein-arginine) is a derivative of rhein isolated from Chinese rhubarb (Rheum Officinale Baill.) that exhibits antioxidant and anti-inflammatory activities. In the present study we investigated the effects of argirein on stress-induced (hypergonadotrophic) and diabetic (hypogonadotrophic) hypogonadism in male rats.
  
  
  METHODS
  Stress-induced and diabetic hypogonadism was induced in male rats via injection of isoproterenol (ISO) or streptozotocin (STZ). ISO-injected rats were treated with argirein (30 mg·kg(-1)·d(-1), po) or testosterone replacement (0.5 mg·kg(-1)·d(-1), sc) for 5 days, and STZ-injected rats were treated with argirein (40-120 mg·kg(-1)·d(-1), po) or aminoguanidine (100 mg·kg(-1)·d(-1), po) for 4 weeks. After the rats were euthanized, blood samples and testes were collected. Serum hormone levels were measured, and the expression of endothelin receptor A (ETA), connexin 43 (Cx43) and other proteins in testes was detected. For in vitro experiments, testis homogenate was prepared from normal male rats, and incubated with ISO (1 μmol/L) or high glucose (27 mmol/L).
  
  
  RESULTS
  ISO injection induced hyper-gonadotrophic hypogonadism characterized by low testosterone and high FSH and LH levels in the serum, whereas STZ injection induced hypogonadotrophic hypogonadism as evidenced by low testosterone and low FSH and LH levels in the serum. In the testes of ISO- and STZ-injected rats, the expression of ETA, MMP-9, NADPH oxidase and pPKCε was significantly increased, and the expression of Cx43 was decreased. Administration of argirein attenuated both the abnormal serum hormone levels and the testis changes in ISO- and STZ-injected rats, and aminoguanidine produced similar actions in STZ-injected rats; testosterone replacement reversed the abnormal serum hormone levels, but did not affect the testis changes in ISO-injected rats. Argirein (0.3-3 μmol/L) exerted similar effects in testis homogenate incubated with ISO or high glucose in vitro.
  
  
  CONCLUSIONS
  Two types of hypogonadism of male rats exhibit increased expression of ETA and depressed expression of Cx43 in testes, despite different patterns of serum FSH and LH. Argirein alleviates the two types of male hypogonadism via normalizing ETA and Cx43 in testes.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.|Department of Pharmacology, University of Adam, Yemen.
authors.forename: Hussein-hamed
authors.initials: HH
authors.lastname: Khan
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.|Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Fang-hong
authors.initials: FH
authors.lastname: Shi
authors.affiliation: Zhejiang University of Traditional Medicine, Hangzhou 311401, China.
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Cong
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: De-zai
authors.initials: DZ
authors.lastname: Dai
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000627:therapeutic use*; D001120:Arginine / Q000737:chemistry / Q000627:therapeutic use*; D018031:Connexin 43 / Q000032:analysis / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000627:therapeutic use*; D007006:Hypogonadism / Q000097:blood / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D007545:Isoproterenol; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000032:analysis / Q000378:metabolism*; D012250:Rheum / Q000737:chemistry; D013311:Streptozocin; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood
chemical_list: D000880:Anthraquinones; D018031:Connexin 43; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D044022:Receptor, Endothelin A; C576350:argirein; D013739:Testosterone; D013311:Streptozocin; D001120:Arginine; D007545:Isoproterenol