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Protective effect of DA-9401 in finasteride-induced apoptosis in rat testis: inositol requiring kinase 1 and c-Jun N-terminal kinase pathway

Soni, KK1; Shin, YS1Choi, BR1; Karna, KK1; Kim, HK2; Chae, MR3; Lee, SW3; Kim, CY4; Yang, SK5; Park, KS6; Park, JK1

1: Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Clinical Trial Center of Medical Device of Chonbuk National University, Jeonju, Korea.; 2: College of Pharmacy, Kyungsung University, Busan, Korea.; 3: Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University Medical School, Samsung Medical Center, Seoul, Republic of Korea.; 4: College of Pharmacy, Hangyang University, Ansan , Republic of Korea.; 5: Department of Urology, College of Medicine, Konkuk University Chungju Hospital,Chungju, Republic of Korea.; 6: Department of Urology, Chonnam National University Medical School, Gwangju, Republic of Korea.

Objective: This study using Sprague-Dawley rats investigated the toxicity of finasteride and recovery by DA-9401.

Material and Method: Forty adult male Sprague-Dawley rats were assigned into four groups: control (CTR), finasteride 1 mg/kg/day (F), finasteride 1 mg/kg + DA-9401 100 mg/kg/day (F + DA 100), finasteride 1 mg/kg + DA-9401 200 mg/kg/day (F + DA 200). Treatments were by oral delivery once daily for consecutive 90 days. The gross anatomical parameters assessed including genital organ weight, vas deferens, sperm count and sperm motility, testosterone and dihydrotestosterone (DHT) and malondialdehyde (MDA) levels, histological and terminal deoxynucleotidyl transferase enzyme mediated dUTP nick end labeling (TUNEL) staining of testis for spermatogenic cell density, Johnsen’s score and apoptosis were analyzed. Testicular tissue was also used for endoplasmic reticulum (ER) stress and apoptotic proteins.

Result: Epididymis weight, seminal vesicle weight, prostate weight, penile weight and vas deferens sperm motility showed significant differences between the F group and the F and CTR, F + DA 100 and F + DA 200 groups. Testosterone level did not significantly change. DHT decreased significantly in the F group compared with the CTR group. Testis tissue revealed significant changes in spermatogenic cell density, Johnsen’s score and apoptotic index. Western blot showed significant changes in ER stress and apoptotic markers.

Conclusion: Finasteride showed reduced fertility and increased ER stress and apoptotic markers, which were recovered by administration of DA-9401 in the Sprague-Dawley rats.

Disclosure:

Work supported by industry: yes, by This study was supported by grants from the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare, & Family Affairs, Republic of Korea (HI14C0018). The Korean Healthcare Technology R&D Project, Ministry for Health, Welfar (industry funding only - investigator initiated and executed study).

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