| 论文简介 |
Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH)
targets smooth muscle contraction in the prostate, for which α1A-adrenoceptor (α1A-AR) antagonists have been
considered to be the primary therapeutic method. We investigated the effects and underlying mechanisms of
isocorynoxeine (ICN), one of indole alkaloids from Uncaria, on the treatment of LUTS secondary to BPH via α1AARs
in mice. The effect of ICN on prostatic contractility was studied via myographic measurements in the
prostates of rabbits. The effects of ICN on bladder function, serum-hormone levels, bladder histology, and
prostate histology were determined in testosterone propionate-induced prostatic hyperplasic wild-type (WT) and
α1A-AR knockout (α1A-KO) mice. The cytotoxicity of ICN in cultured human prostatic stromal cells (WPMY-1)
was assessed by the following: a cell-counting kit, measuring the relaxant effect on WPMY-1 by a collagen gel
contraction assay, intracellular Ca2+ mobilization indicated by Fluo-4, cytoskeletal organization by phalloidin
staining, and expressions of α1A-AR-mediated key messengers by western blot analyses. ICN non-competitively
antagonized the contractions of prostates induced by α1A-AR agonists. ICN treatment improved bladder functions
in prostatic hyperplasic WT mice, whereas it failed to ameliorate bladder functions in prostatic hyperplasic
α1A-KO mice. In WPMY-1, ICN relaxed cell contractions on collagen gels, disrupted F-actin organization, inhibited
α1A-AR agonist-stimulated Ca2+ mobilization, and antagonized α1A-ARs via the RhoA/ROCK2/MLC
signaling pathway. Our results suggest that ICN may be a promising therapeutic drug for targeting α1A-ARs in the
treatment of BPH/LUTS. |
(创新港)
