Effects of isocorynoxeine, from Uncaria, on lower urinary tract dysfunction caused by benign prostatic hyperplasia via antagonism of α1A-adrenoceptors

Abstract

Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, for which α_1A-adrenoceptor (α_1A-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 α_1A-ARs 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 α_1A-AR knockout (α_1A-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 α_1A-AR-mediated key messengers by western blot analyses. ICN non-competitively antagonized the contractions of prostates induced by α_1A-AR agonists. ICN treatment improved bladder functions in prostatic hyperplasic WT mice, whereas it failed to ameliorate bladder functions in prostatic hyperplasic α_1A-KO mice. In WPMY-1, ICN relaxed cell contractions on collagen gels, disrupted F-actin organization, inhibited α_1A-AR agonist-stimulated Ca²⁺ mobilization, and antagonized α_1A-ARs via the RhoA/ROCK2/MLC signaling pathway. Our results suggest that ICN may be a promising therapeutic drug for targeting α_1A-ARs in the treatment of BPH/LUTS.

Keywords: Benign prostatic hyperplasia; Isocorynoxeine; Lower urinary tract symptoms; α(1A)-Adrenoceptor.