Correlation between Cholinergic Innervation, Autophagy, and Etiopathology of Benign Prostatic Hyperplasia

Abstract

Background: Whether cholinergic innervations and/or autophagy have a role in the etiopathology of benign prostatic hyperplasia (BPH) is still unknown. This study aimed to investigate the role of cholinergic innervation and autophagy in the etiopathology of BPH. Methods: Male, 13-week-old spontaneous hypertension rats (spontaneous BPH animal model) were divided into three groups: an experimental group (EG, n = 24), a control group (CG, n = 24), and a normal control group (NC, n = 10). The EG animals were intragastrically injected with tolterodine (3.5 mg/kg, twice a day), CG animals were intragastrically injected with physiological saline, and the NC animals did not receive any treatment. Rats were sacrificed every 4 weeks, and the prostatic gross morphological changes, wet weight/body weight (ww/bw), dry weight/wet weight (dw/ww), histological changes, ultrastructural changes, and LC3 immunohistochemistry were continuously observed and compared. Results: The gross morphological and ww/bw changes in the three groups were similar at every stage. The dw/ww (mg/mg) values of the EG at week 17, 21, 25, and 29 were 0.1478 ± 0.0034, 0.1653 ± 0.0036, 0.1668 ± 0.0045, and 0.1755 ± 0.0034, respectively, and the CG values were 0.1511 ± 0.0029, 0.1734 ± 0.0020, 0.1837 ± 0.0052, and 0.1968 ± 0.0045, respectively. The difference between EG and CG for dw/ww showed statistical significance after 21 weeks of age (week 21: P= 0.016, week 25: P= 0.008, and week 29: P= 0.001). Both EG and CG, prostatic glandular epithelial cell proliferation, and secretory function improved with age, but in EG, these improvements were slower than those in CG, and all the differences were statistically significant after 21 weeks. An increasing number of autophagosomes in the prostatic glandular cell cytoplasm, attenuation of LC3-I immunohistochemical staining, enhancement of LC3-II staining, and the ratio of LC3-II/LC3-I staining were all progressive in both groups, but the rate of change in EG was faster than that in CG, and these differences gained statistical significance after 25 weeks. Comparisons with regard to the above indexes between CG and NC showed no statistical significance at any stage. Conclusions: Cholinergic innervations and activation of autophagy appear to have important functions in the etiopathology of BPH. Drug-mediated blockade of cholinergic innervations could delay the physiopathology processes. Moreover, overactivation of autophagy may also play an important role in this delay.

Keywords

• Autophagy; Cholinergic Innervation; Denervation; Etiopathology; Prostatic Hyperplasia