Abstract
Eviprostat is a popular phytotherapeutic agent for the treatment of lower urinary tract symptoms (LUTS). At present, the signaling mechanisms underlying its therapeutic effects are still poorly understood. Given that cAMP has been reported to suppress cell hyperplasia and hypertrophy in various pathological situations, we asked whether the effect of Eviprostat could be ascribed to the activation of the cAMP signaling pathway. In the study, exposure of cAMP response element (CRE)-secreted alkaline phosphatase (SEAP) (CRE-SEAP)-reporter cells to Eviprostat elevated SEAP secretion, which was associated with an increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and cAMP-response element-binding protein (CREB), as well as enhanced expression of CRE-regulated protein connexin43, indicating an activation of the cAMP signaling pathway. Consistent with these observations, Eviprostat-induced expression of Cx43 was abolished in the presence of adenylyl cyclase inhibitor SQ22536 or PKA inhibitor H89, whereas it was mimicked by adenylyl cyclase activator, forskolin. Further analysis demonstrated that Eviprostat significantly potentiated the effect of phosphodiesterase 3 (PDE3) inhibitor, but not that of PDE4 inhibitor, on CRE activation. Moreover, Eviprostat suppressed PDGF-induced activation of ERK and Akt and inhibited cell proliferation and hillock formation in both mesangial cells and bladder smooth muscle cells. Collectively, activation of the cAMP signaling pathway could be an important mechanism by which Eviprostat exerts its therapeutic effects for LUTS.
Highlights
Benign prostatic hyperplasia (BPH) is a common disease in older men, frequently accompanied by prostatic inflammation [1,2]
Because of the similarity between the effects of cAMP and those of Eviprostat on various cellular processes [5,6,15], we tested the possible activation of cAMP signaling pathway by Eviprostat
We have used a well-characterized cAMP response element (CRE)-secreted alkaline phosphatase (SEAP) (CRE-SEAP)-based reporting system [16,17,18], in which reporter mesangial cells were stably transfected with a vector encoding the reporter gene secretory alkaline phosphatase under the control of CRE
Summary
Benign prostatic hyperplasia (BPH) is a common disease in older men, frequently accompanied by prostatic inflammation [1,2]. It has been reported that prostatic inflammation plays a role in the induction and progression of BPH. BPH leads to bladder outlet obstruction (BOO), which is associated with obvious changes in bladder structure and function characterized by lower urinary tract symptoms (LUTS), such as urinary frequency and urgency. Eviprostat, a plant extract, has widely been used clinically for the treatment of BPH and LUTS in Germany and Japan. Eviprostat consists of five components: extracts from Chimaphila umbellata, Populus tremula, Pulsatilla pratensis and Equisetum arvense and germ oil from Triticum aestivum. Previous studies have revealed that Eviprostat improved voiding function in LUTS patients and exerted anti-inflammatory and anti-oxidative effects in both clinical and basic experiments [3,4]
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