Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle

Abstract

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.

Serum anandamide and lipids associated with linoleic acid can distinguish interstitial cystitis/bladder pain syndrome from overactive bladder: An exploratory study

“…Contrastingly, in animal studies using rats with obstruction‐induced detrusor overactivity, the expression of CB1 increased in the urothelium, detrusor, and spinal cord; however, that of CB2 did not change 31,32 . Metabolic OAB is another subtype of OAB, 33 in which the proinflammatory status may be related to the presentation of OAB symptoms as shown in the animal model of fructose‐fed rats 34 . In this OAB model, the expressions of CB1 and CB2 protein and messenger ribonucleic acid were decreased 35 .…”

“…31,32 Metabolic OAB is another subtype of OAB, 33 in which the proinflammatory status may be related to the presentation of OAB symptoms as shown in the animal model of fructose-fed rats. 34 In this OAB model, the expressions of CB1 and CB2…”

Sea cucumber peptides positively regulate sexual hormones in male mice with acute exhaustive swimming: possibly through the Ca2+/PKA signaling pathway

“…In the cAMP signaling pathway, the metabolites of succinate and lactate could activate the coagulation factor II (thrombin) receptor (GPCR), resulting in the inhibition of cAMP. 28,29 However, the expression of these two metabolites was decreased by SCPH administration. Notably, SCPH significantly upregulated DAG expression, which was related to the sex hormone regulation pathway including the estrogen signaling pathway, calcium signaling pathway, cAMP signaling pathway, and MAPK signaling pathway.…”

The impact of diabetes on overactive bladder presentations and associations with health-seeking behavior in China, South Korea, and Taiwan: Results from a cross-sectional, population-based study

“…15,16 Diabetes is a group of metabolic diseases characterized by persistent hyperglycemia majorly caused by insulin resistance. In the early stage of DBD, the pathophysiology of OAB syndrome may be elicited from several aspects of metabolic disturbances, such as insulin resistance in the bladder mucosa, 17 or excessive metabolites from the tricarboxylic acid cycle (e.g., succinate overproduction), 18,19 and dysregulated oxidative stress, 20 which may trigger the OAB syndrome of diabetic patients through extensive dysfunction in the urothelium, bladder detrusor muscle, and afferent and efferent nerves. 21 In the present study, OAB-wet seems to be a dominant OAB category and appears to be significantly bothersome among diabetic participants.…”