Abstract
This study tested the hypothesis that extracorporeal-shock-wave (ECSW) protected the functional and anatomical integrity of rat urinary-bladder against ketamine-induced damage. In in vitro study, the rat bladder smooth muscle cells (RBdSMCs) were categorized into G1 (sham-control), G2 (RBdSMCs + menadione), G3 (RBdSMCs + ECSW) and G4 (RBdSMCs + menadione + ECSW). The results showed protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), inflammatory markers (MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-6/IL-1ß/MMP-9/iNOS), and cell-stress response signalings (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38/p-53) were significantly increased in G2 than in G1 and G3, and those were significantly reversed in G4 (all p < 0.0001). Adult-male SD rats (n = 24) were equally categorized into group 1 (sham-control), group 2 (ketamine/30 mg/kg/daily i.p. injection for four weeks), group 3 [ketamine/30 mg/kg + ECSW/optimal energy (0.12 mJ/mm2/120 impulses/at 3 h and days 3/7/14/21/28 after ketamine administration)] and group 4 [(ketamine/30 mg/kg + ECSW/higher energy (0.16 mJ/mm2/120 impulses)] and animals were euthanized by day 42. The results showed the urine levels of pro-inflammatory cytokines (TNF-α/IL-6) were lowest in group 1, highest in group 2 and significantly higher in group 3 than in group 4 at days 1/7/14/28 (all p < 0.0001). The duration of urinary bladder contraction was lowest in group 2, highest in group 1 and significantly higher in group 4 than in group 3, whereas the maximal pressure of urinary bladder exhibited an opposite pattern of bladder contraction among the groups (all p < 0.0001). The histopathological findings of fibrosis/inflammation/keratinization and protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), and inflammatory (TLR-2/TLR-4/MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-1ß/MMP-9/iNOS) and cell-stress response (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38) signalings and apoptotic/fibrotic biomarkers (cleaved-caspas3/cleaved-PARB/Smad3/TFG-ß) exhibited an identical pattern of urine proinflammatory cytokine among the groups (all p < 0.0001). ECSW effectively attenuated ketamine-induced bladder damage and dysfunction.
Highlights
Ketamine, a non-competitive N-methyl-D-aspartic acid receptor antagonist, was first discovered more than sixty years ago and was used as a clinical application of anesthetic [1].Of late, ketamine-induced lower urinary tract syndrome (LUTS) has attracted increased attention due to the rising abuse of ketamine in recent years as the role of this drug has become recreational among young adults [2,3,4,5]
(1 × 106 per mL) + menadione (25 μM) (menadione treated the cells for 30 min, followed by washing and continuously cultured for 24 h], group C [Rat Bladder Smooth Muscle Cells (RBdSMCs) (1 × 106 per mL) + ECSW (0.12 mJ/mm2 for 180 impulses)] which was applied to the culture disk/ECSW treatment at 3 h after cell culturing, followed by culturing for 24 h and group D [RBdSMCs (1 × 106 per mL) + menadione
To elucidate whether the ECSW therapy would protect RBdSMCs against the oxidativestress substance damage, the cell culture was categorized into G1, G2 [RBdSMCs + menadione (25 μM)], G3 [RBdSMCs + ECSW
Summary
A non-competitive N-methyl-D-aspartic acid receptor antagonist, was first discovered more than sixty years ago and was used as a clinical application of anesthetic [1]. Of distinctive importance is that there is still lacking an effective treatment for Ketamine-induced LUTS These patients usually require long-term diaper use which always deprives them of the ability to take a long journey. Our previous study [13] revealed that ECSW therapy ameliorated cyclophosphamideinduced rat acute interstitial cystitis through inhibiting inflammation and oxidative stress in both in vitro and in vivo experimental studies. Another previous study [14]. Our recent study [15] has demonstrated that ECSW treatment effectively inhibited radiation-induced chronic cystitis, preserved the urinary bladder contractility and reduced urine retention. Based on the aforementioned studies [13,14,15,16,17], we have proposed that ECSW therapy might improve the ketamine-elicited urinary bladder dysfunction, i.e., incontinence (UI) and urinary retention (UR)
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