Ureteral Botulinum Toxin Attenuates Prostaglandin Expression in an Animal Model
Kevin Krughoff, MD1, Scott Palisoul, BS2, Faith Anderson, BS3, Steven Tau, BS3, Alison Young, MS3, Jason Pettus, MD2, Karen Moodie, DVM4, Matthew Havrda, PhD3, David Chavez, MD1.
1Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA, 2Department of Pathology, Dartmouth-Hitchcock, Lebanon, NH, USA, 3Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA, 4Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
BACKGROUND: Prostaglandin E (PGE) is associated with ureteral peristalsis and inflammation. Clostridium Botulinum toxin type A (BoNT-A) has been shown to impact several chemosensory mediators, however the impact on PGE is unknown. Our goal was to determine the effect of ureteral BoNT-A instillation on local PGE synthase expression in a novel animal model of ureteral inflammation.
METHODS: Cystotomy and unilateral ureteral BoNT-A instillation with ipsilateral distal ureteral ligation was performed on 3 New Zealand white rabbits (2.4-2.8kg). A fourth rabbit underwent 4cc saline instillation to serve as a negative control. A fifth rabbit underwent direct periureteral BoNT-A injection in addition to ureteral instillation to serve as a positive control. Rabbits were survived for 7 days. Ureteral tissue was fixed in formalin and paraffin embedded. Ureteral sections underwent antigen retrieval followed by incubation with PGE synthase antibody and DAB HRP secondary.
RESULTS: All rabbits survived 7 days with one exception which was euthanized on post-operative day five following wound complications. PGE synthase was detected in ureteral tissue of all specimens. BoNT-A exposure was associated with a decrease in PGE synthase signal in a dose-dependent fashion, with direct injection showing the greatest decrease in signal.
CONCLUSIONS:
The feasibility of an in-vivo study of ureteral BoNT-A instillation is demonstrated herein, with preliminary results showing attenuation of ureteral PGE synthase expression with BoNT-A exposure. The ability of BoNT-A to exert chemosensory and/or inflammatory modulating effects without direct injection is possible under conditions of inflammation.
Image 1: Left - Midline cystotomy with ureteral instillation followed by distal ligation. Right - Urethral catheterization and cystorrhaphy leak test. Image 2: Native ureter stained for PGE synthase at 10X magnification. Image 3: 40X magnification of ureter sections with distal ligation. A)No BONT-A exposure. B) 20U BoNT-A ureteral instillation. C) 5U BoNT-A ureteral instillation and 30U direct injection into periureteral tissue and bladder. Image 4: Left and right ureter cross sections from individual rabbit. Left: No ligation, no BoNT-A exposure. Right: 20U BoNT-A instillation followed by distal ligation. 
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