Botulinum toxin infusion into the mesenteric artery has selective action on peristalsis in a rat model: experimental research

A. Borrello, A. Agnes, S. Panunzi, I. Piergentili, O. Rossetto, F. Fabris, S. Magalini, D. Gui

Department of Emergency Surgery, Catholic University of the Sacred Heart, Policlinico Gemelli, Rome, Italy. alebor93@gmail.com

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• Pharmacology

OBJECTIVE: Botulinum toxin type A (BoNT/A) reversibly blocks neurotransmission at voluntary and autonomic cholinergic nerve terminals, inducing paralysis.

The aim of this study was to block panenteric peristalsis in rats through BoNT/A administration into the superior mesenteric artery (SMA) and to understand whether the toxin’s action is selectively restricted to the perfused territory.

MATERIALS AND METHODS: Rats were infused through a 0.25-mm surgically inserted SMA catheter with different doses of BoNT/A (10 U, 20 U, 40 U BOTOX®, Allergan Inc.) or with saline for 24 h. Animals were free to move on an unrestricted diet. As a sign of bowel peristalsis impairment, body weight and oral/water intake were collected for 15 days. Statistical analysis was conducted with nonlinear mixed effects models to study the variation over time of the response variables.

In three 40 U-treated rats, the selectivity of the intra-arterial delivered toxin action was studied by examining bowel and voluntary muscle samples and checking the presence of BoNT/A-cleaved SNAP-25 (the smoking gun of the toxin action) using the Immunofluorescence (IF) method through a specific antibody recognition.

RESULTS: While control rats exhibited an increasing body weight, treated rats showed an initial dose-dependent weight reduction (p<0.001 control vs. treated) with recovery after Day 11 for 10 and 20 U-treated rats. Food and water intake over time showed significantly different half-saturation constants with rats treated with higher doses who reached half of the maximum achievable in a greater number of days (p<0.0001 control vs. treated rats). BoNT/A-cleaved SNAP-25 was identified in bowel wall NMJs and not in voluntary muscles, demonstrating the remarkable selectivity of arterially infused BoNT/A.

CONCLUSIONS: Blockade of intestinal peristalsis, can be induced in rats by slow infusion of BoNT/A into the SMA. The effect is long-lasting, dose-dependent and selective. BoNT/A delivery into the SMA through a percutaneous catheter could prove clinically useful in the treatment of entero-atmospheric fistula by temporarily reducing fistula output.

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