The effect of a neurotoxin (benzalkonium chloride) on the lower esophagus

doi:10.1016/0022-4804(89)90073-5

Journal of Surgical Research

Volume 47, Issue 2, August 1989, Pages 117-119

https://doi.org/10.1016/0022-4804(89)90073-5 Get rights and content

Abstract

Achalasia of the esophagus may be associated with abnormalities of the myenteric plexus (hypo- and anganglionosis). This report evaluates this relationship by studying the effect of benzalkonium chloride (BK, a topical neurotoxin) on the lower esophagus. Following midline laparotomy, topical BK (0.5%) was applied to the muscularis of the lower 1.0 cm of the esophagus for 30 min in 38 Sprague-Dawley rats (200 g). Thirty-eight additional rats acted as controls (unoperated, n = 19; sham laparotomy, n = 19). At 1 and 3 months animals were evaluated for weight gain, daily food intake (g/100 gm body wt), lower esophageal sphincter (LES) manometry, and contrast esophagram. At 3 months, the esophagus was evaluated for histologic study and acetylcholinesterase staining. Esophagram showed distal narrowing with proximal dilatation in BK rats (inner diameter 4.71 ± 0.61 vs 6.17 ± 0.58 in controls, P < 0.001). Daily food intake was significantly less in BK rats (5.57 ± 0.41 g vs controls 7.69 ± 0.33 g P < 0.001). Daily weight gain was also less in BK rats (1.13 ± 0.34 vs controls 1.83 ± 0.25, P < 0.001). An increased LES pressure was noted in BK rats (5.45 ± 0.89 mmHg vs controls 4.04 ± 1.04 mmHg; P < 0.1). A histologic study showed aganglionosis in BK rats with positive cholinesterase staining fibers compared to controls. Topical BK results in distal esophageal aganglionosis characterized by distal narrowing, proximal dilatation, decreased food intake, and limited weight gain when compared to controls. These findings are similar to those observed in achalasia and support a primary neurogenic cause for its etiology.

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Citation Excerpt :
Other models of neurogenic dysfunction have been described throughout the alimentary tract. In 1989, Goto and Grosfeld [23] showed that esophageal denervation using BAC mimicked achalasia. Several studies have also described BAC treatment of the colon and rectum to simulate Hirschsprung disease [7–9,11,14,15,24–27].
Enteric neuromuscular disease is a characteristic of several disease states, including Hirschsprung disease, esophageal achalasia, Chagas disease, and gastroparesis. Medical therapy for these conditions is limited, and surgical intervention may incur significant morbidity. Alternatively, transplantation of neural progenitor cells may regenerate enteric ganglia. Existing aganglionosis model systems are limited by swift animal demise or by spontaneous regeneration of native ganglia. We propose a novel protocol to induce permanent aganglionosis in a segment of rat jejunum, which may serve as an experimental transplantation target for cellular therapy.
This protocol was performed in 17 adult female Sprague–Dawley rats. A laparotomy was performed and a 1-cm segment of jejunum was isolated from continuity. Among 14 rats, the isolated segments were treated with benzalkonium chloride (BAC) for 20 min to induce aganglionosis. Jejunal segment isolation was performed without BAC treatment in three rats. The animals were euthanized at posttreatment days 21–166. Muscle layer diameter was compared among normal, isolated, and BAC-treated isolated jejunal segments. The presence of jejunal ganglia was documented by immunohistochemical staining (IHC) for beta-III tubulin (TUJ1) and S100, markers of neuronal and glial cell lineages, respectively.
Ganglia were identified by IHC in normal and isolated jejunal segments. Isolated segments had significantly hypertrophied smooth muscle layers compared with normal jejunum (diameter 343 ± 53 μm versus 211 ± 37 μm, P < 0.0001). BAC-treated jejunal segments had no IHC evidence of ganglionic structures. Aganglionosis was persistent in all specimens up to 166 days after treatment.
The exclusion of a jejunal segment from continuity and concurrent treatment with BAC results in an effective, reproducible, and permanent model of aganglionosis. Muscular hypertrophy and aganglionosis in the isolated jejunal segment make it an ideal recipient site for transplantation of neuroglial precursor cells.
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Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) from vertebrates, other than their predominant acylcholine hydrolase (esterase) activity, display a genuine aryl acylamidase activity (AAA) capable of hydrolyzing the synthetic substrate o-nitroacetanilide to o-nitroaniline. This AAA activity is strongly inhibited by classical cholinesterase (ChE) inhibitors. In the present study, benzalkonium chloride (BAC), a cationic detergent widely used as a preservative in pharmaceutical preparations, has been shown to distinctly modulate the esterase and AAA activities of BChEs. The detergent BAC was able to inhibit the esterase activity of human serum and horse serum BChEs and AChEs from electric eel and human erythrocyte. The remarkable property of BAC was its ability to profoundly activate the AAA activity of human serum and horse serum BChEs but not the AAA activity of AChEs. Thus BAC seem to preferentially activate the AAA activity of BChEs alone. Results of the study using the ChE active site-specific inhibitor diisopropyl phosphorofluoridate indicated that BAC binds to the active site of ChEs. Furthermore, studies using a structural homolog of BAC indicated that the alkyl group of BAC is essential not only for its interaction with ChEs but also for its distinct effect on the esterase and AAA activities of BChEs. This is the first report of a compound that inhibits the esterase activity, while simultaneously activating the AAA activity, of BChEs.
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^☆: Presented at the Annual Meeting of the Association for Academic Surgery, Salt Lake City, Utah, November 16–19, 1988.

²: Associate Professor, Department of Surgery Kyushu University, Fukuoka, Japan.

³: Lafayette F. Page Professor and Chairman, Department of Surgery, Indiana University School of Medicine; Surgeon-in-Chief, James Whitcomb Riley Hospital for Children, Indianapolis, IN.

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The effect of a neurotoxin (benzalkonium chloride) on the lower esophagus☆

Abstract

Surg. Clin. North Amer.

J. Pediatr. Surg.

Surg. Clin. North Amer.

Amer. J. Med. Sci.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.