Distribution of acotiamide, an orally active acetylcholinesterase inhibitor, into the myenteric plexus of rat and dog stomachs

Yoshii, Kentaro; Yamaguchi, Takashi; Hirayama, Masamichi; Toda, Ryoko; Kinomoto, Toshiko; Kawabata, Yoshihiro; Chiba, Kazuhiro

doi:10.1016/j.lfs.2015.12.020

Cited by 2 publications

(3 citation statements)

References 18 publications

(30 reference statements)

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“…Additionally, its distribution into the stomach, the anticipated site of action for acotiamide, has been suggested to be facilitated using carrier-mediated processes from the blood. However, while several reports have described the distribution of acotiamide in the muscular layer of the stomach, − little information on the mechanism of its transport is available. Therefore, we identified the uptake transporter responsible for distribution of acotiamide into the stomach.…”

Section: Discussionmentioning

confidence: 99%

“…We investigated the pharmacokinetic properties and stomach distribution of acotiamide. − Our previous studies have shown that acotiamide is highly concentrated in the stomach tissue of rats and dogs, suggesting that acotiamide acts on gastric nerves in the myenteric plexus in the gastric muscular layer. , The concentration of acotiamide in the stomach tissue could be associated with its pharmacological effect; − however, there is no concrete molecular explanation for the mechanism of acotiamide accumulation in the stomach tissue after oral administration.…”

Section: Introductionmentioning

confidence: 99%

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Identification of the Uptake Transporter Responsible for Distribution of Acotiamide into Stomach Tissue

et al. 2020

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The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, was Na + -and pH-independent. The initial uptake velocity of acotiamide was saturable with increasing concentrations of acotiamide and was inhibited by selective serotonin reuptake inhibitors, which are potent inhibitors of the plasma membrane monoamine transporter (PMAT). The uptake of acotiamide by PMAT gene-transfected HEK293 cells was saturable, with similar K m (197.9 μM) values to those of uptake by Hs 746T cells (106 μM). Moreover, immunoreactivity of PMAT was found in the gastric smooth muscle and vascular endothelial cells. These results suggest that PMAT contributes to the distribution of acotiamide in the stomach, where it exerts its pharmacological effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of the Uptake Transporter Responsible for Distribution of Acotiamide into Stomach Tissue

et al. 2020

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“…Five days after brain operation, the rats were anesthetized with 10% chloral hydrate and gastric emptying and small intestinal transit time were evaluated. Acotiamide (N‐{2‐[Bis(1‐methylethyl)amino]ethyl}‐2‐[(2‐hydroxy‐4,5‐dimethoxybenzoyl)amino]thiazole‐4‐carboxamide monohydrochloride trihydrate (IUPAC)) was obtained from Zeria Pharmaceutical Co, Ltd. Acotiamide was dissolved in a 5 w/v% glucose solution, and rats were treated with acotiamide via subcutaneous injection at a dose of 30 mg/kg based on previous reports …”

Section: Methodsmentioning

confidence: 99%

Acotiamide attenuates central urocortin 2‐induced intestinal inflammatory responses, and urocortin 2 treatment reduces TNF‐α productions in LPS‐stimulated macrophage cell lines

Yanagawa

Futagami

Sakasegawa

et al. 2020

Neurogastroenterology Motil

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Background To determine whether central and in vitro administration of urocortin 2 (Ucn 2) affected intestinal inflammatory responses in LPS‐stimulated rat models and macrophage cell lines and acotiamide modified mucosal inflammation in this model. Methods Rats were divided into four groups. LPS‐stimulated group (n = 4); LPS‐ and urocortin 2‐treated group (n = 4); LPS‐ and acotiamide‐treated group (n = 4); and LPS‐, urocortin 2‐, and acotiamide‐treated group (n = 4). CD68‐, CCR2‐, and corticotropin‐releasing hormone receptor type 2 (CRHR2)‐positive cells were assessed by immunostaining. Myeloperoxidase (MPO) activity was measured. TNF‐α, IL‐6, and IL‐4 levels were measured by ELISA method. Gastric emptying and small intestinal transit time were determined using Evans blue. Key Results Central administration of Ucn 2 significantly aggravated infiltrations of CD68‐ and CCR2‐positive cells in the intestinal mucosa of LPS‐stimulated rat models compared to those in LPS treatment alone. Interestingly, acotiamide treatment significantly reduced the migrations of both CD68‐ and CCR2‐positive cells in the jejunum of central Ucn 2‐treated LPS‐stimulated rat models. Acotiamide significantly reduced the expression levels of IkB‐α phosphorylation in LPS‐ and MCP‐1‐stimulated NR8383 cells. Central administration of Ucn 2 significantly delayed gastric emptying. In contrast, Ucn 2 stimulation significantly reduced TNF‐α and IL‐6 productions in LPS‐stimulated NR8383 cells and astressin B reversed the inhibition of TNF‐α production in stimulated NR8383 cells. Acotiamide (30 μmol/L) significantly reduced TNF‐α and IL‐6 productions in LPS‐ and MCP‐1‐stimulated NR8383 cells. Conclusions and Inferences Central and in vitro treatments of Ucn 2 affected intestinal inflammatory responses, respectively, and acotiamide improved them.

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Distribution of acotiamide, an orally active acetylcholinesterase inhibitor, into the myenteric plexus of rat and dog stomachs

Abstract: These findings suggest acotiamide distributes to the myenteric plexus of stomach, a putative site of acotiamide action, with adequate concentrations to inhibit AChE, in both of rat and dog stomachs.

Cited by 2 publications

References 18 publications

Identification of the Uptake Transporter Responsible for Distribution of Acotiamide into Stomach Tissue

Identification of the Uptake Transporter Responsible for Distribution of Acotiamide into Stomach Tissue

Acotiamide attenuates central urocortin 2‐induced intestinal inflammatory responses, and urocortin 2 treatment reduces TNF‐α productions in LPS‐stimulated macrophage cell lines

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