MKC-231, a choline uptake enhancer: (3) mode of action of MKC-231 in the enhancement of high-affinity choline uptake

Takashina, Ken; Bessho, Tomoko; Mori, Ryuji; Kawai, Kunji; Eguchi, Junichi; Saitô, Kenichi

doi:10.1007/s00702-008-0049-0

Cited by 17 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33 Animal experiments have reported that MKC-231 significantly improves the learning and memory deficits associated with cholinergic hypofunction by affecting the trafficking of CHT1 and increasing the number of transporters working for HACU at the synaptic membrane. [33][34][35] Furthermore, MKC-231 could antagonize phencyclidine-induced behavioural deficits through increases in septal cholinergic neurons. 36 According to our data, MKC-231 also enhances the normal colonic motility of control rats through upregulation of CHT1 and elevated ACh production.…”

Section: Discussionmentioning

confidence: 99%

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

Lin

2018

J Neurogastroenterol Motil

View full text Add to dashboard Cite

Background/AimsIrritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS.MethodsA rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility.ResultsAfter 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production.ConclusionUpregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.

show abstract

Section: Discussionmentioning

confidence: 99%

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

Lin

2018

J Neurogastroenterol Motil

View full text Add to dashboard Cite

show abstract

“…MKC-231, known as a choline uptake enhancer, has been reported to take CHT1 as its principal target. 40 , 41 Animal experiments have demonstrated that oral administration of MKC-231 significantly improved the learning and memory deficit associated with cholinergic hypofunction by directly affecting the trafficking of CHT1 and increasing the number of transporters. 40 , 41 Furthermore, MKC-231 could antagonize phencyclidine-induced behavioral deficits and reduction in septal cholinergic neurons in rats.…”

Section: Discussionmentioning

confidence: 99%

“…40 , 41 Animal experiments have demonstrated that oral administration of MKC-231 significantly improved the learning and memory deficit associated with cholinergic hypofunction by directly affecting the trafficking of CHT1 and increasing the number of transporters. 40 , 41 Furthermore, MKC-231 could antagonize phencyclidine-induced behavioral deficits and reduction in septal cholinergic neurons in rats. 42 These reports suggest that MKC-231 could be a therapeutic drug for the treatment of Alzheimer’s disease and schizophrenia, but without any significant side effects.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia

Lin¹,

Yu²

2018

JPR

View full text Add to dashboard Cite

BackgroundIrritable bowel syndrome (IBS) is a common disease with hyperalgesia, the mechanisms of which remain elusive. The cholinergic system is known to be involved in pain inhibitory pathways in multiple diseases, and its involvement in IBS is unknown.ObjectiveWe aimed to determine whether high-affinity choline transporter CHT1, a major determinant of the cholinergic signaling capacity, is involved in regulating intestinal sensations associated with stress-induced visceral pain.Materials and methodsAn IBS rat model was established by chronic water avoidance stress (WAS). Colonic pathologic alterations were detected by H&E staining. Visceral sensations were determined by scoring the abdominal withdrawal reflex (AWR) and visceromotor response (VMR) magnitude of the electromyogram in response to colorectal distension (CRD). Abdominal mechanical hyperalgesia was assessed by counting the number of withdrawal events evoked by applying von Frey filaments. Real-time PCR, Western blot, and immunostaining were performed to identify CHT1 expression in the colon. Acetylcholine (ACh) secretion was determined by ELISA. Effects of MKC-231, a choline uptake enhancer, on visceral pain were examined.ResultsAfter 10 days of WAS exposure, AWR score and VMR magnitude in response to CRD were significantly enhanced and the number of withdrawal events was elevated. Protein and mRNA levels of CHT1 were considerably increased in the colon after WAS. CHT1 upregulation in the WAS-exposed group was largely abolished by ammonium pyrrolidinedithiocarbamate. The density of CHT1-positive intramuscular cells and enteric neurons in the myenteric plexus was enhanced in WAS-exposed rats. Pharmacologic enhancement of CHT1 activity by MKC-231 gavage could relieve the visceral pain of WAS rats by upregulating CHT1 protein expression and enhancing ACh production.ConclusionCHT1 may exert an antinociceptive effect in stress-induced visceral pain by modulating ACh synthesis through nuclear factor kappa B signaling. MKC-231 could be used as a potential drug to treat disorders with hyperalgesia.

show abstract

“…The Cresset field based virtual screening tool, Blaze (formerly called FieldScreen), (Cheeseright et al, 2008 , 2009 ) was utilized to search the full Pfizer compound screening collection to identify compounds similar to literature CHT positive allosteric modulator (PAM) MKC-351/coluracetam (Takashina et al, 2008a , b ) or CHT negative allosteric modulator (NAM) ML-352 (Ennis et al, 2015 ). Similarity was assessed using 50% 3D electrostatic and hydrophobic properties (Cheeseright et al, 2006 ) and 50% shape (Grant et al, 1996 ).…”

Section: Methodsmentioning

confidence: 99%

“…There is comparative paucity of relevant known tool molecules that modulate CHT function: published orthosteric inhibitors include hemicholinium-3 (HC-3) and related analogs which have been broadly used since their first discovery in 1955 (Ferguson and Blakely, 2004 ). In addition there is the recently described negative allosteric modulator (NAM) ML-352 (Ennis et al, 2015 ) and putative positive modulators of transporter function including MKC-231/coluracetam (Bessho et al, 2008 ; Takashina et al, 2008a , b ) and staurosporine (STS) (Ruggiero et al, 2012 ). ML-352 and MKC-231 were used as seeds for generating the first set of 887 compounds via Cresset software (a computational approach that generates a 3-dimensional electrostatic shape or “field” which illustrates how the compound may interact with the target).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter

Choudhary

Armstrong

Jorgensen

et al. 2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene). This transporter is comparatively well-characterized but otherwise unexplored as a potential drug target. We therefore sought to identify small molecules that would enable testing of the hypothesis that positive modulation of CHT mediated transport would enhance activity-dependent cholinergic signaling. We utilized existing and novel screening techniques for their ability to reveal both positive and negative modulation of CHT using literature tools. A screening campaign was initiated with a bespoke compound library comprising both the Pfizer Chemogenomic Library (CGL) of 2,753 molecules designed specifically to help enable the elucidation of new mechanisms in phenotypic screens and 887 compounds from a virtual screening campaign to select molecules with field-based similarities to reported negative and positive allosteric modulators. We identified a number of previously unknown active and structurally distinct molecules that could be used as tools to further explore CHT biology or as a starting point for further medicinal chemistry.

show abstract

MKC-231, a choline uptake enhancer: (3) mode of action of MKC-231 in the enhancement of high-affinity choline uptake

Cited by 17 publications

References 32 publications

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia

Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter

Contact Info

Product

Resources

About