Laxative Effects of Phlorotannins Derived from Ecklonia cava on Loperamide-Induced Constipation in SD Rats

This study investigated the laxative effects of phlorotannins (Pt) derived from Ecklonia cava (E. cave) on chronic constipation by evaluating alterations in stool parameters, gastrointestinal motility, histopathological structure, mucin secretion, gastrointestinal hormones, muscarinic cholinergic regulation, and fecal microbiota in SD rats with loperamide (Lop)-induced constipation subjected to Pt treatment. Stool-related parameters (including stool number, weight, and water contents), gastrointestinal motility, and length of intestine were significantly enhanced in the Lop+Pt-treated group as compared to the Lop+Vehicle-treated group. A similar recovery was detected in the histopathological and cytological structure of the mid-colon of Lop+Pt-treated rats, although the level of mucin secretion remained constant. Moreover, rats with Lop-induced constipation subjected to Pt treatment showed significant improvements in water channel expression, gastrointestinal hormone secretions, and expression of muscarinic acetylcholine receptors M2/M3 (mAChRs M2/M3) and their mediators of muscarinic cholinergic regulation. Furthermore, the Lop+Pt-treated group showed a significant recovery of Bifidobacteriaceae, Muribaculaceae, Clostridiaceae, and Eubacteriaceae families in fecal microbiota. Taken together, these results provide the first evidence that exposure of SD rats with Lop-induced constipation to Pt improves the constipation phenotype through the regulation of membrane water channel expression, GI hormones, the mAChR signaling pathway, and fecal microbiota.

Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.

Antioxidant activity and laxative effects of tannin-enriched extract of Ecklonia cava in loperamide-induced constipation of SD rats

To investigate the role of tannin-enriched extracts of Ecklonia cava (TEE) on the regulation of oxidative balance and laxative activity in chronic constipation, we investigated alterations after exposure to TEE, on constipation phenotypes, muscarinic cholinergic regulation, and oxidative stress responses in the transverse colons of SD rats with loperamide (Lop)-induced constipation. This extract contains high levels of total condensed tannin content (326.5 mg/g), and exhibited high inhibitory activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. TEE treatment induced significant improvements in reactive oxygen species (ROS) production, superoxide dismutase (SOD) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation in primary smooth muscles of rat intestine cells (pRISMCs) and transverse colon of constipation model. Also, Lop+TEE treated groups showed alleviated outcomes for the following: most stool parameters, gastrointestinal transit, and intestine length were remarkably recovered; a similar recovery pattern was observed in the histopathological structure, mucin secretion, water channel expression and gastrointestinal hormones secretion in the transverse colon; expressions of muscarinic acetylcholine receptors M2/M3 (mAChR M2/M3) and their mediators on muscarinic cholinergic regulation were significantly recovered. Taken together, these results provide the first evidence that TEE stimulates oxidative stress modulation and muscarinic cholinergic regulation when exerting its laxative effects in chronic constipation models.

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

ABSTRACTIt has been reported that hyperexcitability occurs in a subset of patients with Alzheimer’s disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models.HIGHLIGHTSGranule cells (GCs) in young Tg2576 mice had abnormal synaptic activity.Young Tg2576 GCs had increased excitatory and reduced inhibitory synaptic activity.GC intrinsic properties were altered in young Tg2576 mice.Muscarinic cholinergic regulation of GCs was altered in young Tg2576 mice.Atropine led to a novel spontaneous inward current that was very strong in Tg2576 GCs.