Reduced acetylcholine and elevated muscarinic receptor 2 in duodenal mucosa contribute to the impairment of mucus secretion in 6-hydroxydopamine-induced Parkinson’s disease rats

Abstract

Patients with Parkinson's disease (PD) have a higher incidence rate of duodenal ulcers. The mucus barrier provides the first line of defense for duodenal mucosal protection. However, it is unknown whether duodenal mucus secretion is affected in PD. In the present study, we used the rats microinjected 6-hydroxydopamine (6-OHDA) into the bilateral substantia nigra to investigate duodenal mucus secretion and potential therapeutic targets in duodenal ulcer in PD. Alcian blue-periodic acid-Schiff, transmission electron microscopy, immunofluorescence, duodenal mucosal incubation, and enzyme-linked immunosorbent assays were used. The 6-OHDA rats exhibited mucin accumulation and retention in duodenal goblet cells. Mucin granules were unable to fuse with the apical membranes of goblet cells, and the exocytosis ratio of goblet cells was significantly reduced. Moreover, decreased acetylcholine and increased muscarinic receptor 2 (M 2 R) levels were detected in the duodenal mucosa of 6-OHDA rats. Bilateral vagotomy rats were also characterized by defective duodenal mucus secretion and decreased acetylcholine with increased M 2 R levels in the duodenal mucosa. Application of the cholinomimetic drug carbachol or blocking M 2 R with methoctramine significantly promoted mucus secretion by goblet cells and increased MUC2 content in duodenal mucosa-incubated solutions from 6-OHDA and vagotomy rats. We conclude that the reduced acetylcholine and increased M 2 R contribute to the impaired duodenal mucus secretion of 6-OHDA rats. The study provides new insights into the mechanism of duodenal mucus secretion and potential therapeutic targets for the treatment of duodenal ulcers in PD patients.

Enhanced Contractive Tension and Upregulated Muscarinic Receptor 2/3 in Colorectum Contribute to Constipation in 6-Hydroxydopamine-Induced Parkinson’s Disease Rats

“…Of note, PD patients display a significant loss of acetylcholinesterase signal in the small intestine ( Gjerloff et al, 2015 ; Fedorova et al, 2017 ) and reduced VIP-IR neurons in the colonic submucosal plexus ( Giancola et al, 2017 ). Consistent with these findings, our previous study have shown a drastic decrease ChAT protein expression and ACh content in the gastric corpus and duodenal mucosa of 6-OHDA rats ( Zheng et al, 2014 ; Yan et al, 2021 ). We suppose that the impairment of cholinergic neurotransmission may lead to decrease in the role of EFS in the colorectum of 6-OHDA rats.…”

“…In fact, there is direct evidence that nigral pathology may exacerbate GI dysfunction. We have reported that rats with 6-hydroxydopamine microinjected in the bilateral SN (6-OHDA rats) exhibit delayed gastric emptying ( Zheng et al, 2011 , 2014 ), impaired duodenal mucus secretion ( Yan et al, 2021 ) and outlet obstruction constipation ( Zhang et al, 2015 ). Moreover, dopaminergic neurons in the SN can activate dopamine D 1 receptor on dorsal motor nucleus of the vagus (DMV) neurons to regulate gastric motility in rats ( Anselmi et al, 2017 ).…”

Altered Secretion, Constitution, and Functional Properties of the Gastrointestinal Mucus in a Rat Model of Sporadic Alzheimer’s Disease

“…Previous studies have provided evidence supporting both functional and structural modifications in the gut of the STZ-icv model, as well as changes in the brain–gut axis functionality. , Conducting future experiments to gather additional data on the pathophysiological aspects discussed in our study would greatly contribute to a better understanding of the etiopathogenesis of mucus system dysfunction. For instance, as the vagus nerve plays an important role in the efferent control of mucus secretion, , incorporating vagotomy experiments could provide crucial insights into the role of brain–gut communication, or the lack thereof, in relation to the functioning of the GI mucus system in the STZ-icv model.…”

The absence of gastrointestinal redox dyshomeostasis in the brain-first rat model of Parkinson’s disease induced by bilateral intrastriatal 6-hydroxydopamine

“…[18–20]). Other pathophysiological alterations such as decreased expression of the occludin barrier proteins [21] and impaired production of mucus [22] have also been reported.…”