Pathological remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration

Pellegrini, Carolina; Ippolito, Chiara; Segnani, Cristina; Dolfi, Amelio; Errede, Mariella; Virgintino, Daniela; Fornai, Matteo; Antonioli, Luca; Garelli, Francesca; Nericcio, Anna; Colucci, Rocchina; Cerri, Silvia; Blandini, Fabio; Blandizzi, Corrado; Bernardini, Nunzia

doi:10.1016/j.nbd.2020.104821

Cited by 32 publications

(31 citation statements)

References 42 publications

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“…However, recently Sampath et al 32 reported reduced nNOS expression on all parts of the colon 7 days after MPTP treatment, with a reduction in dimer formation suggesting reduced nNOS activity. In unilateral 6-OHDA-lesioned rats the number of ChAT-ir neurons were reported as decreased or unchanged, whereas there was a reduction in nitrergic and increase in VIP-ergic neurons 21,22,33 , partially agreeing with the present study. All the models used showed a reduction in nigral dopamine cell bodies, however, this was greatest in the 6-OHDAlesioned rat (>90% loss) and the present study (>70% loss; data not shown).…”

Section: Discussionsupporting

confidence: 92%

“…The evidence of an inflammatory response in the proximal colon, albeit mild, is in accord with the reported increase in the expression of pro-inflammatory and glial marker in PD following colonoscopy of the ascending colon 34 , which roughly corresponds to proximal colon in this study, and in the colon of unilaterally 6-OHDA-lesioned rats 33 . However, the magnitude of difference observed between our study and those in the human PD and 6-OHDA-lesioned rats is not surprising as in PD the degeneration is progressive, and in rats the samples were obtained 8 weeks after lesioning 33 while the neuronal cell loss in the MPTP-treated primate is acute and the samples were taken approximately 1.4 years following MPTP lesioning, thus allowing for some recovery from an inflammatory response. Indeed, repair is observed only up to 24 weeks where new neurons appear in the ENS, and only after 5-HT4 receptor stimulation 35 .…”

Section: Discussionsupporting

confidence: 89%

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Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

Coletto

Tough

Pritchard

et al. 2021

npj Parkinsons Dis.

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The pathological changes underlying gastrointestinal (GI) dysfunction in Parkinson’s disease (PD) are poorly understood and the symptoms remain inadequately treated. In this study we compared the functional and neurochemical changes in the enteric nervous system in the colon of adult, L-DOPA-responsive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset, with naïve controls. Measurement of mucosal vectorial ion transport, spontaneous longitudinal smooth muscle activity and immunohistochemical assessment of intrinsic innervation were each performed in discrete colonic regions of naïve and MPTP-treated marmosets. The basal short circuit current (Isc) was lower in MPTP-treated colonic mucosa while mucosal resistance was unchanged. There was no difference in basal cholinergic tone, however, there was an increased excitatory cholinergic response in MPTP-treated tissues when NOS was blocked with L-Nω-nitroarginine. The amplitude and frequency of spontaneous contractions in longitudinal smooth muscle as well as carbachol-evoked post-junctional contractile responses were unaltered, despite a decrease in choline acetyltransferase and an increase in the vasoactive intestinal polypeptide neuron numbers per ganglion in the proximal colon. There was a low-level inflammation in the proximal but not the distal colon accompanied by a change in α-synuclein immunoreactivity. This study suggests that MPTP treatment produces long-term alterations in colonic mucosal function associated with amplified muscarinic mucosal activity but decreased cholinergic innervation in myenteric plexi and increased nitrergic enteric neurotransmission. This suggests that long-term changes in either central or peripheral dopaminergic neurotransmission may lead to adaptive changes in colonic function resulting in alterations in ion transport across mucosal epithelia that may result in GI dysfunction in PD.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

Coletto

Tough

Pritchard

et al. 2021

npj Parkinsons Dis.

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“…In this study, 6-OHDA has been used for sympathetic denervation by others in various studies [6,45,46]. To achieve effective denervation, we tested different dosages of 6-OHDA including one-time 200 mg/kg, two-times 100 mg/kg, two-times 50 mg/kg, and threetimes 80 mg/kg in our preliminary experiments (data not shown).…”

Section: Chemical Denervationmentioning

confidence: 99%

Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice

Mallesh

Schneider

Schneiker

et al. 2021

IJMS

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Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.

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“…43 In particular, the histological analysis revealed the concomitance of a mucous metaplasia of colonic epithelium, an increased number of goblet cells, containing metachromatic acid mucin, and a fast epithelial turnover in colonic crypts, suggesting a renewal and differentiation of epithelial cells into goblet phenotype to reinforce the intestinal barrier (Table 1). 43 In addition, 6-OHDA rats displayed a decrease in colonic expression of TMEM16A/ANO1, mucosal hydration along with a decrease in fecal water content that could contribute to delay in colonic transit (Table 1). [43][44][45] Of note, 6-OHDA rats displayed a marked collagen deposition along with an increase in vimentinpositive fibroblast-like cells some of which resulted proliferating cellular nuclear antigen (PCNA)-positive as well as several epithelial cells of the crypts, while α-SMA-positive cells resulted decreased.…”

Section: Pathological Remodeling Of the Intestinal Mucosal Barrier And Enteric Neuromuscular Compartment In Pd Intestinal Mucosal Barriermentioning

confidence: 99%

“…43 In addition, 6-OHDA rats displayed a decrease in colonic expression of TMEM16A/ANO1, mucosal hydration along with a decrease in fecal water content that could contribute to delay in colonic transit (Table 1). [43][44][45] Of note, 6-OHDA rats displayed a marked collagen deposition along with an increase in vimentinpositive fibroblast-like cells some of which resulted proliferating cellular nuclear antigen (PCNA)-positive as well as several epithelial cells of the crypts, while α-SMA-positive cells resulted decreased. 43 These findings suggest that central nigrostriatal denervation is associated with gut fibrotic remodelling that could contribute to alterations both of intestinal permeability and motor disturbances.…”

Section: Pathological Remodeling Of the Intestinal Mucosal Barrier And Enteric Neuromuscular Compartment In Pd Intestinal Mucosal Barriermentioning

confidence: 99%

From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson’s disease

et al. 2021

Self Cite

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Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson’s disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and pre-clinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.

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Pathological remodelling of colonic wall following dopaminergic nigrostriatal neurodegeneration

Cited by 32 publications

References 42 publications

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

Dysregulation of epithelial ion transport and neurochemical changes in the colon of a parkinsonian primate

Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice

From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson’s disease

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