Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine

Thomasi, Beatriz Bastos de Moraes; Valdetaro, Luisa; Ricciardi, Maria Carolina Garcia; Hayashide, Lívia; Fernandes, Ana Carolina Moraes Neves; Mussauer, Amanda; Silva, Mayara Lídia da; Faria-Melibeu, Adriana da Cunha; Ribeiro, Manuel Gustavo Leitão; Coelho-Aguiar, Juliana de Mattos; Campello-Costa, Paula; Moura‐Neto, Vivaldo; Tavares-Gomes, Ana Lúcia

doi:10.1016/j.brainresbull.2022.06.013

Cited by 12 publications

(13 citation statements)

References 71 publications

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Homolak

Joja

Grabaric

et al. 2022

Preprint

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The gut-brain axis plays an important role in Parkinson′s disease (PD) by acting as a route for vagal propagation of aggregated α-synuclein in the gut-first endophenotype and as a mediator of gastrointestinal dyshomeostasis via the nigro-vagal pathway in the brain-first endophenotype of the disease. One important mechanism by which the gut-brain axis may promote PD is by regulating gastrointestinal redox homeostasis as overwhelming evidence suggests that oxidative stress plays a key role in the etiopathogenesis and progression of PD and the gastrointestinal tract maintains redox homeostasis of the organism by acting as a critical barrier to environmental and microbiological electrophilic challenges. The present aim was to utilize the bilateral intrastriatal 6-hydroxydopamine (6-OHDA) brain-first PD model to study the effects of isolated central pathology on redox homeostasis of the gastrointestinal tract. Three-month-old male Wistar rats were either not treated (intact controls; CTR) or treated bilaterally intrastriatally with vehicle (CIS) or 6-OHDA (6-OHDA). Motor deficits were assessed with the rotarod performance test and the duodenum, ileum, and colon were dissected for biochemical analyses 12 weeks after the treatment. Lipid peroxidation, total antioxidant capacity, low-molecular thiols, and protein sulfhydryls, the activity of total and Mn/Fe superoxide dismutases, and total and azide-insensitive catalase/peroxidase were measured. Univariate and multivariate models of redox biomarkers provide solid evidence against the existence of pronounced gastrointestinal redox dyshomeostasis. The results indicate that the dysfunction of the nigro-vagal system and not motor deficit may be a key mediator of gastrointestinal dyshomeostasis in brain-first 6-OHDA-induced rodent models of PD.

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Homolak

Joja

Grabaric

et al. 2022

Preprint

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“…Therefore, decreased GFAP expression and GDNF content could be the result of decreased ACh content in the colon of 6‐OHDA treated rats. The upregulation of GFAP with altered occludin protein have been observed in the colon of mice bearing unilateral striatal lesions caused by 6‐OHDA (de Moraes Thomasi et al, 2022). These discrepancies could be related to the different model preparations and different time points after 6‐OHDA administration.…”

Section: Discussionmentioning

confidence: 96%

“…tent could be the result of decreased ACh content in the colon of 6-OHDA treated rats. The upregulation of GFAP with altered occludin protein have been observed in the colon of mice bearing unilateral striatal lesions caused by 6-OHDA(de Moraes Thomasi et al, 2022).These discrepancies could be related to the different model preparations and different time points after 6-OHDA administration. GDNF protects mucosal barrier function by upregulating the expression of tight junction proteins and decreasing mucosal permeability (Zhang et al, 2010).…”

mentioning

confidence: 99%

Dopamine regulates colonic glial cell‐derived neurotrophic factor secretion through cholinergic dependent and independent pathways

Zhang,

Sun,

Quan

et al. 2023

British J Pharmacology

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Background and PurposeGlial cell‐derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine (DA) promotes GDNF release in astrocytes. We aimed to investigate the regulation of DA on the colonic GDNF secretion.Experimental approachD1 receptor knockout (D1R−/−) mice, adeno‐associated viral 9 ‐ short hairpin RNA carrying D2R (AAV9‐shD2R)‐treated mice, 6‐hydroxydopamine (6‐OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubated fluid of colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for the GDNF and ACh measurement.Key ResultsD2R‐immunoreactivity (IR), but not D1R‐IR, was observed on the EGCs. Both D1R‐IR and D2R‐IR were co‐localized on cholinergic neurons. Low concentrations of DA induced colonic GDNF secretion in a concentration‐dependent manner, which was mimicked by a D1R agonist SKF38393, inhibited by TTX and atropine, and eliminated in D1R‐/‐ mice. SKF38393‐induced colonic ACh release was absent in D1R‐/‐ mice. High concentrations of DA suppressed colonic GDNF secretion, which was mimicked by D2R agonist quinpirole, and absent in AAV‐shD2R‐treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca2+ level in primary cultured EGCs. Besides, carbachol (analog of ACh) promoted the release of GDNF. Quinpirole inhibited the colonic ACh release, which was eliminated in the AAV9‐shD2R‐treated mice. 6‐OHDA rats with low ACh and high DA content showed decreased GDNF content and increased mucosal permeability in the colon.Conclusion and ImplicationsLow concentrations of DA promote colonic GDNF secretion via D1R on cholinergic neurons, whereas at high concentrations, DA inhibits the GDNF secretion via D2R on EGCs and/or cholinergic neurons.

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“…Accordingly, it is well known that inflammatory bowel disease (IBDs) patients are at risk for PD (Lee et al, 2021;Li et al, 2023). Breakdown of the intestinal epithelial barrier (IEB) and gut inflammation has been described during PD, along with the changes in the enteric neurochemical code and enteric glial reactivity (Clairembault et al, 2014(Clairembault et al, , 2015Corbille et al, 2016;Coletto et al, 2021;Thomasi et al, 2022). Therefore, regardless of whether PD originates bottom-up or top-down through the gut-brain axis, peripheral neuroinflammatory responses are known to be associated with the disorder.…”

Section: Neuroinflammation Through the Gut-brain Axis In Parkinson's ...mentioning

confidence: 99%

“…In other words, checking areas of the nervous system as well as layer-specific responses in the intestine and their possible interactions. Multiple groups have demonstrated that enteric glia is activated in the myenteric plexus in several types of animal models of PD, whether bottom-up or top-down models (Perez-Pardo et al, 2019;Dodiya et al, 2020;Pellegrini et al, 2020Pellegrini et al, , 2022Palanisamy et al, 2022;Thomasi et al, 2022). The bottom-up (or body-first) hypothesis postulates the body periphery, mainly the ENS, as the first site of pathologic processes that would be spread out until CNS via inflammatory and anatomical pathways as it progresses.…”

Section: Neuroinflammation Through the Gut-brain Axis In Parkinson's ...mentioning

confidence: 99%

Enteric glia as a player of gut-brain interactions during Parkinson’s disease

Thomasi,

Valdetaro,

Ricciardi

et al. 2023

Front. Neurosci.

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The enteric glia has been shown as a potential component of neuroimmune interactions that signal in the gut-brain axis during Parkinson’s disease (PD). Enteric glia are a peripheral glial type found in the enteric nervous system (ENS) that, associated with enteric neurons, command various gastrointestinal (GI) functions. They are a unique cell type, with distinct phenotypes and distribution in the gut layers, which establish relevant neuroimmune modulation and regulate neuronal function. Comprehension of enteric glial roles during prodromal and symptomatic phases of PD should be a priority in neurogastroenterology research, as the reactive enteric glial profile, gastrointestinal dysfunction, and colonic inflammation have been verified during the prodromal phase of PD—a moment that may be interesting for interventions. In this review, we explore the mechanisms that should govern enteric glial signaling through the gut-brain axis to understand pathological events and verify the possible windows and pathways for therapeutic intervention. Enteric glia directly modulate several functional aspects of the intestine, such as motility, visceral sensory signaling, and immune polarization, key GI processes found deregulated in patients with PD. The search for glial biomarkers, the investigation of temporal–spatial events involving glial reactivity/signaling, and the proposal of enteric glia-based therapies are clearly demanded for innovative and intestine-related management of PD.

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Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine

Cited by 12 publications

References 71 publications

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

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

Dopamine regulates colonic glial cell‐derived neurotrophic factor secretion through cholinergic dependent and independent pathways

Enteric glia as a player of gut-brain interactions during Parkinson’s disease

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