Chronic DSS-Induced Colitis Exacerbates Parkinson's Disease Phenotype and Its Pathological Features Following Intragastric Rotenone Exposure

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F25%3A00082310" target="_blank" >RIV/00159816:_____/25:00082310 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/25:00140666

Výsledek na webu

<a href="https://pubs.acs.org/doi/10.1021/acsptsci.4c00286" target="_blank" >https://pubs.acs.org/doi/10.1021/acsptsci.4c00286</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsptsci.4c00286" target="_blank" >10.1021/acsptsci.4c00286</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Chronic DSS-Induced Colitis Exacerbates Parkinson's Disease Phenotype and Its Pathological Features Following Intragastric Rotenone Exposure

Popis výsledku v původním jazyce

Background: Parkinson&apos;s disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating alpha-syn pathologic alterations and subsequent neurodegeneration into the brain. Objectives: This study aimed to explore the enduring impact of dextran sodium sulfate (DSS)-mediated colitis on the vulnerability of central dopaminergic neurons to subsequent rotenone exposure. Methods: To induce chronic colitis, 10-month-old C57BL/6 mice were pre-exposed to 3 cycles of 1 week of 1% (w/v) DSS administration in drinking water followed by 2 weeks of regular drinking water. After colitis induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 17th week, colon, brain stem, and midbrain tissue were isolated and analyzed for alpha-syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that chronic rotenone administration in the presence of preexisting colitis led to a further increase in colonic pro-inflammatory mediator expressions, alpha-syn expression, and reduced colonic tight junction protein expressions. We also found early impairment of GI functions and worsened grip strength in rotenone-exposed colitic mice. Furthermore, alpha-syn pathology specific to the colitic mice exposed to rotenone showed dopaminergic neurons degeneration and astroglial activation in substantia nigra and striatum, including regions of the brain stem, i.e., dorsal motor of the vagus and locus coeruleus. Finally, the result of 16S rRNA gene sequencing analysis indicated that colitic mice, after being exposed to rotenone, exhibited a discernible trend in their microbiota composition (Catenibacterium, Turicibactor, and clostridium sensue stricto 1), linking it to the development of PD. Conclusions: These findings indicate that prolonged low-dose rotenone exposure, combined with an early inflammatory intestinal milieu, provides a preconditioning effect on alpha-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.

Název v anglickém jazyce

Chronic DSS-Induced Colitis Exacerbates Parkinson's Disease Phenotype and Its Pathological Features Following Intragastric Rotenone Exposure

Popis výsledku anglicky

Background: Parkinson&apos;s disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating alpha-syn pathologic alterations and subsequent neurodegeneration into the brain. Objectives: This study aimed to explore the enduring impact of dextran sodium sulfate (DSS)-mediated colitis on the vulnerability of central dopaminergic neurons to subsequent rotenone exposure. Methods: To induce chronic colitis, 10-month-old C57BL/6 mice were pre-exposed to 3 cycles of 1 week of 1% (w/v) DSS administration in drinking water followed by 2 weeks of regular drinking water. After colitis induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 17th week, colon, brain stem, and midbrain tissue were isolated and analyzed for alpha-syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that chronic rotenone administration in the presence of preexisting colitis led to a further increase in colonic pro-inflammatory mediator expressions, alpha-syn expression, and reduced colonic tight junction protein expressions. We also found early impairment of GI functions and worsened grip strength in rotenone-exposed colitic mice. Furthermore, alpha-syn pathology specific to the colitic mice exposed to rotenone showed dopaminergic neurons degeneration and astroglial activation in substantia nigra and striatum, including regions of the brain stem, i.e., dorsal motor of the vagus and locus coeruleus. Finally, the result of 16S rRNA gene sequencing analysis indicated that colitic mice, after being exposed to rotenone, exhibited a discernible trend in their microbiota composition (Catenibacterium, Turicibactor, and clostridium sensue stricto 1), linking it to the development of PD. Conclusions: These findings indicate that prolonged low-dose rotenone exposure, combined with an early inflammatory intestinal milieu, provides a preconditioning effect on alpha-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

<a href="/cs/project/LX22NPO5107" target="_blank" >LX22NPO5107: Národní ústav pro neurologický výzkum</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Pharmacology &amp; Translational Science

ISSN

2575-9108

e-ISSN

2575-9108

Svazek periodika

8

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

22

Strana od-do

346-367

Kód UT WoS článku

001406692300001

EID výsledku v databázi Scopus

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