Background: Parkinson's disease (PD) is intricately linked to gastrointestinal inflammation and the presence of neurotoxins in the gut, integrating α-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 α-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, α-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, α-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 α-syn pathology and exerts neurodegeneration in the intragastric rotenone PD mouse model.

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This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson's disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson's disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson's disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.

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