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BackgroundThe contribution of gastrointestinal (GI) inflammation and local exposure to neurotoxins in the gut offers the most in-depth explanation of Parkinson’s disease (PD) etiopathogenesis through abnormal accumulation and spreading of alpha-synuclein (α-syn) aggregates from the gut to the brain.ObjectivesThis study was designed to investigate whether dextran sodium sulfate (DSS)-mediated colitis may have lasting effects on dopaminergic pathways in the brain and whether or not colitis exacerbated susceptibility to later exposure to the neurotoxin rotenone.MethodsTo induce chronic colitis, 10 months old C57BL/6 mice were pre-exposed to 3 cycles of 7 days of 1% (w/v) DSS administration in drinking water followed by 14 days 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 8thweek after colitis, 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.ResultsWe found that local rotenone exposure for 8 weeks did not affect colitis severity and colonic tight junction(TJ) protein expression (ZO-1, Occludin, and Claudin-1). On the other hand, we found that while eight weeks of chronic rotenone administration led to an increase in inflammatory markers, the presence of pre-existing colitis resulted in a considerable change in gut microbiota composition and a decrease in TJ’s protein expression. In addition, the administration of rotenone in mice post-colitis caused gastrointestinal function impairment and poor behavioral performances. Itworsened rotenone-induced α-syn pathology in the colon, which extended upward and resulted in severe dopaminergic neuron loss and significant astroglia activation in the dorsal motor nucleus of the vagus (DMV), locus coeruleus, substantia nigra as well as in striatum. Interestingly, in the case of rotenone alone, we found that α-syn induced ChAT+neuronal death is restricted to the DMV. These findings indicate that long-term rotenone exposure in conjunction with early inflammatory intestinal milieu exacerbates the progression of α-syn pathology and aggravates neurodegeneration in the intragastric mouse PD model.ConclusionsThis work provides detailed insight into the involvement of GI inflammation triggered after a neurotoxic insult in the colon and explores their potential to impact central dopaminergic degeneration in PD. This way, we can identify potential therapeutic targets that stop the enteric inflammatory processes involved in progressing PD.Graphical AbstractHighlightsLow-dose intragastric rotenone post-colitis aggravates gastrointestinal dysfunction and accelerates the onset of motor impairment.Low-dose intragastric rotenone did not alter colitis clinical and histological aspects.Low-dose intragastric rotenone post-colitis exacerbated the progression of α-syn pathology from the GI tract to the brain, leading in central dopaminergic neuronal degeneration.

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range0.20-13.47 μg ml(-1)). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.