Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease

Abstract Background Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease. Methods In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere. Results Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher. Conclusions Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.</p

PoS Tagging, Lemmatization and Dependency Parsing of West Frisian

We present a lemmatizer/PoS tagger/dependency parser for West Frisian using a corpus of 44,714 words in 3,126 sentences that were annotated according to the guidelines of Universal Dependencies version 2. PoS tags were assigned to words by using a Dutch PoS tagger that was applied to a Dutch word-by-word translation, or to sentences of a Dutch parallel text. Best results were obtained when using word-by-word translations that were created by using the previous version of the Frisian translation program Oersetter. Morphologic and syntactic annotations were generated on the basis of a Dutch word-by-word translation as well. The performance of the lemmatizer/tagger/annotator when it was trained using default parameters was compared to the performance that was obtained when using the parameter values that were used for training the LassySmall UD 2.5 corpus. We study the effects of different hyperparameter settings on the accuracy of the annotation pipeline. The Frisian lemmatizer/PoS tagger/dependency parser is released as a web app and as a web service