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

In the search for low-cost year-round feeds: Pen-level growth performance of local and crossbred Ugandan pigs fed forage- or silage-based diets versus commercial diet

Smallholder pig farmers in East Africa report that lack of feed, seasonal feed shortages, quality and cost are key constraints to pig rearing. Commercially prepared pig diets are too expensive and people and pigs compete for food. Smallholder farmers typically feed nutritionally unbalanced diets, resulting in low average daily gain (ADG) and poor farmer profits. Our objective was to compare the ADG of Ugandan pigs fed forage- or silage-based or commercial diets. Ugandan weaner-grower pigs were randomly assigned to forage- or silage-based diets or commercial diet. Pigs were weighed every 3 weeks from 9 to 32 weeks of age. Pen-level ADG and feed conversion were compared across diets using multiple linear regression. The ADG of pigs fed forage- or silage-based diets was lower than those fed commercial diets between 9 and 24 weeks of age (p  0.05). Between 28 and 32 weeks, pigs fed forage-based diets had lower ADG than those on other diets (p  0.05). Least squares mean ADG (g/pig/day) for pigs fed forage- or silage-based diets or commercial diet were 36, and 52, and 294 respectively at 9–15 weeks; 163, 212, 329 at 15–19 weeks; 112, 362, 574 at 20–24 weeks and 694, 994, and 1233 at 28 to 32 weeks of age. It was concluded that forage- and silage-based diets are unsuitable for small, newly weaned pigs. Feeding forage- or silage-based diets to finishing pigs is more suitable. Forage- and silage based diets are year-round low-cost pig-feeding strategies that will improve the growth performance of East African pigs, thereby increasing pig farmer income and food security

Summary data of potency and parameter information from semi-mechanistic PKPD modeling of prolactin release following administration of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride in rats

We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, “A comparison of two semi-mechanistic models for prolactin release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats” (Taneja et al., 2016) [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1. Model parameters required to explore the precursor pool model are presented in Table 2. In Table 3, estimated parameter comparisons for both models are presented, when separate potencies are estimated for risperidone and paliperidone, as compared to a common potency for both drugs. In Table 4, parameter estimates are compared when the drug effect is parameterized in terms of drug concentration or receptor occupancy

Blood-brain barrier perturbations by uremic toxins: key contributors in chronic kidney disease-induced neurological disorders?

Chronic kidney disease is multifactorial and estimated to affect more than 840 million people worldwide constituting a major global health crisis. The number of patients will continue to rise mostly because of the aging population and the increased prevalence of comorbidities such as diabetes and hypertension. Patients with advanced stages display a loss of kidney function leading to an accumulation of, a.o. protein-bound uremic toxins that are poorly eliminated by renal replacement therapies. This systemic retention of toxic metabolites, known as the uremic syndrome, affects other organs. Indeed, neurological complications such as cognitive impairment, uremic encephalopathy, and anxiety have been reported in chronic kidney disease patients. Several factors are involved, including hemodynamic disorders and blood-brain barrier (BBB) impairment. The BBB guarantees the exchange of solutes between the blood and the brain through a complex cellular organization and a diverse range of transport proteins. We hypothesize that the increased exposure of the brain to protein-bound uremic toxins is involved in BBB disruption and induces a perturbation in the activity of endothelial membrane transporters. This phenomenon could play a part in the evolution of neurological disorders driven by this kidney-brain crosstalk impairment. In this review, we present chronic kidney disease-induced neurological complications by focusing on the pathological relationship between the BBB and protein-bound uremic toxins. The importance of mechanistically delineating the impact of protein-bound uremic toxins on BBB integrity and membrane drug transporter expression and function in brain endothelial capillary cells is highlighted. Additionally, we put forward current knowledge gaps in the literature

Testing the Cosmic Coincidence Problem and the Nature of Dark Energy

Dark energy models which alter the relative scaling behavior of dark energy and matter could provide a natural solution to the cosmic coincidence problem - why the densities of dark energy and dark matter are comparable today. A generalized class of dark energy models is introduced which allows non-canonical scaling of the ratio of dark matter and dark energy with the Robertson-Walker scale factor a(t). Upcoming observations, such as a high redshift supernova survey, application of the Alcock-Paczynski test to quasar pairs, and cluster evolution, will strongly constrain the relative scaling of dark matter and dark energy as well as the equation of state of the dark energy. Thus, whether there actually is a coincidence problem, and the extent of cosmic coincidence in the universe's recent past can be answered observationally in the near future. Determining whether today is a special time in the history of the universe will be a SNAP.Comment: 5 pages, 3 figures, revtex4, submitted to PR

[11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein

Background:

Alteration in P-glycoprotein Functionality Affects Intrabrain Distribution of Quinidine More Than Brain Entry—A Study in Rats Subjected to Status Epilepticus by Kainate

This study aimed to investigate the use of quinidine microdialysis to study potential changes in brain P-glycoprotein functionality after induction of status epilepticus (SE) by kainate. Rats were infused with 10 or 20 mg/kg quinidine over 30 min or 4 h. Plasma, brain extracellular fluid (brain ECF), and end-of-experiment total brain concentrations of quinidine were determined during 7 h after the start of the infusion. Effect of pretreatment with tariquidar (15 mg/kg, administered 30 min before the start of the quinidine infusion) on the brain distribution of quinidine was assessed. This approach was repeated in kainate-treated rats. Quinidine kinetics were analyzed with population modeling (NONMEM). The quinidine microdialysis assay clearly revealed differences in brain distribution upon changes in P-glycoprotein functionality by pre-administration of tariquidar, which resulted in a 7.2-fold increase in brain ECF and a 40-fold increase in total brain quinidine concentration. After kainate treatment alone, however, no difference in quinidine transport across the blood–brain barrier was found, but kainate-treated rats tended to have a lower total brain concentration but a higher brain ECF concentration of quinidine than saline-treated rats. This study did not provide evidence for the hypothesis that P-glycoprotein function at the blood–brain barrier is altered at 1 week after SE induction, but rather suggests that P-glycoprotein function might be altered at the brain parenchymal level

Structure of a two-G-tetrad intramolecular G-quadruplex formed by a variant human telomeric sequence in K+ solution: insights into the interconversion of human telomeric G-quadruplex structures

Human telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. The telomeric sequence shows intrinsic structure polymorphism. Here we report a novel intramolecular G-quadruplex structure formed by a variant human telomeric sequence in K+ solution. This sequence forms a basket-type intramolecular G-quadruplex with only two G-tetrads but multiple-layer capping structures formed by loop residues. While it is shown that this structure can only be detected in the specifically truncated telomeric sequences without any 5′-flanking residues, our results suggest that this two-G-tetrad conformation is likely to be an intermediate form of the interconversion of different telomeric G-quadruplex conformations

A Case of Recurrent Multifocal Central Giant Cell Granulomas

One case of recurrent multifocal central giant cell granulomas (CGCG) is presented. Initially, the lesions presented concurrently in the maxilla and mandible with subsequent recurrence in the mandible. Now, two recurrences are seen in the maxillary sinus and ethmoid region. The literature regarding multifocal CGCG is reviewed