The main hallmarks of Alzheimer's disease (AD) are senile plaques, neurofibrillary tangles and neuronal death. The McGill-R-Thy1-APP rat is one of the few transgenic rat models of AD that displays progressive amyloid pathology. This study aimed to further characterise this rat model, focusing on the pathological changes in the hippocampal formation and the parahippocampal region. These structures, that are important for episodic memory and spatial navigation, are affected in the early stages of the disease. This study used unbiased stereology to investigate possible neuronal loss in the CA1, subiculum and entorhinal cortex of 18-month-old homozygous McGill-R-Thy1-APP rats, and also quantified the plaque load in all the areas of the hippocampal formation and parahippocampal region from 9 to 18 months old. A significant reduction of neurons at 18 months was only seen in the subiculum. The first plaque pathology was seen at 9 months in the subiculum. Although the quantified plaque load was variable between animals, the pattern of spatiotemporal progression was similar for all animals. The spread of plaque pathology mainly affected anatomically connected regions. Overall, the plaque pathology observed in the transgenic rats was similar to the early phases of amyloid beta (Aβ)-deposition described in human patients. The findings here thus indicate that the McGill-R-Thy1-APP rat could be a good model of the Aβ pathology in AD, but less so with respect to neuron loss.

Ibuprofen binds to plasma albumin and could interfere with the binding of bilirubin in jaundiced newborn infants. Most clinical studies have not shown increased concentrations of unbound bilirubin (UB) in plasma from infants treated with ibuprofen for a patent ductus arteriosus. However, studies in vitro have not been equally conclusive. Plasma were obtained from routine samples from jaundiced newborn infants and pooled. Total and UB were measured with the peroxidase method after addition of ibuprofen or sulfisoxazole as a known bilirubin displacer. Final ibuprofen concentrations varied from 0.43 to 2.6 mM. Bilirubin concentrations were varied from 176 to 708 M by adding bilirubin to plasma samples. Ibuprofen caused a linear increase in UB up to ϩ54% at a concentration of 1.8 mM, compared with an increase of 87% by sulfisoxazole (1.32 mM). A double reciprocal plot of molar concentrations of bound versus UB at bilirubin concentrations ranging from 176 to 708 M showed a competitive displacement of bilirubin by ibuprofen. The data indicate that ibuprofen is a competitive displacer of bilirubin in vitro. Ibuprofen should be used with caution in premature infants with a significant hyperbilirubinemia. (Pediatr Res 67: 614-618, 2010) T he significance of unconjugated hyperbilirubinemia is the potential for development of bilirubin neurotoxicity and kernicterus. Most healthy term infants with a total serum bilirubin (TB) concentration reaching 425 to 680 M will, however, escape with no significant damage when treated with phototherapy and/or exchange transfusion according to guidelines (1). However, 8 to 9% of the kernicterus cases occur at a TB concentration Ͻ425 M. Kernicterus has also been reported at TB concentrations Ͻ340 M (2,3). In premature infants, bilirubin toxicity has been observed at even lower TB concentrations (4,5). More recently, high peak TB has been associated with poor long-term prognosis and adverse neurodevelopmental outcome in extremely low birth weight infants (6,7).The binding site of bilirubin on the albumin molecule is still uncertain, but most likely bilirubin binds to albumin at one high affinity binding site in a 1:1 molar ratio (3,8 -10). Clinical and experimental data have also suggested different secondary binding sites. However, these secondary binding sites may not be of any physiologic importance (10). At equilibrium, ϳ0.005% of bilirubin will be unbound bilirubin (UB). The albumin-bilirubin complex has a high molecular weight and cannot cross capillary walls, whereas UB is available for tissue distribution and elimination (9,11). Bilirubin is not toxic while bound to albumin (BB), and it is thought that the concentration of UB is a better predictor of toxicity than TB. The distribution and elimination of UB causes a shift in the equilibrium, and more bilirubin is released from albumin. The concentration of UB is influenced by several factors like the concentration of TB (2), albumin, and the binding capacity of albumin (5). Of clinical importance is the fact that the bindi...

The aim of the present study was to clarify the in vitro potential of the purified Chinese herbal constituents LZX-A (neferine), QTJ (sinomenine), YHS (tetrahydropalmitine) and SQZG (notoginsenoside R1) to displace the highly bound bilirubin from albumin binding sites in plasma from jaundiced newborn infants. Sulfisoxazole (1.32 mM) was used as a positive control for bilirubin displacement. The displacing potential of the herbal constituents was investigated at assumed therapeutic concentrations and up to 100 times higher. Total (TB) and unbound (UB) bilirubin in plasma were measured by the peroxidase method. Sulfisoxazole increased the UB concentration in plasma by more than 60%. An increased % displacement of bilirubin was found at higher TB levels confirming the presence also of lower affinity binding sites for bilirubin in plasma. None of the purified herbal constituents showed any bilirubin displacing properties and were unaffected by the level of TB in plasma. The combination of sulfisoxazole and the herbal constituents showed no synergistic effect. It is concluded that none of the investigated purified herbal constituents possess any significant potential in vitro to increase the UB concentration in plasma from jaundiced newborn infants.