In Vivo Characterization of a Novel γ-Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects.

Substantial evidence implicates β-amyloid (Aβ) peptides in the etiology of Alzheimer's disease (AD). Aβ is produced by the proteolytic cleavage of the amyloid precursor protein by β- and γ-secretase suggesting that γ-secretase inhibition may provide therapeutic benefit for AD. Although many γ-secretase inhibitors have been shown to be potent at lowering Aβ, some have also been shown to have side effects following repeated administration.

Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Accumulation of amyloid beta-peptide (Abeta) is considered a key step in the etiology of Alzheimer's disease. Abeta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease.

Investigation of the profiling depth in matrix-assisted laser desorption/ionization imaging mass spectrometry.

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry is generally considered to be a surface analysis technique. In this report, the profiling depth of imaging mass spectrometry was examined. MALDI matrix solution was found to be able to gain access to the tissue interior and extract analyte molecules to the tissue surface.

Recombinant human relaxin reduces hypoxic pulmonary hypertension in the rat.

The fibroproliferative changes in pulmonary artery (PA) remodeling are partially prevented by antifibrotic agents. Relaxin (Rlx), a hormone involved in loosening collagen bundles in ligaments during parturition, has antifibrotic and vasodilator properties that may prevent pulmonary vascular remodeling. In the hypoxia model of pulmonary hypertension, two doses of recombinant human relaxin (rhRlx 24 [high] or 5 [low] mg X 10(-2)/kg d(-1)) were administered subcutaneously continuously for 10d to hypoxic (10% O2) rats.

Receptor activator of NF-[kappa]B ligand arrests bone growth and promotes cortical bone resorption in growing rats.

Receptor activator of NF-kappaB ligand (RANKL), produced by osteoblastic lineage cells and activated T cells, is an essential factor for osteoclast differentiation, activation, and survival. Therefore, RANKL is a focal point of therapies targeting bone diseases where there is an imbalance of bone metabolism in favor of bone resorption. The present study assesses the effects of exogenous RANKL on growing bone.

In vivo rat assay: bone remodeling and steroid effects on juvenile bone by pQCT quantification in 7 days.

Anesthetized Sprague-Dawley weanling rats were scanned for bone mineral density (BMD) values after 7 days of treatment to determine whether resorption/growth at the proximal tibia can be quantified by peripheral quantitative computed tomography scanning techniques. Because the weanling rat is in a rapid growth stage, all groups showed significant increases in change from baseline values of BMD. Bisphosphonate treatment produced significant dose-related changes in BMD with average increases of 195 and 241% (10 and 20 microg/kg) vs.