Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice

金沢大学医薬保健研究域医学系Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.3082047

PECULIAR NUCLEAR INCLUSION, NUCLEOLOID BODY, IN LYMPHOCYTES

Peculiar nuclear inclusions, "nucleoloid bodies", were found in nuclei of several types of cells in mouse lymph nodes and in sheep hemal nodes. The nucleoloid bodies were morphologically independent of the nucleolus and the chromatin. They were spherical in shape, ranging from 200 to 900mμ in size, with outer and inner layers that could be differentiated. The outer layer consisted of numerous filaments arranged concentrically or spirally which encircle completely the inner layer. The filaments were helical coils, measuring 70〜80 Å in width. The diameter of the fibril coiled into the helix was approximately 20〜30 Å. The same helical fibrils were also found in the chromatins of nucleoplasm around the nucleoloid bodies. The inner layer was composed of a homogeneous substance of lower electron density and of a variable number of dense granules which were similar to ribosomes in appearance. At high magnification, however, the granules seemed to be twisted threads in which thinner fibrils were coiled. The threads were 200〜250 Å in width and the helical fibrils measured about 50 Å in diameter. The nucleoloid bodies were separated into two types. The first type was small, about 200〜300 mμ in size, and had no or a few dense granular elements in the inner layer. The second type was larger, over 400 mμ in size, whose inner layer had numerous granular elements. The nucleoloid bodies were most often observed in small lymphocytes, in particular the large bodies (second type) were almost limited to the small lymphocytes, though rarely in plasma cells as well. Even if nucleoloid bodies were found in cells other than small lymphocytes, it was rare finding and usually involved the small bodies (first type) only. The nucleoloid bodies seemed to derive from the true nucleoli and were observed in the chromosomes throughout mitosis. From the ultrastructure of the nucleoloid bodies, it was suggested that the bodies consist of a specialized nuclear protein unlike the chromosomes

Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice

Yasuhiko Yamamoto et al. show that oxytocin is transported into the brain by the receptor for advanced glycation end-products (RAGE) on the blood-brain barrier. This study explains how circulating oxytocin crosses the blood-brain barrier, which is important to manifest oxytocin’s maternal bonding effects

Safety and efficacy of sodium caprate in promoting oral drug absorption : from in vitro to the clinic

A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium. To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository. Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be co-released in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C10) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies. In specific clinical examples, we review how C10-based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Science Foundation Irelan