Differentiating the Neuropharmacological Properties of Nicotinic Acetylcholine Receptor-Activating Alkaloids.

Alkaloids that target nicotinic acetylcholine receptors (nAChR) are of great interest because of the critical role they play in mood and anxiety. However, understanding of the neuropharmacological effects of nicotinic alkaloids, such as cotinine and anatabine, is very limited. In this study, we investigated the neuropharmacological effects of three naturally occurring alkaloids-nicotine, cotinine, and anatabine-in vitro and in vivo. A single injection of nicotine induced anxiolytic-like behavioral features in mice by using the SmartCube® behavioral profiling system, while cotinine and anatabine had no detectable effect. The results were corroborated by using the zebrafish novel tank test (NTT), which showed a profound anxiolytic-like effect induced by multiple doses of nicotine after a single 20-min treatment. When the regulation of dopamine and norepinephrine release-the neurotransmitter systems relevant for anxiety-were examined in vitro, we found that nicotine stimulated the release of both norepinephrine and dopamine, while cotinine and anatabine mainly stimulated the dopamine release. The molecular targets of nicotine were confirmed to be nAChRs with its most potent activities against α4ß2 and α6/3ß2ß3 subtypes in vitro. Anatabine was a weaker agonist for these receptors than nicotine. Cotinine was the least potent nAChR compound, only being able to activate α4ß2 and α6/3ß2ß3 subtypes at high doses and no detectable activities against α3ß4 and α7 subtypes at the concentrations tested. The observed effects were unlikely due to the off-target effect, because these alkaloids did not bind or regulate >160 other molecular targets in vitro. Thus, the present results suggest that natural nicotinic alkaloids can induce an anxiolytic-like behavior in nonclinical animal models, potency of which may depend on the activation of various nAChRs and regulation of various neurotransmitter systems. Further investigations would help understand their effects on humans, because non-clinical studies should not be taken as a direct indication for human behavior and nicotine is not risk free.

High Magnesium Corrosion Rate has an Effect on Osteoclast and Mesenchymal Stem Cell Role During Bone Remodelling.

The aim of this study was to gain an understanding on the collective cellular effects of magnesium (Mg) corrosion products on the behaviour of cells responsible for bone formation and remodelling. The response of mesenchymal stem cells (MSCs) and osteoclast cells to both soluble (Mg ions) and insoluble (granule) corrosion products were recapitulated in vitro by controlling the concentration of the corrosion products. Clearance of corrosion granules by MSCs was also inspected by TEM analysis at sub-cellular level. The effect of Mg corrosion products varied depending on the state of differentiation of cells, concentration and length of exposure. The presence of the corrosion products significantly altered the cells' metabolic and proliferative activities, which further affected cell fusion/differentiation. While cells tolerated higher than physiological range of Mg concentration (16 mM), concentrations below 10 mM were beneficial for cell growth. Furthermore, MSCs were shown to contribute to the clearance of intercellular corrosion granules, whilst high concentrations of corrosion products negatively impacted on osteoclast progenitor cell number and mature osteoclast cell function.