Ionophore ability of carnosine and its trehalose conjugate assists copper signal to trigger Brain Derived Neurotrophic Factor and Vascular Endothelial Growth Factor activation in vitro

L-carnosine (?-alanyl-L-histidine) (Car hereafter) is a natural dipeptide widely distributedin mammalian tissues and reaching high concentrations (0.7-2.0 mM) in the brain. The molecularfeatures of the dipeptide underlie the antioxidant, anti-aggregating and metal chelating abilityshowed in a large number of physiological effects, while the biological mechanisms involved inthe protective role found against several diseases cannot be explained on the basis of the abovementioned properties alone, requiring further research efforts. It has been reported that L-carnosineincreases the secretion and expression of various neurotrophic factors and affects copper homeostasisin nervous cells inducing Cu cellular uptake in keeping with the key metal-sensing system. Having inmind this L-carnosine ability, here we report the copper-binding and ionophore ability of L-carnosineto activate tyrosine kinase cascade pathways in PC12 cells and stimulate the expression of BDNF.Furthermore, the study was extended to verify the ability of the dipeptide to favor copper signalinginducing the expression of VEGF. Being aware that the potential protective action of L-carnosine isdrastically hampered by its hydrolysis, we also report on the behavior of a conjugate of L-carnosinewith trehalose that blocks the carnosinase degradative activity. Overall, our findings describe acopper tuning effect on the ability of L-carnosine and, particularly its conjugate, to activate tyrosinekinase cascade pathways.

Carnosine (?-alanyl-L-histidine) is a natural dipeptide widely distributed in mammalian tissues and presented at high concentrations (0.7-2.0mM) in the brain. More recent research has been focused on a potential role for carnosine to exert a wider range of physiological effects. The potential therapeutic ability against several diseases cannot be attributed to a single biochemical pathway as that related to the well-known antioxidant properties. It was reported previously that carnosine augments the secretion and expression of various neurotrophic factors. Moreover, carnosine in-tercepts the regulatory routes of Cu homeostasis in nervous cells influencing intracellular Cu entry and affecting the key Cu-sensing system. Having in mind this carnosine ability, here we report on the role played by carnosine-assisted copper to activate tyrosine kinase cascade pathways in PC12 cells, stimulating the expression of the trophic factor BDNF by means of CREB. Furthermore, the study was extended to the ability of carnosine to favor copper signaling inducing expression of VEGF. Taking in consideration that the potential therapeutic action of carnosine is drastically hampered by its hydrolysis, we also report on the behavior of a conjugate of Car with trehalose. Overall, our findings describe a copper tuning effect on the ability of carnosine and more its con-jugate with trehalose to activate tyrosine kinase cascade pathways.