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

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.