Ageing affects many cellular processes which favor chronic neurodegenerative diseases, among them Alzheimer’s disease (AD). AD is a complex pathology which involves more than 20 million individuals in the world. AD is characterized by memory loss and other cognitive deficiencies, by the progressive dissolution of the personality as well as of the intellectual capacities. AD is accompanied by damages to brain capillaries, impairment of cholinergic transmission in both the hippocampus and the cerebral cortex as well as by extracellular accumulation of β-amyloid (Aβ) plaques and intracellular tau protein aggregates in different area of the brain. In addition, it has been shown that oxidative stress, related to an abnormal production of reactive oxygen species (ROS) and nitrogen species (RNS) and/or depletion of the antioxidant defences, is an important early event in AD.[2] An increasing amount of experimental data suggests that AD is a cerebral microvascular disorder with neurodegenerative consequences, rather than the opposite. Microvascular disorders occurring in advanced ageing or in the presence of increased oxidative stress are consequent to the endothelial dysfunction, namely to a reduced capacity of the endothelial cells to produce nitric oxide (NO). On this basis we designed new “multifunctional” molecules potentially useful in modifying the development and the progress of AD. These products were obtained by combining the structure of L-carnosine, a natural dipeptide endowed with a complex and multifactorial antioxidant action, with nitrooxy NO-donor moieties. These two pharmacophores were joined through an amide bond which, in a previous work, allowed us to obtain compounds stable in human serum, overcoming the major drawback of carnosine, while preserving its beneficial properties. Synthesis, serum stability, vasodilating properties, antioxidant activity, ability to scavenge reactive carbonyl species (RCS) as well as copper (II) chelating properties of the obtained models are reported.
NO-donor Carnosine Derivatives As Potential Neuroprotective Agents
MONTANARO, GABRIELE;BERTINARIA, Massimo;GIORGIS, Marta;ROLANDO, Barbara;FRUTTERO, Roberta;GASCO, Alberto
2011-01-01
Abstract
Ageing affects many cellular processes which favor chronic neurodegenerative diseases, among them Alzheimer’s disease (AD). AD is a complex pathology which involves more than 20 million individuals in the world. AD is characterized by memory loss and other cognitive deficiencies, by the progressive dissolution of the personality as well as of the intellectual capacities. AD is accompanied by damages to brain capillaries, impairment of cholinergic transmission in both the hippocampus and the cerebral cortex as well as by extracellular accumulation of β-amyloid (Aβ) plaques and intracellular tau protein aggregates in different area of the brain. In addition, it has been shown that oxidative stress, related to an abnormal production of reactive oxygen species (ROS) and nitrogen species (RNS) and/or depletion of the antioxidant defences, is an important early event in AD.[2] An increasing amount of experimental data suggests that AD is a cerebral microvascular disorder with neurodegenerative consequences, rather than the opposite. Microvascular disorders occurring in advanced ageing or in the presence of increased oxidative stress are consequent to the endothelial dysfunction, namely to a reduced capacity of the endothelial cells to produce nitric oxide (NO). On this basis we designed new “multifunctional” molecules potentially useful in modifying the development and the progress of AD. These products were obtained by combining the structure of L-carnosine, a natural dipeptide endowed with a complex and multifactorial antioxidant action, with nitrooxy NO-donor moieties. These two pharmacophores were joined through an amide bond which, in a previous work, allowed us to obtain compounds stable in human serum, overcoming the major drawback of carnosine, while preserving its beneficial properties. Synthesis, serum stability, vasodilating properties, antioxidant activity, ability to scavenge reactive carbonyl species (RCS) as well as copper (II) chelating properties of the obtained models are reported.
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