INVESTIGADORES
MURRAY Ana paula
artículos
Título:
A novel pharmacological activity of caffeine in the cholinergic system
Autor/es:
FABIANI, CAMILA; MURRAY, ANA PAULA; CORRADI, JEREM√ćAS; ANTOLLINI, SILVIA SUSANA
Revista:
NEUROPHARMACOLOGY
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Año: 2018 vol. 135 p. 464 - 473
ISSN:
0028-3908
Resumen:
Cholinergic deficit is regarded as an important factor responsible for Alzheimer's disease (AD) symptoms.Acetylcholinesterase (AChE) and nicotinic receptor (AChR) are two molecular targets for the treatment ofthis disease. We found here that methanolic extracts of Camellia sinensis exhibited anticholinesteraseactivity and induced AChR conformational changes. From bioguided fractionation we confirmed thatcaffeine was the active compound exerting such effects. It is well-known that caffeine acts as an inhibitorof AChE and here we explored the effect of caffeine on the AChR by combining single channel recordingsand fluorescent measurements. From single channel recordings we observed that caffeine activated bothmuscle and a7 AChRs at low concentrations, and behaved as an open channel blocker which was evidentat high concentrations. Fluorescent measurements were performed with the conformational sensitiveprobe crystal violet (CrV) and AChR rich membranes from Torpedo californica. Caffeine induced changesin the KD value of CrV in a concentration-dependent manner taking the AChR closer to a desentisizedstate. In the presence of a-bungarotoxin, an AChR competitive antagonist, high concentrations of caffeineincreased the KD value of CrV, compatible with a competition with CrV molecules for the luminalchannel. Our electrophysiological and fluorescent experiments show that caffeine has a dual effect onnicotinic receptors, behaving as an agonist and an ion channel blocker, probably through distinct AChRsites with quite different affinities. Thus, caffeine or its derivatives can be considered for the design ofpromising multitarget-directed drugs for AD treatment by modulation of different targets in thecholinergic pathway