New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System.

Cholinergic deficit is a characteristic factor of several pathologies, such as myasthenia gravis, some types of congenital myasthenic syndromes, and Alzheimer's Disease. Two molecular targets for its treatment are acetylcholinesterase (AChE) and nicotinic acetylcholine receptor (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Here, we present new bifunctional caffeine derivatives consisting of a theophylline ring connected to amino groups by different linkers. All of them were more potent AChE inhibitors than caffeine. Furthermore, although some of them also activated muscle nAChR as partial agonists, not all of them stabilized nAChR in its desensitized conformation. To understand the molecular mechanism underlying these results, we performed docking studies on AChE and nAChR. The nAChR agonist behavior of the compounds depends on their accessory group, whereas their ability to stabilize the receptor in a desensitized state depends on the interactions of the linker at the binding site. Our results show that the new compounds can inhibit AChE and activate nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in cholinergic deficit.

Actividad gastroprotectora, tamizaje fitoquímico y actividad atrapadora de radicales libres de Aloysia Gratissima (Verbenaceae) / Phytochemical screning, gastroprotective activity and free radical scavenging activity of Aloysia gratissima (Verbenaceae)

Se evaluó la actividad gastroprotectora de la infusión proveniente de las hojas de Aloysia gratissima (Verbenaceae), especie nativa de interés medicinal que se desarrolla en el sudoeste bonaerense, utilizando un modelo de inducción de úlceras gástricas con etanol en ratones. Se realizó un tamizaje fitoquímico para detectar la presencia de compuestos que podrían ser responsables de la actividad gastroprotectora de la planta. Se determinó el contenido de fenoles totales y la capacidad atrapadora de radicales libres mediante el método del Folin-Ciocalteu y del 2,2'-difenil-1-picrilhidrazilo (DPPH), respectivamente. Los ensayos demostraron que la infusión de la planta, administrada por vía oral en dosis de 100, 500 y 1000 mg/kg, ejerció una gastroprotección significativa frente a la inducción de úlceras. Se detectó una actividad atrapadora de radicales libres de 47,5%, similar a la sustancia de referencia (BHT). El estudio fitoquímico detectó la presencia de flavonoides y otros polifenoles, sustancias con reconocida capacidad antioxidante. Estos metabolitos ejercen efectos protectores en diferentes modelos experimentales de inducción de úlceras mediante mecanismos que pueden involucrar la neutralización de radicales libres, lo que podría explicar la actividad gastroprotectora de la planta. Estos hallazgos requieren estudios adicionales de A. gratissima como una posible terapia frente a la úlcera gástrica. (AU)

The gastroprotective activity of the infusion from the leaves of Aloysia gratissima (Verbenaceae), a native species of medicinal interest growing in South West Buenos Aires, was evaluated in an ethanol-induced gastric ulcer model in mice. Phytochemical screening was carried out in order to determine the presence of compounds that could be responsible for the pharmacological effects of the plant. Total phenolic content and the free radical scavenging activity of the plant were determined using the Folin-Ciocalteu and the 2,2'-diphenyl1-picrylhydrazyl (DPPH) method, respectively. Assays demonstrated that the infusion, orally administered at 100, 500, and 1000 mg/kg doses, exerted a significant gastroprotection effect against ulcer induction (P<0,05). A free radical scavenging activity of 47.5% -similar to the reference substance (BHT)- was detected. Phytochemical screening revealed the presence of antioxidant compounds such as flavonoids and other phenolic compounds. These compounds exert protective effects in different experimental models of ulcer induction that could involve free radical neutralization, which could explain the gastroprotective activity of the plant. These promising results support additional studies of A. gratissima as a potential therapy against gastric ulcer. (AU)