Copyright © 2008 Elsevier Inc. All rights reserved.
Neuroprotective effect of the new thiadiazolidinone NP00111 against oxygen-glucose deprivation in rat hippocampal slices: Implication of ERK1/2 and PPARγ receptors
Rosa AO, Egea J, Martínez A, García AG, López MG.
Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Thiadiazolidinones (TDZDs) are small molecules that inhibit glycogen synthase kinase 3-beta (GSK3-beta) activity in a non competitive manner to ATP. NP00111, a new TDZD, besides causing inhibition of GSK-3beta, has also shown to be an agonist of PPARgamma . Since phosphorylation and consequent inhibition of GSK-3beta by PI-3K/Akt and agonism of PPARgamma have shown to afford neuroprotection in several in vitro and in vivo models, we have studied the potential neuroprotective effect of NP00111 in an "in vitro" model of ischemia-reperfusion. NP00111, at the concentration of 10 muM, significantly protected adult rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) for 1 h followed by 3 h re-oxygenation, measured as lactic dehydrogenase (LDH) released to the extracellular media. The protective effects of NP00111 were more pronounced during the re-oxygenation period in comparison to the OGD period. Other GSK-3beta inhibitors like lithium or AR-A014418 did not afford protection in this model. However, the PPARgamma agonist rosiglitazone was protective at 3 muM. Protection afforded by NP00111 and rosiglitazone were prevented by the PPARgamma antagonist GW9662, suggesting that both NP00111 and rosiglitazone were preventing cell death caused by oxygen-glucose deprivation via activation of PPARgamma. NP00111 increased by two fold phosphorylation of ERK1/2 and its protective effects were lost when the hippocampal slices were co-incubated with the mitogen-activated protein kinase (MAPK) inhibitor PD98059. In conclusion, the novel TDZD NP00111 was protective against OGD in rat hippocampal slices by a mechanism related to phosphorylation of ERK1/2 via activation of PPARgamma.
13 mayo 2008
Científicos del Hospital La Fe de Valencia. Los médicos han encontrado 13 nuevas mutaciones del gen BCRA1 y BCRA2 de estos tipos de cáncer ....
.... tras el estudio genético de 620 familias valencianas. Según sus conclusiones, los pacientes con esta enfermedad pueden experimentar alteraciones en estos genes. Si esto ocurre, las hijas que heredan la mutación tienen una probabilidad de hasta el 70 por ciento de desarrollar la patología en el pecho, sobretodo en edades comprendidas entre los 25 y los 65 años. Y en el caso del cáncer de ovario, las posibilidades se sitúan entre el 15 por ciento y el 45 por ciento.....
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