Detalle de: S4-04-06

GSK–3 is a serine/threonine kinase with an astoundingly diverse number of actions in intracellular signalling systems. It plays crucial roles in several human diseases having great potential for therapeutic intervention. Currently, GSK–3 inhibitors arise as promising drugs for the pharmacotherapy of several acute pathologies as cancer, diabetes, stroke, mood disorders, inflammation or Alzheimer′s disease (AD), among others. Recently, a large body of evidence has accumulated linking GSK–3 with tau hyperphosphorylation, and more recently, Aβ production, the two pathological hallmarks of AD. The small heterocyclic thiadiazolidindiones (TDZDs) represent the first non–ATP competitive GSK3 inhibitors reported to date and have been proposed as new disease–modifying agents for the effective treatment of neurodegenerative disorders where tau phosphorylation plays a key role, such as AD. TDZDs have favourable ADME–Tox drugable properties and their therapeutic potential has been proved using different animal models. A prolonged oral administration of a TDZD compound to the GSK3β conditional transgenic mice (Tet/GSK3β) produces a significant decrease on tau phosphorylation both in the hippocampus and cortex areas where the transgene is expressed. Moreover, this TDZD compound is able to improve cognition (by object recognition test), and diminish the cortex and hippocampus amyloid plaque load in an APP–PS1 double transgenic mouse after 2 months of oral administration. The positive observed effects in these studies together with some other neuroprotective properties found on this family of compounds, confirm the potential of TDZDs as new therapeutic agents for the inhibition of GSK3 and tau phosphorylation in AD and other tauopathies.