The new indirubin derivative inhibitors of glycogen synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured neurons

摘要: Alterations in glycogen synthase kinase-3β (GSK3β) and protein phosphatase-2A (PP2A) have been proposed to be involved the abnormal tau phosphorylation aggregation linked Alzheimer's disease (AD). Interconnections between GSK3β PP2A signaling pathways are well established. Targeting kinases was represent a therapeutic strategy for AD. However, which should blocked what extent, keeping mind that physiological roles? Because most kinase inhibitors relatively specific many of them interfere with cell cycle, it is necessary develop more devoid toxicity. Here, we used inhibition by okadaic acid (OKA) primary cultured cortical neurons as an vitro model increased apoptosis. We tested effects two newly characterized indirubin derivative GSK3, 6-BIDECO (6-bromoindirubin-3'-[O-(N,N-diethylcarbamyl)-oxime] 6-BIMYEO (6-bromoindirubin-3'-[O-(2-morpholin-1-ylethyl)-oxime] hydrochloride) on OKA-induced neuronal Both compounds exhibit higher selectivity toward GSK3 compared other (for 6-BIDECO, IC50 0.03 μM >10 CDK1, 10 CDK5; 6-BIMYEO, 0.11 1.8 0.9 CDK5). show at micromolar concentrations not neurotoxic potently reversed apoptosis induced OKA. The neuroprotection these further validated animal models