| Autor: |
Lahmy, Valentine, Meunier, Johann, Malmström, Susanna, Naert, Gaelle, Givalois, Laurent, Kim, Seung Hyun, Villard, Vanessa, Vamvakides, Alexandre, Maurice, Tangui |
| Předmět: |
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| Zdroj: |
Neuropsychopharmacology; Aug2013, Vol. 38 Issue 9, p1706-1723, 18p, 1 Chart, 9 Graphs |
| Abstrakt: |
The main objective of the present study was to establish whether the mixed σ1/muscarinic ligand ANAVEX2-73, shown to be neuroprotective in Alzheimer's disease (AD) models in vivo and currently in clinical phase I/IIa, could have the ability to reduce the appearance of hyperphosphorylated Tau and amyloid-β1-42 (Aβ1-42) in the Aβ25-35 mouse model of AD. We therefore first confirmed that Aβ25-35 injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3β (GSK-3β) in the mouse hippocampus. Second, we showed that the kinase activation, and resulting Tau alteration, directly contributed to the amyloid toxicity, as co-administration of the selective GSK-3β inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and Aβ25-35-induced memory impairments. Third, we analyzed the ANAVEX2-73 effect on Tau phosphorylation and activation of the related kinase pathways (Akt and GSK-3β). And fourth, we also addressed the impact of the drug on Aβ25-35-induced Aβ1-42 seeding and observed that the compound significantly blocked the increase in Aβ1-42 and C99 levels in the hippocampus, suggesting that it may alleviate amyloid load in AD models. The comparison with PRE-084, a selective and reference σ1 receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and σ1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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