Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism*
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Amyloid beta-Peptides / administration & dosage
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Amyloid beta-Peptides / biosynthesis*
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Amyloid beta-Peptides / toxicity
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Animals
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Dose-Response Relationship, Drug
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Furans / pharmacology*
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Furans / therapeutic use
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Hippocampus / drug effects
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Hippocampus / metabolism
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Infusions, Intraventricular
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Male
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Memory Disorders / chemically induced
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Memory Disorders / drug therapy
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Mice
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Morpholines / pharmacology
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Morpholines / therapeutic use
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Muscarinic Agonists / pharmacology*
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Muscarinic Agonists / therapeutic use
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Oxadiazoles / administration & dosage
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Oxadiazoles / pharmacology
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Oxadiazoles / therapeutic use
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Peptide Fragments / administration & dosage
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Peptide Fragments / biosynthesis*
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Peptide Fragments / metabolism
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Peptide Fragments / toxicity
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-akt / metabolism
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Receptors, sigma / agonists*
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Signal Transduction / drug effects
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Thiadiazoles / pharmacology
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Thiadiazoles / therapeutic use
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tau Proteins / metabolism*
Substances
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2-thio(3-iodobenzyl)-5-(1-pyridyl)-(1,3,4)oxadiazole
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Amyloid beta-Peptides
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Furans
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Mapt protein, mouse
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Morpholines
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Muscarinic Agonists
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Neuroprotective Agents
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Oxadiazoles
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Peptide Fragments
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Protein Kinase Inhibitors
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Pyridines
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Receptors, sigma
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Thiadiazoles
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amyloid beta-protein (1-42)
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amyloid beta-protein (25-35)
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tau Proteins
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tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride
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2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
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xanomeline
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3