Chronic treatment with the tetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic cholinergic and sigma-1 ligand, alleviates pathology in Tg2576 mice, a transgenic Alzheimer's disease model
Saturday, Nov 09, 2013, 4:00 PM - 5:00 PM
++C.03.i. In vivo Abeta toxicity
, V. LAHMY
, V. VILLARD
, A. VAMVAKIDES
INSERM U.710, Montpellier, France;
AMYLGEN, Montpellier, France;
ANAVEX LIFE SCIENCES, Pallini, Greece
Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) is a novel compound binding to muscarinic cholinergic and sigma-1 receptors with affinities in the low micromolar range. We previously reported that the drug showed anti-amnesic and neuroprotective potential in the Alzheimer's disease (AD) model in mice induced by the icv injection of oligomeric amyloid(25-35) peptide. In particular, the drug attenuated the oxidative stress, caspases induction, cellular loss, Aß1-42 seeding, Tau hyperphosphorylation, mitochondrial dysfunction and learning and memory deficits observed several days after Aß25-35 injection. The mechanism of action appeared to involve synergically muscarinic cholinergic receptors and the sigma-1 chaperone protein, a potent sensor/modulator of cellular responses. In the present study, we treated 10-month old Tg2576 mice, overexpressing the swedish hAPP mutation,, with ANAVEX2-73, 3 mg/kg/day per os, during two months. 40 male and 60 female mice were used and data were analyzed for each gender and globally. Vehicle-treated Tg2576 showed significant alterations of spontaneous alternation in Y-maze at 11 and 12 month of age and of place learning in the water-maze at 12 months. These deficits were prevented by the ANAVEX2-73 treatment. Animals were sacrificed after the behavioral procedures and used for biochemical analyses. Tg2576 mice presented an increased cerebral oxidative stress (measured by oxidation rate of dichlorofuorescein diacetate) and a synaptic alteration (measured by a decrease in synaptophysin content). Both were normalized in ANAVEX2-73 treated mice. We confirmed a positive impact of the compound on brain plasticity by measuring (by qPCR analysis) increased expression of Arc, Egr-1, NR2A, NR2B and PSD95 mRNA. However, the compound only marginally decreased soluble and insoluble Aß1-42 brain contents, and only in male mice. Morphological analyses are in progress. This first set of data confirmed the efficacy of the mixed muscarinic cholinergic receptor ligand and sigma-1 receptor agonist in a chronic transgenic mouse model of AD. The compound allows an effective brain protection during the most aggressive phase of the pathology.
B. Contracted Research/Research Grant (principal investigator for a drug study, collaborator or consultant and pending and current grants). If you are a PI for a drug study, report that research relationship even if those funds come to an institution.; ANAVEX LIFE SCIENCES. F. Consulting Fees (e.g., advisory boards); AMYLGEN.
A. Employment/Salary (full or part-time):; CIFRE funding AMYLGEN.
A. Employment/Salary (full or part-time):; AMYLGEN.
A. Employment/Salary (full or part-time):; ANAVEX LIFE SCIENCES.
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