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TY - JOUR AU - Villard, Vanessa AU - Espallergues, Julie AU - Keller, Emeline AU - Alkam, Tursun AU - Nitta, Atsumi AU - Yamada, Kiyofumi AU - Nabeshima, Toshitaka AU - Vamvakides, Alexandre AU - Maurice, Tangui PY - 2009 DA - 2009/05/01 TI - Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice JO - Neuropsychopharmacology SP - 1552 EP - 1566 VL - 34 IS - 6 AB - The antiamnesic and neuroprotective activities of the new aminotetrahydrofuran derivative tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41), a nonselective muscarinic receptor ligand and σ1 protein activator, were examined in mice injected intracerebroventricularly with amyloid β25–35 (Aβ25–35) peptide (9 nmol). Aβ25–35 impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1–1000 μg/kg i.p.) was administered 7 days after Aβ25–35, ie, 20 min before the behavioral tests, it significantly reversed the Aβ25–35-induced deficits, the most active doses being in the 3–100 μg/kg range. When the compound was preadministered 20 min before Aβ25–35, ie, 7 days before the tests, it prevented the learning impairments at 30–100 μg/kg. Morphological analysis of corticolimbic structures showed that Aβ25–35 induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 μg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Aβ25–35-induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Aβ25–35-induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Aβ25–35-induced caspase-9 expression. The compound also blocked the Aβ25–35-induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the σ1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 μg/kg) against Aβ25–35-induced learning impairments, suggesting that muscarinic and σ1 targets are involved in the drug effect. A synergic effect could indeed account for the very low active doses measured in vivo. These data outline the therapeutic potential of ANAVEX1-41 as a neuroprotective agent in Alzheimer's disease. SN - 1740-634X UR - https://doi.org/10.1038/npp.2008.212 DO - 10.1038/npp.2008.212 ID - Villard2009 ER -