Résumé
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 sigma(1) protein activator, were examined in mice injected intracerebroventricularly with amyloid beta(25-35) (A beta(25-35)) peptide (9 nmol). A beta(25-35) impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1 -1000 mu g/kg i. p.) was administered 7 days after A beta(25-35), ie, 20 min before the behavioral tests, it significantly reversed the A beta(25-35)-induced deficits, the most active doses being in the 3 - 100 mu g/kg range. When the compound was preadministered 20 min before A beta(25-35), ie, 7 days before the tests, it prevented the learning impairments at 30-100 mu g/kg. Morphological analysis of corticolimbic structures showed that A beta(25-35) induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 mg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an A beta(25-35)-induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of A beta(25-35)-induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent A beta(25-35)-induced caspase-9 expression. The compound also blocked the A beta(25-35)-induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the s1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 mu g/kg) against A beta(25-35)-induced learning impairments, suggesting that muscarinic and sigma(1) 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.