Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid Β 25-35 -induced toxicity in mice

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