1. ¹INSERM U.710, Montpellier, France
2. ²University of Montpellier 2, Montpellier, France
3. ³EPHE, Paris, France
4. ⁴Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
5. ⁵Department of Basic Medicine, College of Traditional Uighur Medicine, Hotan, China
6. ⁶Department of Chemical Pharmacology, Graduate School of Pharmaceutical Science, Meijo University, Nagoya, Japan
7. ⁷Anavex Life Sciences, Pallini, Greece

Correspondence: Dr T Maurice, INSERM U.710, EPHE, University of Montpellier II, c.c. 105, place Eugène Bataillon, 34095 Montpellier cedex 5, France. Tel: +33 4 67 14 36 23; Fax: +33 4 67 14 33 86; E-mail: Tangui.Maurice@univ-montp2.fr

Received 25 July 2008; Revised 21 October 2008; Accepted 22 October 2008; Published online 3 December 2008.

Abstract

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 _25–35 (A_25–35) peptide (9 nmol). A_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 A_25–35, ie, 20 min before the behavioral tests, it significantly reversed the A_25–35-induced deficits, the most active doses being in the 3–100 g/kg range. When the compound was preadministered 20 min before A_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 A_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 A_25–35-induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of A_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_25–35-induced caspase-9 expression. The compound also blocked the A_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 A_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.