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

Vanessa Villard, Julie Espallergues, Emeline Keller, Tursun Alkam, Atsumi Nitta, Kiyofumi Yamada, Toshitaka Nabeshima, Alexandre Vamvakides, Tangui Maurice

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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 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.

Original languageEnglish
Pages (from-to)1552-1566
Number of pages15
JournalNeuropsychopharmacology
Volume34
Issue number6
DOIs
Publication statusPublished - 01-05-2009

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

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    Villard, V., Espallergues, J., Keller, E., Alkam, T., Nitta, A., Yamada, K., Nabeshima, T., Vamvakides, A., & Maurice, T. (2009). Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid Β 25-35 -induced toxicity in mice. Neuropsychopharmacology, 34(6), 1552-1566. https://doi.org/10.1038/npp.2008.212