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

Research output: Contribution to journalArticle

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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

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Neuroprotective Agents
Amyloid
Hippocampus
Learning
Hippocampal CA1 Region
Proteins
Muscarinic Antagonists
Scopolamine Hydrobromide
N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride tetrahydro-N
Caspase 9
Glial Fibrillary Acidic Protein
Muscarinic Receptors
Short-Term Memory
Caspase 3
Pharmaceutical Preparations
Cholinergic Agents
Lipid Peroxidation
Alzheimer Disease
Oxidative Stress
Apoptosis

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Villard, Vanessa ; Espallergues, Julie ; Keller, Emeline ; Alkam, Tursun ; Nitta, Atsumi ; Yamada, Kiyofumi ; Nabeshima, Toshitaka ; Vamvakides, Alexandre ; Maurice, Tangui. / Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid Β 25-35 -induced toxicity in mice. In: Neuropsychopharmacology. 2009 ; Vol. 34, No. 6. pp. 1552-1566.
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Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid Β 25-35 -induced toxicity in mice. / Villard, Vanessa; Espallergues, Julie; Keller, Emeline; Alkam, Tursun; Nitta, Atsumi; Yamada, Kiyofumi; Nabeshima, Toshitaka; Vamvakides, Alexandre; Maurice, Tangui.

In: Neuropsychopharmacology, Vol. 34, No. 6, 01.05.2009, p. 1552-1566.

Research output: Contribution to journalArticle

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T1 - Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid Β 25-35 -induced toxicity in mice

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

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N2 - 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.

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