Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid beta(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 sigma1 protein activator, were examined in mice injected intracerebroventricularly with amyloid beta(25-35) (Abeta(25-35)) peptide (9 nmol). Abeta(25-35) impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1-1000 microg/kg i.p.) was administered 7 days after Abeta(25-35), ie, 20 min before the behavioral tests, it significantly reversed the Abeta(25-35)-induced deficits, the most active doses being in the 3-100 microg/kg range. When the compound was preadministered 20 min before Abeta(25-35), ie, 7 days before the tests, it prevented the learning impairments at 30-100 microg/kg. Morphological analysis of corticolimbic structures showed that Abeta(25-35) induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 microg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Abeta(25-35)-induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Abeta(25-35)-induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Abeta(25-35)-induced caspase-9 expression. The compound also blocked the Abeta(25-35)-induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the sigma1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 microg/kg) against Abeta(25-35)-induced learning impairments, suggesting that muscarinic and sigma1 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.
Villard
Vanessa
V
INSERM U.710, University of Montpellier 2, Montpellier, France
Espallergues
Julie
J
Keller
Emeline
E
Alkam
Tursun
T
Nitta
Atsumi
A
Yamada
Kiyofumi
K
Nabeshima
Toshitaka
T
Vamvakides
Alexandre
A
Maurice
Tangui
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology; D005663:Furans / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*; D012601:Scopolamine / Q000494:pharmacology; D013028:Space Perception / Q000187:drug effects
D016229:Amyloid beta-Peptides; D005029:Ethylenediamines; D005663:Furans; D005904:Glial Fibrillary Acidic Protein; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C525028:tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D012601:Scopolamine; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9