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P3‐254: Exebryl‐1: A novel small molecule currently in human clinical trials as a disease‐modifying drug for the treatment of Alzheimer's disease
Author(s) -
Snow Alan D.,
Cummings Joel,
Lake Thomas,
Hu Qubai,
Esposito Luke,
Cam Judy,
Hudson Michael,
Smith Elizabeth,
Runnels Steve
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.04.925
Subject(s) - morris water navigation task , genetically modified mouse , transgene , hippocampus , pharmacology , amyloid precursor protein , in vivo , in vitro , amyloid beta , disease , drug , chemistry , alzheimer's disease , medicine , neuroscience , biology , biochemistry , genetics , gene
injections of vehicle, CHF5074 (10 or 30 or 100 mg/kg) or DAPT (100 mg/ kg) 24 and 3 hours before the training session. Wild-type animals received vehicle, CHF5074 (100 mg/kg) or DAPT (100 mg/kg). Freezing was expressed as a percentage of time in each portion of the test in which the animal remained immobile (at least 95% of his body for at least 500 msec) and analyzed using two-way ANOVA (with transgene and treatments ad fixed factors) followed by the Holm-Sidak’s comparison procedure vs the vehicle-treated groups. Results: Compared to vehicle-treated wild-type mice, vehicle-treated transgenic animals had significantly lower freezing to the context (59.1 6 3.9% vs 77.5 6 2.6%, p < 0.001). CHF5074 showed a bell-shaped dose-response curve with a non-significant increase of the contextual freezing with the 10 mg/kg dose (66.1 6 3.6%, p 1⁄4 0.128), a significant improvement with 30 mg/kg (71.5 6 3.9%, p 1⁄4 0.008) and no effects with the highest dose of 100 mg/kg (58.1 6 4.6%). Compared to transgenic controls, DAPT 100 mg/kg had not effects on contextual freezing (55.6 6 5.8%). In wild-type mice, neither CHF5074 (100 mg/kg) nor DAPT (100 mg/kg) had effects on behavior compared to vehicle-treated animals. No significant effects of drug treatments were observed in hippocampal-independent cue conditioning. Conclusions: These data show that acute treatment with CHF5074 improves hippocampal-dependent memory in a transgenic mouse model of AD and support its development as potentially disease-modifying agent of AD.