title: Brain toxicity and inflammation induced in vivo in mice by the amyloid-β forty-two inducer aftin-4, a roscovitine derivative.
abstract: Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.
authors.affiliation: Amylgen, Montferrier-sur-Lez, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.affiliation: Amylgen, Montferrier-sur-Lez, France.
authors.forename: Nozha
authors.initials: N
authors.lastname: Borjini
authors.affiliation: Amylgen, Montferrier-sur-Lez, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Gillis
authors.affiliation: Amylgen, Montferrier-sur-Lez, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Villard
authors.affiliation: Amylgen, Montferrier-sur-Lez, France INSERM U. 710, University of Montpellier 2, Montpellier, France.
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced* / Q000503:physiopathology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology*; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007859:Learning Disabilities / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology
chemical_list: C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002087:Butyrates; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D007189:Indans; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010880:Piperidines; C579636:aftin-4; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000077265:Donepezil; D053829:Amyloid Precursor Protein Secretases; D000225:Adenine; D007052:Ibuprofen
keywords: A$\beta_{1-42}$; Alzheimer's disease; aftins; amyloid toxicity in vivo; memory deficits