title: PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice.
abstract: ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca(2+) overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , C/Diego de León, 62, 28006 Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lorrio
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.forename: Rocío
authors.initials: R
authors.lastname: Lajarín-Cuesta
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Martínez-Sanz
authors.forename: Martín
authors.initials: M
authors.lastname: Estrada
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Jose
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000517:prevention & control*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006624:Hippocampus / Q000187:drug effects; D008569:Memory Disorders / Q000517:prevention & control*; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009840:Oligomycins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000187:drug effects* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D012402:Rotenone / Q000633:toxicity; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D016875:tau Proteins / Q000378:metabolism
chemical_list: D009287:Naphthyridines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009840:Oligomycins; C551006:ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo(b)(1,8)naphthyridine-3-carboxylate; D016875:tau Proteins; D012402:Rotenone; C031004:oligomycin A; D012601:Scopolamine; D054648:Protein Phosphatase 2