PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice
| Autor: | Mercedes Villarroya, Laura González-Lafuente, Francisco J. Martínez-Sanz, Martín Estrada, Abdelouahid Samadi, Cristóbal de los Ríos, María Isabel Rodríguez-Franco, José Marco-Contelles, Rocío Lajarín-Cuesta, Alejandro Romero, Silvia Lorrio, Manuela G. López |
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| Rok vydání: | 2013 |
| Předmět: |
Physiology
Drug Evaluation Preclinical Excitotoxicity Hippocampus Pharmacology medicine.disease_cause Biochemistry Brain Ischemia memory Ser/Thr phosphatases Mice chemistry.chemical_compound Molecular Targeted Therapy Protein Phosphatase 2 Phosphorylation Molecular Structure Cerebral Infarction General Medicine stroke PP2A Neuroprotective Agents medicine.anatomical_structure Blood-Brain Barrier neuroprotection Chemical and Drug Induced Liver Injury Alzheimer’s disease medicine.drug Cognitive Neuroscience Scopolamine ITH12246 Nerve Tissue Proteins tau Proteins Blood–brain barrier Neuroprotection Cell Line Rotenone medicine Animals Memory impairment Calcium Signaling Naphthyridines Memory Disorders business.industry Muscarinic antagonist Cell Biology Okadaic acid Rats Disease Models Animal Oxidative Stress chemistry Oligomycins business Protein Processing Post-Translational Neuroscience Oxidative stress |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/cn400050p |
| Popis: | 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 Ca2+ 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. |
| Databáze: | OpenAIRE |
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