PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice

Silvia Lorrio, Alejandro Romero, Laura González-Lafuente, Rocío Lajarín-Cuesta, Francisco J. Martínez-Sanz, Martín Estrada, Abdelouahid Samadi, Jose Marco-Contelles, María Isabel Rodríguez-Franco, Mercedes Villarroya, Manuela G. López, Cristóbal De Los Ríos

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1267-1277
Number of pages11
JournalACS Chemical Neuroscience
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 18 2013
Externally publishedYes

Keywords

  • Alzheimer's disease
  • ITH12246
  • PP2A
  • Ser/Thr phosphatases
  • memory
  • neuroprotection
  • stroke

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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