Effects on Immune Cells of a New 1,8-Naphthyridin-2-One Derivative and Its Analogues as Selective CB2 Agonists: Implications in Multiple Sclerosis

Anna Maria Malfitano, Chiara Laezza, Alba D'Alessandro, Claudio Procaccini, Giuseppe Saccomanni, Tiziano Tuccinardi, Clementina Manera, Marco Macchia, Giuseppe Matarese, Patrizia Gazzerro, Maurizio Bifulco

Research output: Contribution to journalArticle

Abstract

The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-α production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro-inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation.

Original languageEnglish
Article numbere62511
JournalPLoS One
Volume8
Issue number5
DOIs
Publication statusPublished - May 1 2013

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Malfitano, A. M., Laezza, C., D'Alessandro, A., Procaccini, C., Saccomanni, G., Tuccinardi, T., Manera, C., Macchia, M., Matarese, G., Gazzerro, P., & Bifulco, M. (2013). Effects on Immune Cells of a New 1,8-Naphthyridin-2-One Derivative and Its Analogues as Selective CB2 Agonists: Implications in Multiple Sclerosis. PLoS One, 8(5), [e62511]. https://doi.org/10.1371/journal.pone.0062511