Effects on immune cells of a new 1,8-naphthyridin-2-one derivative and its analogues as selective CB2 agonists: implications in multiple sclerosis.

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.

• Authors: Anna Maria Malfitano, Chiara Laezza, Alba D'Alessandro, Claudio Procaccini, Giuseppe Saccomanni, Tiziano Tuccinardi, Clementina Manera, Marco Macchia, Giuseppe Matarese, Patrizia Gazzerro, Maurizio Bifulco
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e62511 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23658734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Antigens, CD
• Antigens, Differentiation, T-Lymphocyte
• CD69 antigen
• Immunosuppressive Agents
• Lectins, C-Type
• Myelin Basic Protein
• N-(4-methylcyclohexyl)-1-benzyl-1,8-naphthyridin-2(1H)-on-3-carboxamide
• N-cycloheptyl-1-(2-morpholin-4-ylethyl)quinolin-2(1H)-on-3-carboxamide
• N-cycloheptyl-1-(p-fluorobenzyl)-1,2-dihydro-2-oxopyridine-3-carboxamide
• NF-kappa B
• Naphthyridines
• Pyridones
• Quinolones
• Receptor, Cannabinoid, CB2
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Cyclooxygenase 2
• PTGS2 protein, human
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Anti-Inflammatory Agents (pharmacology)
• Antigens, CD (metabolism)
• Antigens, Differentiation, T-Lymphocyte (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Cyclooxygenase 2 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Expression
• Humans
• Immunosuppressive Agents (pharmacology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Lectins, C-Type (metabolism)
• Lymphocyte Activation
• Multiple Sclerosis (drug therapy, immunology)
• Myelin Basic Protein (physiology)
• NF-kappa B (metabolism)
• Naphthyridines (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridones (pharmacology)
• Quinolones (pharmacology)
• Receptor, Cannabinoid, CB2 (agonists, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis)