title: Immunomodulatory properties of 1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15.
abstract: 1,2-Dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide derivative VL15 has been recently developed as a selective cannabinoid CB2 receptor compound. Given the high selectivity of this compound at the cannabinoid CB2 receptor and the well-known protective function of this receptor in neurological disorders with autoimmune component like multiple sclerosis, we assessed the immunomodulatory properties of VL15. We assessed on activated peripheral blood mononuclear cells), proliferation and viability, cell cycle progression and measured activation markers and the expression of phosphorylated proteins. We found that VL15 reduces PBMC proliferation slightly affecting cell vitality, blocks the cell cycle progression and down-regulates the levels of T cell activation markers as well as the expression of phosphorylated proteins, NF-kB, IKKαβ, IKBα, ERK and Akt. VL15 was also used in drug-permeability assays on Caco-2 cell line to evaluate its oral bioavailability and on MDCKII-hMDR1 cell lines to estimate its propensity to cross the blood-brain barrier by passive diffusion, in order to potentially maintain its efficiency on the infiltrating auto-reactive lymphocytes in the central nervous system. In these models, VL15 showed high intestinal absorption and good blood-brain barrier penetration. Our findings suggest that VL15, by controlling the immune response, might find potential application as orally administered drug in pathologies like multiple sclerosis.
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, Fisciano, Salerno, Italy. Electronic address: amalfitano@unisa.it.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Malfitano
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale, IEOS, CNR, Napoli, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80134, Napoli, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Marasco
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126, Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, Fisciano, Salerno, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126, Pisa, Italy. Electronic address: clementina.manera@farm.unipi.it.
authors.forename: Clementina
authors.initials: C
authors.lastname: Manera
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009287:Naphthyridines / Q000737:chemistry*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
chemical_list: D007155:Immunologic Factors; D016328:NF-kappa B; D009287:Naphthyridines; D043885:Receptor, Cannabinoid, CB2
keywords: 1,8-Naphthyridine-3-carboxamide derivative; Blood-brain barrier diffusion; Cannabinoid CB2 receptor; Immunomodulation; Intestinal absorption; Neurodegeneration