In vitro, ex vivo and in vivo immunopharmacological activities of the isoxazoline compound VGX-1027: modulation of cytokine synthesis and prevention of both organ-specific and systemic autoimmune diseases in murine models.
We have presently studied the in vitro, ex vivo and in vivo immunopharmacological effects of VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid]. This compound reduced the secretion of IL-1beta, TNF-alpha and IL-10 from purified murine macrophages stimulated "in vitro" with lipopolysaccharide (LPS), and it also modified the signaling pathways induced in these cells by LPS entailing reduced activation of NF-kappaB and p38 MAP kinase pathways along with up-regulation of ERK pathways. VGX-1027 appeared to spare T cell function as it was unable to modify the proliferation and/or secretion of IL-2, IFN-gamma and IL-4 induced in purified murine CD4+ T cells from stimulation with either CD3+CD28 or ConA. These effects on macrophages may account for the capacity of VGX-1027 to markedly ameliorate the course of both acute and chronic immunoinflammatory diseases in mice such as carrageenan-induced pleurisy, LPS-induced lethality and type II collagen-induced arthritis. Acute and subacute toxicological studies show that the drug is not toxic at the doses that exert biological effects in these preclinical models. These data warrant additional studies for the potential use of VGX-1027 in the clinical setting.
Stojanovic
Ivana
I
Department of Immunology, Institute for Biological Research Sinisa Stankovic, Belgrade, Serbia and Montenegro.
Cuzzocrea
Salvatore
S
Mangano
Katia
K
Mazzon
Emanuela
E
Miljkovic
Djordje
D
Wang
Mingjun
M
Donia
Marco
M
Al Abed
Yousef
Y
Kim
Joseph
J
Nicoletti
Ferdinando
F
Stosic-Grujicic
Stanislava
S
Claesson
Mogens
M
D000085:Acetates / Q000494:pharmacology* / Q000633:toxicity; D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology* / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D010998:Pleurisy / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012772:Shock, Septic / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D015996:Survival Rate
C518641:3-phenyl-4,5-dihydro-5-isoxazole acetic acid; D000085:Acetates; D016207:Cytokines; D020672:I-kappa B Proteins; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D010080:Oxazoles; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D020928:Mitogen-Activated Protein Kinases