Abstract
Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor mesopram. In vitro, mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in mesopram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of mesopram and provide a rationale for its clinical development.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Acute Disease
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Animals
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / therapeutic use
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Cell Division / drug effects
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Cells, Cultured
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Central Nervous System / drug effects
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Central Nervous System / immunology
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Central Nervous System / metabolism
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Central Nervous System / pathology
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Chronic Disease
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use*
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Female
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Humans
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Inflammation / drug therapy
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Inflammation / metabolism
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Inflammation / pathology
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Interferon-gamma / biosynthesis
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Interferon-gamma / metabolism
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Interleukin-5 / biosynthesis
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Interleukin-5 / metabolism
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Lymphocyte Activation / drug effects
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Mice
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Mice, Inbred Strains
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Multiple Sclerosis / drug therapy
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Oxazoles / pharmacology*
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Oxazoles / therapeutic use*
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Rats
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Rats, Inbred Lew
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Recurrence
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Spleen / drug effects
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Spleen / immunology
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Substrate Specificity
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Th1 Cells / cytology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / cytology
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Th2 Cells / drug effects
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Enzyme Inhibitors
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Interleukin-5
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Oxazoles
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Tumor Necrosis Factor-alpha
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mesopram
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Interferon-gamma
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4