Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats.
Experimental autoimmune encephalomyelitis (EAE) in Lewis rats, an animal model mimicking some aspects of multiple sclerosis, was treated with the type IV-specific phosphodiesterase inhibitor Rolipram. Actively induced EAE evoked by immunization with myelin basic protein (MBP) in complete Freund's adjuvant was delayed but only slightly ameliorated in its maximal severity by preventive treatment with Rolipram (2 x 3 mg/kg per day) starting on the day of immunization. Therapeutic administration of Rolipram (2 x 5 mg/kg per day) was begun within hours after onset of first clinical signs of EAE but could not modify the further course of the disease. Both doses had significant side effects. Injection of 5 mg Rolipram/kg provoked transient slackening and unsteady gait while chronic application of 6 mg/kg/day strongly accelerated the weight gain in adolescent rats. EAE adoptively transferred by injection of encephalitogenic T line blasts was shortened and significantly suppressed in its severity by application of Rolipram (2 x 5 mg/kg per day) starting on the day of cell transfer. In corresponding lumbar spinal cord sections density of inflammatory infiltration by T cells and macrophages was reduced. Rolipram did not prevent generation of an antigen-specific immune response in vivo. In vitro the drug inconsistently inhibited MBP-induced activation of encephalitogenic T cells. TNF-alpha secretion by encephalitogenic T cells was limited only when T cell proliferation was also affected. In contrast, TNF-alpha production by LPS-activated macrophages was consistently and markedly suppressed by Rolipram. However, since the encephalitogenic T line cells produced at least 100 times more TNF-alpha than the same number of Rolipram-sensitive macrophages, the impact of Rolipram on the total amount of TNF-alpha synthesized in EAE may be limited. Together with our histological findings, the data suggest that relevant immunosuppressive mechanisms of Rolipram may be the inhibition of migration of leukocytes into the central nervous system and to some extent its inhibitory effect on T cell proliferation and macrophage activity. The downregulatory effects of Rolipram may be partially counteracted by its augmenting impact on the production of nitric oxide by macrophages.
Jung
S
S
Department of Neurology, Julius-Maximilians Universität Würzburg, Germany.
Zielasek
J
J
Köllner
G
G
Donhauser
T
T
Toyka
K
K
Hartung
H P
HP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D004676:Myelin Basic Protein / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D020889:Rolipram; D013116:Spinal Cord / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D020889:Rolipram