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.