Treatment with the phosphodiesterase type 4 inhibitor rolipram fails to inhibit blood brain barrier disruption in MS

摘要

Rolipram, a prototypic phosphodiesterase-4 inhibitor is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis (EAE). Additionally, Rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of Rolipram in suppressing inflammatory disease activity in MS in a proof-of-principle phase I/II open label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during three months (four MRIs) of pre-treatment baseline and eight months of Rolipram therapy. The primary outcome was the change in contrast-enhancing lesions (CEL) between baseline and last four months of Rolipram therapy. Previously defined biomarkers of Rolipram-mediated immunomodulation were evaluated during study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease in the brain inflammatory activity measured by contrast-enhancing lesions (CEL) on brain MRI. At the administered doses Rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of Rolipram in EAE versus MS are at present not clear.