Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, 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 multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the 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-enhanced lesions 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 experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.
A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system . Nausea, emesis, and related general gastrointestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections.
Why would Rolipram inhibit EAE and make MS worse. One can only guess but there is one common feature and this is the ability of rolipram to inhibit tumor necrosis factor. Anti-TNF in animals can inhibit the development of EAE, but anti-TNF can make MS worse, so should disease worsening with Rolipram have been an expected result?
Ibubilast is another PDE4 inhibitor that inhibits EAE but made no impact on releapse rate or lesions in an MS trial and thankfully did not make MS worse when studied in a large number of MSers. Indeed it seemed to slow progression, so now there are two trials in progression, one in US and one in the UK.