Rolipram

Background

The small-molecule Rolipram is an inhibitor of phosphodiesterase 4 (PDE4), which catalyzes the hydrolysis of cyclic-AMP (cAMP) to regulate cellular responses to a number of extracellular signals. Rolipram inhibits multiple isozymes of PDE4, including PDE4A (IC₅₀ = 3 nM), PDE4B (IC₅₀ = 130 nM), and PDE4D (IC₅₀ = 240 nM). Treatment of myeloid cells with Rolipram resulted in phosphorylation of cAMP-response element-binding protein (CREB) and implied the presence of both high (PDE4A4) and low affinity (PDE4B, PDE4D) components (1). Rolipram and other phosphodiesterase inhibitors were seen as having potential therapeutic benefits in preclinical models of psychiatric and neurologic diseases. Unfortunately, severe dose-limiting side effects (e.g., nausea, vomiting) limited the clinical application of PDE inhibitors (2). Still, Rolipram treatment in a mouse model of intracerebral hemorrhage demonstrated some neuroprotective benefits through activation of the cAMP/AMPK/SIRT1 pathway (3). Rolipram treatment of fibroblasts from ligamentum flavum hypertrophy patients inhibited PDE4A and PDE4B activity, blocked TGF-β1 by restoring p-ERK1/2 expression, and inhibited expression of fibrosis-related proteins (4).