Phosphodiesterase 4 (PDE4) family of enzymes are the most common phosphodiesterases (PDEs) found in immune cells. They are primarily responsible for hydrolyzing cAMP within immune cells and cells of the central nervous system. PDE4 inhibitors are active substances used to block the degradation of cyclic adenosine monophosphate (cAMP) by PDE4. Here we introduce a PDE4 inhibitor, Rolipram (ZK 62711), with potential anti-inflammatory activity.

Rolipram is a selective PDE4 inhibitor and reduces inflammation in an MKP-1-dependent manner.

Rolipram is a selective PDE4 inhibitor that inhibits all PDE4 isoforms A, B, C, and D. The IC50s for inhibiting PDE4A, PDE4B and PDE4D are 3 nM, 130 nM and 240 nM respectively. Rolipram inhibits LPS-induced TNF production in J774 cells in a dose-dependent manner (IC50 25.9 nM). Rolipram is also found to enhance the expression of MKP-1. Together with the inhibition of PDE4, it exerts anti-inflammatory effects.

Rolipram similarly inhibits the activity of immunopurified PDE4B and PDE4D with IC50s of 130 nM and 240 nM, respectively. In contrast, Rolipram inhibited the activity of immunopurified PDE4A with a significantly lower IC50 of approximately 3 nM. Rolipram increases phosphorylation of cAMP response element binding protein (CREB) in U937 cells in a dose-dependent manner (IC50 approximately 1-120 nM). Rolipram dose-dependently inhibits IFN-γ-stimulated p38 MAPK phosphorylation in a simple monotonic manner with an IC50 of approximately 290 nM.

Repeated administration of Rolipram (1.25 mg/kg, ip) reduces the number of failed escape attempts in learned helpless rats. MAPK phosphatase-1 (MKP-1) is an endogenous inhibitor of p38 MAPK signaling that limits inflammatory gene expression and inflammation. Rolipram (100 mg/kg; ip; single dose) also inhibits TNF production in peritoneal macrophages (PMs) of WT mice but had no significant effect in MKP-1-/- mice. Therefore, Rolipram could reduce Carrageenan-induced paw inflammation in WT mice but not in MKP-1-/- mice.

In summary, Rolipram is a selective PDE4 inhibitor with anti-inflammatory activity.


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