Phosphodiesterase type 4 inhibitors - Potential in the treatment of multiple sclerosis?

Phosphodiesterases (PDEs) are involved in the regulation of intracellular l evels of the second messengers cyclic adenosine monophosphate (cAMP) and cy clic guanosine monophosphate (cGMP). These enzymes hydrolyse the cyclic nuc leotides to the corresponding nucleoside 5'-monophosphates. Nine PDE subtyp es have been identified; these differ in their substrate specificity and mo de of activation. The type 4 PDE (PDE4) hydrolyses cAMP, is activated by el evated levels of cAMP, and is inhibited by rolipram. Inhibition of enzyme a ctivity has been shown to modulate the activity of cells of the immune syst em. The production of tumour necrosis factor (TNF)alpha by activated monocy tes and macrophages is inhibited, and cytokine secretion and proliferation of type 1 T helper cells are suppressed. Both immune cell activation and th eir concomitant induction of cytokine secretion are implicated in multiple sclerosis (MS), which is the major demyelinating disease of the central ner vous system. Studies with the selective PDE4 inhibitor rolipram in experime ntal autoimmune encephalomyelitis (an animal model of MS) in mice, rats and nonhuman primates have demonstrated the efficacy of the compound in this d isease model, suggesting that PDE4 inhibitors could ameliorate the clinical course of MS. Unfortunately, clinical trials with PDE4 inhibitors revealed the major adverse effects of these drugs, namely nausea and vomiting. Howe ver, novel PDE4 inhibitors, which target only a subpopulation of PDE4 enzym es, may provoke fewer adverse effects. The efficacy of a PDE4 inhibitor in MS still needs to be demonstrated in a well designed clinical trial.