Cyclic nucleotide phosphodiesterases (
PDEs) are responsible for the breakdown of
cyclic nucleotides, cyclic
adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP). As such, they are crucial regulators of levels of
cyclic nucleotide-mediated signaling. cAMP signaling and cGMP signaling have been associated with neuroplasticity and protection, and influencing their levels in the cell by inhibition of
PDEs has become a much studied target for treatment in a wide array of disorders, including
neurodegenerative disorders. In this review, we will focus on the involvement of
PDEs in
neurodegenerative disorders. In comparison with preclinical work, data on human patients are scarce.
Alzheimer's disease is associated with changes in PDE4, PDE7, and PDE8 expression in the brain. Altered functioning of PDE4 as well as PDE11 is associated with
major depressive disorder. In
multiple sclerosis, there are indications of alterations in expression of several PDE subtypes in the central nervous system; however, evidence is indirect. In
Huntington's disease and
Parkinson's disease, most research has focused on PDE1B and PDE10, because of their abundant presence in striatal neurons. In another rare, neurodegenerative striatal motor disorder, that is, autosomal-dominant striatal degeneration, genetic defects in PDE8B gene are thought to underlie the neurodegenerative processes. Although the latter disorder has showed a causative dysfunction of
PDEs, this does not hold for the
neurodegenerative disorders discussed above, in which changes in PDE levels seemingly rather represent secondary changes and compensation to prior existing dysfunction. However, normalizing
cyclic nucleotide signaling via PDE inhibition remains interesting for the treatment of
neurodegenerative disorders.