Inhibition of phosphodiesterases as a strategy to achieve neuroprotection in Huntington's disease

Huntington's disease (HD) is a fatal neurodegenerative condition, due to a mutation in the IT15 gene encoding for huntingtin. Currently, disease-modifying therapy is not available for HD, and only symptomatic drugs are administered for the management of symptoms. In the last few years, preclinical and clinical studies have indicated that pharmacological strategies aimed at inhibiting cyclic nucleotide phosphodiesterase (PDEs) may develop into a novel therapeutic approach in neurodegenerative disorders. PDEs are a family of enzymes that hydrolyze cyclic nucleotides into monophosphate isoforms. Cyclic nucleotides are second messengers that transduce the signal of hormones and neurotransmitters in many physiological processes, such as protein kinase cascades and synaptic transmission. An alteration in their balance results in the dysregulation of different biological mechanisms (transcriptional dysregulation, immune cell activation, inflammatory mechanisms, and regeneration) that are involved in neurological diseases. In this review, we discuss the action of phosphodiesterase inhibitors and their role as therapeutic agents in HD.