Phosphodiesterases (
PDEs) are
enzymes that hydrolyze and inactivate 3', 5'-cyclic
adenosine monophosphate (cAMP) and/or 3', 5'-cyclic
guanosine monophosphate (cGMP). The regulation of intracellular signaling pathways mediated by
cyclic nucleotides is imperative to synaptic plasticity and memory in animals. Because
PDEs play an important role in this regulation, PDE inhibitors are considered as candidate compounds for treating cognitive and
memory disorders. In the present study, we tested whether
cilostazol, a selective
PDE3 inhibitor, prevents the cognitive deterioration that occurs during the course of normal aging in mice. Ten months of
cilostazol administration (1.5%) in 13-month-old mice improved spatial memory when tested at 23 months of age. First, it prevented the decline in the ability of these aged mice to recognize a change in an object's location in the object recognition task. Second, spatial memory of these
cilostazol-treated aged mice in the Morris water maze was comparable to that of untreated middle-aged mice (13 months old).
Cilostazol administration had no effect on the emotional states and physical ability of aged mice. Thus, long-term
cilostazol administration prevented hippocampus-dependent memory decline in aged mice, allowing them to achieve a level of cognitive performance similar to middle-aged mice and without negative behavioral side effects. Considering its well-established safety in other medical contexts,
cilostazol may be a potential therapeutic candidate
drug for staving off
cognitive decline in the aging human population.