Cilostazol improves hippocampus-dependent long-term memory in mice.
BACKGROUND
Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function.


OBJECTIVE
We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway.


RESULTS
Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long-term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB-positive cells in hippocampal dentate gyrus.


CONCLUSIONS
These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.
Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, 173-0015, Japan.
Shuichi
S
Yanai
Yuki
Y
Semba
Hideki
H
Ito
Shogo
S
Endo
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000077407:Cilostazol; D003463:Cues; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism; D005239:Fear; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D057567:Memory, Long-Term / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000242:Cyclic AMP; D000077407:Cilostazol