The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during aging.
Our previous studies have shown that there is a lower cGMP concentration in the aged brain as well as an alteration in the activity of cGMP-hydrolyzing phosphodiesterases (PDEs) and nitric oxide synthase (NOS). The aim of this study was to investigate the effect of specific inhibitors of selected PDEs on object recognition memory and locomotor activity during aging, and to correlate their action with NOS activity in the following brain regions: hippocampus, striatum, and cerebral cortex. The study was carried out using 3, 12, and 24 month-old rats. Inhibitors of PDE2 and PDE5 (Bayer 60-7550 and zaprinast, respectively) were used. Evaluation of memory and locomotor activity was carried out using an object recognition task and the open field test. NOS activity was determined using a radiochemical method after behavioral analysis in the cytosolic fraction from all brain areas investigated. We have found that the inhibitor of PDE2, Bay60-7550, improves object recognition memory in all age groups investigated and increases basal constitutive NOS activity in the hippocampus and striatum. Moreover, in 3 month-old rats, additional inhibition of PDE5 by zaprinast improves object memory and elevates NOS activity in all brain regions studied. Specific inhibition of nNOS eliminates the effect of Bay60-7550 on memory function and on NOS activity in 24 month-old rats. In summary, our results indicate that inhibition of PDE2 is able to improve cognition and memory function in 3, 12, and 24 month-old rats through the enhancement of nNOS activity in the brain, whereas inhibition of PDE5 is effective only in 3 month-old animals.
Domek-Łopacińska
K
K
Department of Cellular Signaling, Medical Research Center, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. kdomek@cmdik.pan.pl
Strosznajder
J B
JB
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009043:Motor Activity / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D018697:Nootropic Agents / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000502:physiology
D018697:Nootropic Agents; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D019001:Nitric Oxide Synthase; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast