Biology Reference
In-Depth Information
correlate negatively with olfactory sensitivity in healthy participants, which is
confirmed by patients with major depressive disorder (Pollatos et al.
2007
; Pause
et al.
2001
). PDE2 is also found in pituitary and adrenal cortex (Blokland et al.
2006
).
Menniti and coworkers (
2006
) suggested that PDE2 influences cAMP metabolism in
the pituitary and adrenal cortex, while it regulates cGMP signaling in the cerebral
cortex and hippocampus. In primary neuronal cultures, inhibition of PDE2 with
the selective inhibitor EHNA enhances
N
-methyl-
D
-aspartate (NMDA) receptor-
mediated cGMP levels, but cAMP is unaffected (Suvarna and O'Donnell
2002
).
The highly selective PDE2 inhibitor BAY 60-7550, which unlike EHNA does
not inhibit adenosine deaminase, increases cGMP levels in the presence of NMDA
or guanylyl cyclase activators. Although BAY 60-7550 also increases NMDA
receptor-induced cAMP levels in cultured neurons, the magnitude of this effect
is markedly less than the increase in cGMP (Masood et al.
2009
). Several reports
suggest cyclic nucleotide pathways can crosstalk to modulate each other's syn-
thesis, degradation, and actions (Surapisitchat et al.
2007
; Aizawa et al.
2003
).
It is possible that the high level of cGMP acts by binding to an allosteric site on
PDE2 that activates PDE2-mediated breakdown of cAMP in neurons (Pelligrino
and Wang
1998
).
BAY 60-7550 has been observed to fully reverse the working memory deficit
induced by the NMDA receptor antagonist MK-801. It improves the performance of
rats in social and object recognition memory tasks, and reverses MK801-induced
deficits in spontaneous alternation in a T-maze test (Boess et al.
2004
). BAY 60-7550
also improves short-term object recognition performance after an acute tryptophan
depletion-induced memory deficit (van Donkelaar et al.
2008
). These results are in
agreement with a report suggesting that BAY 60-7550 improves acquisition and
consolidation in the object recognition task in rats with age-related cognitive impair-
ments (Domek-Łopaci
´
ska and Strosznajder
2008
). It is known that there is a lower
cGMP concentration in the aged brain and an alteration in the activity of cGMP-
hydrolyzing PDEs. Therefore, the mechanism behind the beneficial effects of PDE2
inhibitors on cognition defects may be related to stimulating the cGMP-regulated
signal cascade and subsequently enhancing neuronal plasticity (Boess et al.
2004
).
PDE2 inhibition is able to attenuate oxidative stress-induced anxiety in mice, as
well as anxiety-like behaviors produced by other means (Masood et al.
2008
,
2009
).
The anxiolytic effects of two PDE2 inhibitors Bay 60-7550 and ND7001 are
observed in the elevated plus-maze, hole-board, and open-field tests in both stressed
and nonstressed mice; antagonism experiments suggest these behavioral effects
result from increased cGMP signaling (Figs.
1
and
2
). The effects on oxidative
stress are confirmed using primary neuronal cultures, which show that Bay 60-7550
and ND7001 reverse oxidant-induced increases in reactive oxygen species and
improve the total antioxidant capacity in cerebral cortical neurons. These various
behavioral and neurochemical data suggest that PDE2 may be a useful pharmaco-
logical target for treatment of neurodegenerative and psychiatric diseases that
involve increased oxidative stress.
