Biology Reference
In-Depth Information
sildenafil and tadalafil stimulate neurogenesis after stroke in rats (Zhang et al.
2002a
,
b
,
2006
). In addition, PDE5 inhibition has been reported to modulate the
antidepressant effect of venlafaxine and bupropion (Dhir and Kulkarni
2007a
,
b
).
Brink and coworkers (
2008
) only observed an antidepressant-like effect of sildena-
fil after blocking central muscarinic receptors, indicating the crosstalk with cholin-
ergic pathways.
PDE2 might be a link between cAMP and cGMP signaling mechanisms in
neurons (Hajjhussein et al.
2007
). Studies have shown that PDE2 inhibitor BAY
60-7550, which exerts positive effects on learning and memory, enhances the
induction of LTP in hippocampus (Boess et al.
2004
). PDE2 inhibitors also increase
NOS activity (Domek-Łopaci
´
ska and Strosznajder
2008
), suggesting a possible
feedback effect on NO-mediated cGMP signaling. In addition, Bay 60-7550 also
prevents neurochemical and anxiogenic-like behavioral effects induced by oxidative
stress in mice; this appears to be mediated through NO-cGMP signaling (Masood
et al.
2008
). Recent research further demonstrates a key role for cGMP signaling in
the effects of PDE2 inhibitors on neurons as well as on their anxiolytic effects on
behavior (Masood et al.
2009
). Thus, cGMP-specific PDEs might serve as potential
therapeutic targets to improve neuronal function in neurological and psychiatric
disorders, particularly those where increased oxidative stress is a contributing factor.
Elevated cGMP levels are thought to act in part through activating cGMP-
dependent protein kinases (PKGs), which act in parallel with PKA to phosphorylate
the transcription factor CREB (Pilz and Broderick
2005
; Lu et al.
1999
). Previous
studies have shown that cGMP/PKG/CREB pathway, just like cAMP/PKA/CREB
cascade, can induce the synthesis of proteins which are important for LTP and
memory consolidation (Abel et al.
1997
). Since beta-amyloid protein has been
demonstrated to reduce CREB phosphorylation (Puzzo et al.
2005
), enhancers of
cAMP/PKA/CREB or cGMP/PKG/CREB may represent new classes of anti-
Alzheimer's disease drugs by targeting the downstream consequences of beta-
amyloid (Rutten et al.
2007
). Consistent with this, PDE5 inhibitors, which are
thought to activate cGMP/PKG/CREB, have been proposed to be memory enhan-
cers (Rose et al.
2005
). Compared to PDE4 inhibitors, which induce various side
effects, PDE5 inhibitors might have broader therapeutic application in cognition
and mood disorders (Souness et al.
2000
). PDE10 is a dual-substrate enzyme, and
PDE10A has been shown to hydrolyze both cAMP and cGMP in the medium spiny
neurons (Strick et al.
2010
). PDE10A inhibition in primary cortical and hippocam-
pal neurons increases CREB phosphorylation in the nucleus (Menniti et al.
2006
).
Although the mechanism underlying this process is still unclear, PDE10A is
becoming an interesting target for understanding and treating CNS disorders.
4.4 PDE Inhibitors and Neuroplasticity
Apoptosis or programmed cell death is essential for the normal functioning and
development of the nervous system (Quiroz et al.
2010
). Neuronal apoptosis is
