Biology Reference
In-Depth Information
vasodilation is its key therapeutic action. The PDE5 selective inhibitors sildenafil,
vardenafil, and tadalafil are used to manage erectile dysfunction and pulmonary
hypertension. There are three variants of PDE5, PDE5A1, A2, and A3 that are
distinguished based on their N-terminal sequence. PDE5A1 and PDE5A2 are
ubiquitous, but PDE5A3 is specifically expressed in smooth muscles (Lin
2004
).
A single PDE5A gene encodes the three isoforms and the initial three exons
(A1, A3, A2) encode the isoform-specific sequences.
Cyclic GMP levels are determined by the balance between activities of guanylyl
cyclases and the PDEs that break down cGMP in the whole cell (Francis et al.
2010
).
The most common mechanism of modulation of PDE5 activity seems to be through
N-terminal GAF domains that interact with cGMP and regulate catalytic activity
(Heikaus et al.
2009
). In mammals, PDE5 is found to contain N-terminal GAF A
and GAF B domains (Bender and Beavo
2006
; Martinez et al.
2002
). Due to its
significant expression in cerebellar Purkinje cells in the brain, PDE5 contributes to
cognitive processes through cGMP regulation (Rapoport et al.
2000
; Hartell
1996
).
PDE5 inhibitors such as sildenafil and vardenafil have been shown to be not only
effective in treatment of erectile dysfunction (Crowe and Streetman
2002
; Fink et al.
2002
), but also are candidate drugs for cognition enhancement (Prickaerts
et al.
2004
). PDE5 inhibitors are reported to improve memory performance,
although it must be mentioned that an improved performance has been observed
in learning tasks in the passive avoidance test but not in the water maze task
(Prickaerts et al.
2004
). Earlier studies suggested that vardenafil improves early
processes of memory consolidation when it is administered immediately after the
first trial in the novel object recognition task (Prickaerts et al.
2002
). However,
memory enhancing effects are not observed when vardenafil is administered at a
later time point after training (3 or 6 h after the first trial) (Prickaerts et al.
2004
;
Rutten et al.
2007
). These findings are in agreement with studies that suggest that
vardenafil is able to attenuate the acute tryptophan depletion-induced object recog-
nition impairment (van Donkelaar et al.
2008
).
Sildenafil has been shown to ameliorate the deficit in performance in a T-maze
task induced by a muscarinic acetylcholine receptor antagonist (Devan et al.
2004
).
It is also found to influence long-term memory retention in mice by modulating
mechanisms involved in memory storage (Baratti and Boccia
1999
). Other studies
have shown that sildenafil improves acquisition and retention of memory in mice
tested in the modified elevated plus maze (Singh and Parle
2003
). Sildenafil
administered immediately after training on the first day produces a dose-dependent
improvement of memory during testing on the second day (Singh and Parle
2003
).
A recent study showed that sildenafil rescues synaptic and memory deficits in an
APP/PS1 transgenic mouse model of amyloid deposition. This effect is associated
with a long-lasting reduction of beta-amyloid levels after sildenafil treatment
(Puzzo et al.
2009
). Moreover, sildenafil can cross the blood-brain barrier and
increase neurogenesis, which could have effects on memory (Uthayathas et al.
2007
; Zhang et al.
2002a
,
b
).
PDE5 inhibitors have also been proposed for the treatment of depression.
Liebenberg and coworkers showed that sildenafil and tadalafil have significant
