Phosphodiesterases in the Central Nervous System: Implications in Mood and Cognitive Disorders - Phosphodiesterases as Drug Targets - page 463

3.8 PDE8
Although PDE8 is expressed in brain (Kobayashi et al. 2003 ), there are no
published reports of the psychopharmacological effects of PDE8 inhibitors.
Altered PDE8 mRNA expression in the postmortem hippocampus of patients
with Alzheimer's disease (P´rez-Torres et al. 2003 ) suggests a potential role in
cognitive function.
3.9 PDE9
BAY 73-6691 is a novel, potent, and selective PDE9 inhibitor that is currently
under preclinical development for the treatment of Alzheimer's disease (Wunder
et al. 2005 ). BAY 73-6691 enhances acquisition, consolidation, and retention of
long-term memory in a social recognition task and tends to enhance long-term
memory in an object recognition task (van der Staay et al. 2008 ). It attenuates the
scopolamine-induced retention deficit in a passive avoidance task, and MK-801-
induced short-term memory deficit in a T-maze alternation task. A recent study
reported that an inhibitor of PDE9 improves learning and memory in older rats but
not in young ones (Domek-Łopaci ´ ska and Strosznajder 2010 ). An increase in
PDE9 expression and activity and a decrease in cGMP concentration are also found
in the aged rat brain in this study. The results support the notion that PDE9
inhibition may be a novel means for treating memory deficits that are associated
with aging and neurodegenerative disorders such as Alzheimer's disease.
3.10 PDE10
The PDE10 family was originally identified simultaneously by three different
groups (Fujishige et al. 1999 ; Loughney et al. 1999 ; Soderling et al. 1999 ). There
is only one gene in the PDE10 family, PDE10A, which hydrolyzes both cAMP
and cGMP in vitro. The four major isoforms of PDE10A are PDE10A1-4, which
differ at their N- and C-termini, whereas the GAF domains are identical. The GAF
domain of PDE10 binds and regulates via cAMP rather than cGMP (Gross-
Langenhoff et al. 2006 ). This occurs for a chimeric protein of the PDE10 GAF
domains with a bacterial adenylyl cyclase catalytic domain as the binding of
cAMP-stimulated cyclase catalytic activity (Bender and Beavo 2006 ). Whether
there is a functional allosteric effect of the cAMP-stimulated GAF domain for the
regulation the intracellular PDE10 remains unknown.
In rodents, PDE10A mRNA is highly expressed in the caudate-putamen, hippo-
campus, cerebral cortex, olfactory tubercle, thalamus, and spinal cord (Hebb et al.
2004 ; Hu et al. 2004 ; O'Conner et al. 2004 ; Siuciak et al. 2006 ; Xie et al. 2006 ).