Biology Reference
In-Depth Information
CREB levels may contribute to memory deficits, mood disorders, and altered nerve
growth and regeneration (Monti et al.
2006
).
PDE4, which hydrolyzes cAMP specifically, regulates many crucial signaling
cascades involved in learning and memory (Ahmed and Frey
2005
; Blokland et al.
2006
; Menniti et al.
2006
). PDE4 inhibitors, by increasing the cAMP concentration
and activating CREB phosphorylation, enhance LTP and improve spatial and
associative memory in mice (Barad et al.
1998
; Bach et al.
1999
). Mice carrying
a truncated form of CREB protein-binding protein (CBP) show several develop-
mental abnormalities similar to patients with mental retardation. CBP is a 265 kDa
nuclear protein that is a coactivator molecule for a number of transcription factors,
including CREB and several nuclear receptors. Memory deficits in step through
passive avoidance test and fear conditioning test are found in mice with mutations
of CBP (Oike et al.
1999
); rolipram ameliorates impairments of long-term memory
and CREB signaling caused by CBP mutation (Bourtchouladze et al.
2003
).
PDE4 is also implicated in hippocampal neurogenesis, which is associated with
memory and mood disorders (Epp et al.
2007
). Repeated administration of rolipram
improves the survival ratio of newborn neurons through activating cAMP/CREB
signaling, as evidenced by increased in cAMP, PKA activity, and pCREB expres-
sion (Fujioka et al.
2004
; Li et al.
2009
). Interestingly, it was found that the effect of
rolipram on CREB is in a brain region-specific manner, in which increased pCREB
expression is observed in the hippocampus but not the frontal cortex. However, it is
reported that the pCREB expression in newborn neurons in the hippocampus only
partially contributes to the behavioral effects of rolipram (Li et al.
2009
). When
coadministered with the tricyclic antidepressant imipramine, rolipram significantly
increases in the level of pCREB and its downstream effector BDNF in the frontal
cortex and hippocampus of learned helplessness rats. Moreover, the escape failures
in these rats are completely eliminated by coadministration of rolipram with
imipramine (Itoh et al.
2004
). These results indicate that activation of CREB may
be involved in the antidepressant effects involving PDE4 and cAMP signaling.
Recent studies show that PDE7 and PDE8, which are cAMP-specific enzymes,
are thought to regulate the cAMP levels in the human striatum and dentate gyrus
(Sasaki et al.
2004
). Enhanced levels of PDE7 and PDE8 mRNAs are observed in
the hippocampus of patients with Alzheimer's disease and dementia (P
ยด
rez-Torres
et al.
2003
). Therefore, selective PDE7 and PDE8 inhibitors might be able to
enhance cAMP concentrations without inducing the side effects associated with
PDE4 inhibitors (Sasaki et al.
2000
).
4.2 PDE Inhibitors and the MAPK-ERK Pathway
The activation of CREB also occurs via the MAPK/ERK pathway; MAPK inhibi-
tors reduce CREB phosphorylation when given together with PKA inhibitors
(Gao et al.
2004
). The MAPK pathway is thought to stimulate CREB via activation
of p90 ribosomal S6 kinase 2 (RSK2) (Anjum and Blenis
2008
). It has been
