Current Pharmaceutical Design, 2005, 11, 000-0001
1381-6128/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
Phosphodiesterase Inhibitors for Cognitive Enhancement
Gregory M. Rose*, Allen Hopper, Michael De Vivo and Ashok Tehim
Memory Pharmaceuticals Corp., 100 Philips Parkway, Montvale, NJ 07645, USA
Abstract: An effective treatment for age-related cognitive deficits remains an unmet medical need. Currently available
drugs for the symptomatic treatment of Alzheimer’s disease or other dementias have limited efficacy. This may be due to
their action at only one of the many neurotransmitter systems involved in the complex mechanisms that underlie
cognition. An alternative approach would be to target second messenger systems that are utilized by multiple
neurotransmitters. Cyclic adenosine monophosphate (cAMP) is a second messenger that plays a key role in biochemical
processes that regulate the cognitive process of memory consolidation. Prolongation of cAMP signals can be
accomplished by inhibiting phosphodiesterases (PDEs). Eleven PDE families, comprised of more than 50 distinct
members, are currently known. This review summarizes the evidence demonstrating that rolipram, a selective inhibitor of
cAMP-selective PDE4 enzymes, has positive effects on learning and memory in animal models. These data provide
support for the general approach of second messenger modulation as a potential therapeutic approach to treat cognitive
dysfunction, and specifically suggest that PDE4 inhibitors may have utility for improving the symptoms of cognitive
decline associated with neurodegenerative and psychiatric diseases.
Key Words: Cognition, Memory, Alzheimer’s disease, PDE4, Rolipram.
The need for effective ways to treat cognitive deficits is
becoming increasingly pressing. Progress in other areas of
medicine during the last century, notably in controlling and
treating infectious diseases and cardiovascular disorders, has
substantially enhanced longevity. One consequence of living
longer seems to be a predisposition to the “wearing out” of
certain aspects of central nervous system function. In some
cases, such as presbyopia (the loss of ability to focus on very
near objects), the affliction is relatively benign. On the other
hand, age-related impairments in mental functioning can be
Alzheimer’s disease (AD) is the best-known age-related
malady that results in severely impaired cognitive function.
It has been reported that AD affects approximately 10% of
the population at age 65, but this percentage increases
dramatically, to nearly 50%, by age 85 . Current estimates
are that 13.2 million people in the United States will be
afflicted with AD by the year 2050, triple the number
diagnosed with the disease in 2000 . The annual cost of
caring for AD victims in the US is greater than 6 billion
dollars . While these figures are impressive enough in
themselves, other age-related medical conditions, including
Mild Cognitive Impairment (MCI, a possible prodromal
syndrome for AD), Parkinson’s disease, vascular dementia,
and stroke are accompanied by varying degrees of loss of
cognitive function [4-7]. Other disorders, such as schizo-
phrenia and depression, can affect individuals at any age and
are also recognized to include memory loss and other types
of cognitive impairment [8, 9]. In addition, recent studies
have shown that coronary artery bypass grafting, a surgical
*Address correspondence to this author at the Memory Pharmaceuticals,
100 Philips Parkway, Montvale, NJ 07645, USA;
procedure commonly performed to relieve atherosclerosis,
induces cognitive deficits in a substantial fraction of patients
Currently available therapies to relieve cognitive deficits
were developed based primarily upon neuropathological
observations of the brains of AD victims. In addition to the
widely distributed neurofibrillary tangles and beta-amyloid
containing plaques that were first used to describe the
condition, it was found that a population of neurons in the
basal forebrain region appeared to be selectively destroyed in
AD . Since these neurons were known to use acetyl-
choline as their neurotransmitter, a logical approach to
treating AD seemed to be to create drugs to boost cholinergic
function in the brain. (A similar approach has been effective
in initially treating Parkinson’s disease, which is caused by
the selective loss of dopamine-containing neurons.) The
result of this effort has been the development of acetylchol-
inesterase inhibitors, compounds that delay the inactivation
of cholinergic signals by preventing breakdown of synap-
tically released acetylcholine.
Several acetylcholinesterase inhibitors (notably done-
pezil, rivastigmine and galanthamine) are currently marketed
for the treatment of AD . The treatment goal of these
compounds is to improve cognitive function rather than to
alter the disease process itself. (The actual cause of AD
remains unknown.) Unfortunately, only mild and transient
improvements are seen in the subset of patients who are able
to tolerate treatment with these drugs .
Recently a drug with an alternative mechanism of action
has been approved for symptomatic treatment of AD. This
compound, memantine, partially blocks the action of the
neurotransmitter glutamate at the N-methyl-D-aspartate
(NMDA) subclass of its receptors. It is hypothesized that
these receptors become overactive in AD brain; thus,
memantine’s partial blockade acts to restore normal function
2 Current Pharmaceutical Design, 2005, Vol. 11, No. 00Rose et al.
. While more studies are needed, it appears that the
ability of memantine to improve cognitive function is no
better than that of acetylcholinesterase inhibitors [15, 16].
Interestingly, the most effective way to use memantine
appears to be to administer it concurrently with an acetylchol-
inesterase inhibitor . This polypharmaceutical approach
may be better because of the now general recognition that
many neurotransmitter systems, including acetylcholine,
serotonin, norepinephrine and glutamate, are altered in AD
. There is experimental evidence supporting a role for
each of these neurotransmitters, by themselves, in cognitive
function. It may therefore be necessary to correct problems
in all of these systems to significantly improve cognition in
AD or other conditions. A practical route to achieve this goal
may be to modulate second messenger systems that are
engaged by synaptic activity.
Second messengers play a critical role in triggering
intraneuronal signaling cascades following the activation of
receptors by neurotransmitters, neuropeptides and hormones.
In particular, cyclic adenosine monophosphate (cAMP) and
cyclic guanine monophosphate (cGMP) are used for signal
transduction in virtually every pathway that has been thus far
described as playing a role in cognition. One important
consequence of increasing intracellular levels of these two
second messengers is the activation cAMP- and cGMP-
specific protein kinases, leading, via phosphorylation of a
variety of substrates, to the regulation of diverse intracellular
processes. With respect to mediating cognitive function,
substantial evidence indicates that cAMP-dependent activa-
tion of protein kinase A (PKA) or mitogen-activated protein
(MAP) kinase leads to the activation of the transcription
factor cAMP-response element binding protein (CREB),
ultimately triggering gene expression and subsequent protein
synthesis that is essential for long-term memory formation
Cyclic-AMP and -GMP are created from ATP or GTP by
the catalytic enzymes adenylyl or guanylyl cyclase, respect-
ively, and are degraded by members of a family of enzymes
called phosphodiesterases (PDEs) . A surprisingly large
number of phosphodiesterases have been identified; these
have been grouped into eleven families based upon their
sequence, substrate affinities and pharmacological proper-
ties. All PDEs have a common catalytic domain, but PDE4,
PDE7 and PDE8 are strongly selective for cAMP over
cGMP while the converse is true for PDE5 and PDE6.
Different genes encode members of a given PDE family, and
multiple isoforms of enzyme subtypes also exist, resulting in
more than fifty PDE enzymes described to date. Evidence
suggests that this seemingly excessive number of PDE
variants is localized in different subcellular compartments,
where they participate differentially in the regulation of
cAMP- or cGMP-mediated processes .
Experimental work in animal models has generated sub-
stantial support for the idea that PDE inhibition can enhance
aspects of cognition, particularly learning and memory. Most
of the work in this area has focused on the cAMP-specific
PDE4 family. Distinct genes encode four PDE4 subtypes (A,
B, C, D); multiple isoforms of each subtype bring the
number of PDE4s to at least sixteen . The mRNA for all
PDE4 subtypes is expressed in the brain, although PDE4C
expression is generally lower and shows a more restricted
pattern of distribution across brain regions than is seen for
other PDE4 subtypes . The distribution of PDE4s in the
brain is remarkably segregated, suggesting that each subtype
may have a unique functional role [24, 25]
The first evidence that cAMP-specific PDE could play a
role in learning and memory was provided by studies in the
fruit fly, Drosophila melanogaster. Fruit flies are able to
learn and remember simple associative tasks; studies of
mutant strains allowed the identification of single genes that
affect learning and memory (reviewed in ). At least three
genes that affect cAMP signaling and affect memory have
been identified in Drosophila. Flies with the dunce mutation
have a defect in a cAMP-specific PDE similar to mammalian
PDE4; other flies have mutations in genes that encode for
adenylyl cyclase or PKA. Enzyme deficiencies in the
adenylyl cyclase and PKA mutants result in reduced cAMP
signaling and memory deficits. However, the dunce PDE
mutant has substantially elevated cAMP levels. This paradox
has led to the conclusion that the ability to modulate cAMP,
rather than the baseline amount of cAMP, is key for normal
memory formation in Drosophila .
More recently, extending the genetic approach to mice
has provided evidence that PDE4D may be preferentially
involved in modulating memory . This work evaluated
mice that selectively lacked PDE4B or PDE4D genes,
generated by homologous recombination. PDE4D knockout
animals showed better long-term memory than wild-type
controls in two spatial memory tasks, the Morris water maze
and the radial arm maze. Both these tests depend upon the
hippocampus, a brain region known to be critical for long-
term memory formation  that is a target of the neuro-
pathology seen in Alzheimer’s disease . Mice lacking
PDE4B did not show improved performance in these tests,
suggesting a selective role for PDE4D in cognition.
The remainder of the evidence for a beneficial effect of
PDE4 inhibition on cognitive function has come from phar-
macological studies. Few PDE4 inhibitors are commercially
available. The best characterized of these is rolipram [(±)-4-
32] (Fig. 1), which will be the focus of the remainder of this
review. Rolipram potently inhibits all PDE4 subtypes ,
but has no known activity at other PDEs, neurotransmitter
receptors, or enzymes. (Selective inhibitors for individual
PDE4 subtypes are not currently available.) Rolipram is a
chiral molecule; the R-enantiomer is 3- to 10-fold more
potent than the S-enantiomer at inhibiting various PDE4
isoforms (Table 1). The results discussed in this review were
Fig. (1). Rolipram, a selective inhibitor of PDE4 enzymes.
Phosphodiesterase Inhibitors for Cognitive EnhancementCurrent Pharmaceutical Design, 2005, Vol. 11, No. 00 3
from studies that employed racemic rolipram unless other-
wise noted. Rolipram is well absorbed, has good bioavail-
ability in rats and in man after oral administration, and
readily crosses the blood-brain barrier. The half-life of orally
administered rolipram is 1-3 hours in all species examined
There is excellent correspondence between rolipram
binding and the distribution of PDE4 subtype mRNAs in
different regions of rat, monkey and human brain. In parti-
cular, strong rolipram binding is seen in the hippocampus,
paralleling the presence of mRNAs for PDE4A, B and D
. A potentially important aspect of rolipram binding is
that two sites, having different affinity states (the so-called
low-affinity and high-affinity rolipram binding sites, or
LARBS and HARBS), have been described in membrane
preparations from brain but not from peripheral tissues .
It appears that both the LARBS and HARBS involve
rolipram’s binding to the same catalytic site of PDE4, and
that two affinity states may not exist for other PDE4 inhi-
bitors. Unfortunately, only the HARBS is usually detected in
studies examining rolipram binding to brain sections (e.g.
) because binding to the LARBS dissociates during the
tissue processing (James O’Donnell, personal communica-
tion). Current evidence suggests that rolipram binding to the
LARBS or HARBS may regulate different components of its
pharmacological activity, with central nervous system effects
thought to be mediated primarily by the HARBS .
A major obstacle to developing effective therapeutics for
cognitive enhancement is the lack of knowledge about how
the brain carries out complex processes like learning and
remembering. However, studies in animals have identified
potential mechanisms for memory encoding. Most studied is
the phenomenon of long-term potentiation (LTP), a long-
lasting, use-dependent increase in synaptic strength. LTP
was first described in the hippocampus [38, 39] and has
many properties in common with memory [40, 41]. Rolipram
has been shown to lower the threshold for inducing hippo-
campal LTP , to restore its duration in aged mice , to
reverse the impairing effect of beta amyloid (Aβ1-42) peptide
 and to restore LTP in a transgenic mouse model of
Alzheimer’s disease . All these results are consistent with
the idea that rolipram should enhance learning and memory.
A second potential mechanism for memory encoding that
is currently receiving considerable attention is neurogenesis.
Despite early evidence to the contrary , it had long been
popularly thought that the population of neurons remained
constant in the adult central nervous system of mammals and
then declined with aging or as the consequence of neurolo-
gical diseases. Recent studies have contradicted this dogma,
demonstrating that new neurons are generated throughout the
lifespan, including in human brain [47, 48]. The hippo-
campus is one of the most active sites for adult brain
neurogenesis, and the birth of new hippocampal neurons has
been linked to memory formation [49, 50]. In addition, an
age-related decline in hippocampal neurogenesis has been
correlated with memory dysfunction . The regulation of
neurogenesis is not completely understood, but recent work
suggests that a cAMP-dependent signal transduction cascade
is among the pathways involved . In support of this idea,
rolipram treatment has been shown to enhance hippocampal
neurogenesis . Increasing neuronal proliferation or
survival provides an additional route by which rolipram
could improve cognitive function.
A number of studies have demonstrated that rolipram
can, in fact, enhance cognitive performance in animal
models. Most commonly, rolipram has been administered to
young animals to reverse behavioral impairments induced by
another drug. The first report of this effect was by Randt et
al. . In this study, young adult mice were trained in a
passive avoidance paradigm. Animals given anisomycin, a
protein synthesis inhibitor, had impaired memory for the
training experience. Rolipram reversed the amnestic effect of
anisomycin if it was administered immediately after training,
but not if it was given three hours later. Subsequent studies
reported similar rolipram-induced rescue of memory impair-
ments in passive avoidance caused by cycloheximide (another
protein synthesis inhibitor), scopolamine (a muscarinic
cholinergic antagonist) or electroconvulsive shock treatment,
but in these experiments rolipram was administered prior to
In a compelling review, Sarter et al.  compared the
activity of a number of putative cognitive enhancers in the
passive avoidance paradigm with their value in treating
cognitive impairments in humans. A notable lack of corres-
pondence between the results of rodent and human studies
led him to conclude that this model did not have predictive
validity. Given this caveat, it is encouraging that rolipram
has demonstrated efficacy in other models of pharmacol-
ogical impairment. Several studies have employed the 8-arm
radial maze, a test of spatial memory that requires the hippo-
campus . In this task, rolipram improved impairments in
both working and reference memory caused by scopolamine
or MK-801 (an NMDA receptor antagonist) [56, 60, 61].
Egawa et al. tested both (±)-rolipram and its optical
isomers, and found that the rank order for the potency of
Table 1. Inhibitory Potency of Rolipram and its Enantiomers at Human PDE4 Enzyme Isoforms and Binding to the High-
Affinity Rolipram Binding site (HARBS)
COMPOUNDPDE4A PDE4B PDE4D HARBS
(±) Rolipram103401 116 12
R-(-)-Rolipram72 27873 8.3
Values are IC50s (nM) to inhibit PDE4 enzyme activity or to displace 3H-rolipram (HARBS).
4 Current Pharmaceutical Design, 2005, Vol. 11, No. 00 Rose et al.
three compounds was consistent with their ability to inhibit
PDE4 enzymes [(-)-rolipram > (±)-rolipram > (+)-rolipram;
see Table 1]. Imanishsi et al. also reported that rolipram
reduced impairments caused by scopolamine or electrocon-
vulsive shock in a simpler 3-panel runway spatial task .
Finally, ten days of treatment with rolipram following micro-
sphere-induced embolism (a stroke model) significantly
reduced learning impairments in the Morris water maze,
another hippocampus-dependent spatial memory task .
Fewer studies have evaluated the effects of rolipram on
memory in young subjects in the absence of lesion- or
pharmacologically-induced impairments. One method of
doing this is to use a minimal training paradigm so that a
weak, rapidly decaying memory is formed. This approach
has been used to show that pretraining or immediate post-
training administration of rolipram strengthened the memory
trace for contextual fear conditioning in young mice, another
hippocampus-dependent task [20, 43]. In other work involv-
ing young adult subjects, rolipram was also shown to
enhance a weak passive avoidance memory in mice .
Ramos et al.  reported that orally administered rolipram
tended to improve prefrontal cortex-based working memory
in young rhesus monkeys, but the effect did not reach
Studies in aged animals have also shown that rolipram
can improve cognition or relieve age-related cognitive
deficits in hippocampus-dependent memory tasks. Studies by
Barad et al.  demonstrated that 18-month old C57BL6
mice performed as well as young animals in a minimal
training version of the contextual fear conditioning task. The
memory of aged mice was also improved to an equivalent
extent by pretraining rolipram administration. Another study
using aged C57BL6 mice by Bach et al.  documented the
emergence of a spatial memory impairment in a circular
platform task where the animals needed to learn which of a
number of choices provided escape from an open field. This
is a difficult task for mice, requiring several weeks of train-
ing. Less than 25% of a population of 18-month old mice
was able to learn the task, in contrast to most (>85%) 3- and
6-month old animals. However, daily rolipram treatment
beginning after two weeks of training significantly improved
the performance of aged mice to a level comparable to young
animals. In contrast to these positive results, aged rhesus
monkeys given rolipram did not show improvements in a
working memory task that requires the prefrontal cortex
. This may indicate that rolipram’s ability to enhance
memory is restricted to particular species or memory systems.
Genetically modified mice have opened new horizons in
terms of creating animal models for studying human
diseases. Some of these models have been used to further
explore the effects of rolipram on cognitive function.
Rubinstein-Taybi syndrome is a genetic disorder that results
in mental retardation and is associated with dysfunctional
expression of CREB binding protein. A mouse model of the
disease (heterozygous C-terminal truncation mutation of
CREB binding protein) showed impaired long-term memory
in passive avoidance and cued fear conditioning tasks .
These animals also showed weakened object recognition
memory compared to wild-type controls, but this deficit was
normalized by treatment with rolipram prior to training .
The effect of rolipram on memory function has also been
examined in transgenic mouse models of Alzheimer’s
disease. Tg2576 mice overexpress the Swedish mutation of
the human amyloid precursor protein. Comery et al. 
reported that 5- and 8-month old mice had deficits in
contextual fear conditioning memory compared to wild-type
littermates. Rolipram administration prior to training
significantly improved memory in both age groups. Gong et
al.  examined the effects of rolipram treatment in mice
carrying mutations of both human amyloid precursor protein
and presenilin 1 (APP-PS1). Amyloid-containing plaques
appear in the hippocampus of these mice by 3 months of age,
concomitant with impairments in contextual fear condition-
ing and in the radial arm water maze (a more difficult
version of the conventional Morris water maze; both are
spatial memory tasks). A single dose of rolipram signifi-
cantly improved fear conditioning memory in APP-PS1 mice
but did not relieve the deficit in the radial arm water maze.
However, APP-PS1 mice that were treated daily with
rolipram for 3 weeks were significantly improved when they
were tested at 6 months of age, some 2 months after the
treatment regimen ended. These results provide initial evi-
dence for the exciting possibility that PDE4 inhibitors could
induce enduring improvements in cognitive function in AD
Given the impressive preclinical evidence for rolipram’s
potential as a cognitive enhancer, it would be logical to
assume that it had been tested in humans for this effect.
However, the only published studies with rolipram in
humans have been for the treatment of depression (recently
reviewed by Renau ). Evidence is accumulating that
antidepressant drugs affect many of the same cAMP-depend-
ent pathways that are hypothesized to be involved in cogni-
tion. Several clinical trials of rolipram in depressed patients
were conducted, showing varying degrees of beneficial
effect. These trials also highlighted a previously recognized
vulnerability of rolipram: the side effect of emesis . The
ability of PDE4 inhibitors to induce nausea and vomiting is
common to all known compounds of this class [70, 71].
Although there is some evidence that tolerance develops to
this side effect, it limits the clinical utility of these agents,
including rolipram. Whether the problem of emesis can be
overcome is not yet known, but the presence of selected
PDE4 subtypes in brain regions thought to mediate emesis
(e.g., the area postrema) leaves open the possibility that
subtype-selective PDE4 inhibitors could enhance cognition
without inducing emesis.
In conclusion, developing effective treatments for cogni-
tive impairments, particularly those associated with aging
and age-related diseases, is becoming an increasingly
important goal. The limited efficacy of currently marketed
treatments may be due to properties of the particular com-
pounds (e.g., potency, selectivity or therapeutic index).
However, it is also reasonable to suggest that targeting only
one of the several neurotransmitter systems that regulate
cognitive function constrains the utility of such drugs. A
superior approach may be to manipulate second messenger
systems that represent common effector pathways, effect-
ively boosting the activity of multiple neurotransmitter
systems. The cAMP pathway is one such target. A wealth of
data indicates that PDE4 participates in cellular processes
Phosphodiesterase Inhibitors for Cognitive EnhancementCurrent Pharmaceutical Design, 2005, Vol. 11, No. 00 5 Download full-text
that modulate cognitive function and that inhibition of PDE4
can lead to enhanced memory. While substantial progress
still needs to be made to validate their utility in humans,
PDE inhibitors offer bright promise as a novel means for
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