The development of improved drug treatments for Alzheimers disease AD and other agerelated neurodege

1

• Introduction
• The development of improved drug treatments for
  Alzheimers disease (AD) and other age-related
  neurodegenerative conditions remains a major
  challenge of current biomedical research. The two
  approved drug treatment strategies in clinical
  use for AD afford only modest reductions in the
  enhancement of cognition or attenuation of the
  cognitive impairment during different stages of
  the disease.
• The lack of alternative treatment options has
  stimulated novel approaches to drug discovery,
  several of which are based on the
  neuropathological features that define AD, e.g.,
  deposition of insoluble amyloid-T peptide,
  formation of neurofibrillary tangles and
  inflammatory responses leading to neuronal cell
  death (Vardy et al., 2006).
• An alternative approach is to start with events
  that contribute to the beginning stages of normal
  cognitive processing (e.g., learning and memory
  formation) and proceed systematically through the
  chain of signal transduction events that may
  become dysfunctional and eventually lead to the
  neuropathological endpoints. In this way, drug
  discovery may build upon prior knowledge that has
  obtained a certain level of justification and
  usefulness (Bartus, 2000 Bartus et al., 1982),
  or so-called proof of principle in current
  clinical practice.
• Based on this strategy, evidence suggests that
  signal transduction mechanisms that closely
  follow neurotransmitter-receptor interactions may
  be useful targets in the search for alternative
  drug treatments. Phosphodiesterase enzymes limit
  signal transduction by the second messengers,
  cyclic adenosine 3U-5U-monophosphate (cAMP)
  and/or cyclic guanosine 3U-5U-monophosphate
  (cGMP).
• Preclinical studies using PDE type 5 (PDE5)
  inhibitors that increase cGMP signaling have also
  demonstrated improved learning and memory
  performance in rodents (Blokland et al., 2006
  Devan et al., 2005 Prickaerts et al., 2004). For
  example, we have shown that the PDE5 inhibitor
  sildenafil citrate (Viagra) attenuates a complex
  maze learning impairment induced by systemic
  administration of the cholinergic muscarinic
  receptor antagonist, scopolamine (Devan et al.,
  2004) and the nonspecific nitric oxide synthase
  (NOS) inhibitor, NX-L-nitro-arginine methyl ester
  (L-NAME) (Devan et al., 2006).
• The current study will look at the influence of a
  more potent PDE-5 inhibitor Vardenafil HCl on
  spatial memory enhacement.
  

Methods Morris Water Maze Subjects 11 Long Ev
ans Hooded 11 mo. old rats 12 Long Evans Ho
oded 24 mo. old rats Apparatus The pool was a
large circular galvanized steel tank
(measurements) painted white on the inside. It
was 23 cm deep and filled with opaque white water
(25 C) to a depth of 32 cm. A video camera
located in the ceiling directly above the
apparatus sent information to a VHS recorder and
computer tracking system located in an adjacent
room (HVS ltd., Hampton, UK). Procedure 4 days
prior to the beginning of the training and 3
days during the acquisition training rats were
given 3 mg/kg of vardenafil or saline. Rats were
trained to swim to a hidden platform in the
northeast quadrant. Each rat experienced 2 blocks
of 4 trials, a total of 8 trials each per day.
The rats began each trial from a randomly
assigned start point (N, S, E, and W). All trials
were 60 sec in length. On trial day 4 the rats
were given a 60 sec swim (probe test) in the pool
with the platform removed starting form the west
location.
2

College of Liberal Arts
Preclinical Research on the Cognitive Enhancing
Effects of Phosphodiesterase (PDE) Inhibitors
Attenuation of an Age-related Spatial Memory
Impairment
Bennett Kelley-Bell, Deven Brady, Liza Benovenli
and Michael Elias Faculty Sponsor Dr. Bryan Deva
n
Department of Psychology
The Morris water maze emptied to show the hidden
platform location in relation to distal room cues
A rat standing on the hidden platform following
successful spatial localization.
Results Despite the lack of any drug effect durin
g place acquisition, aged rats that received
vardenafil showed evidence of improved retention
on a 60 sec probe test (without the escape
platform present) conducted 1 week following
learning in the new environment.
Figure 2. Mean latency (/- SEM) to find the
hidden platform during place learning in a new
environment by 24 mo rats receiving daily
injections of 0.5 mg/kg vardenafil (n7) or
saline (n6) for 1 week (4 days before and 3 days
during the task). Animals received prior
training at 6 mo of age to familiarize them with
the procedural components of the task.
3
Preliminary analyses showed that vardenafil
improved the initial heading error to the former
platform location (Fig. 3) and slightly increased
the amount of time spent in the former goal
quadrant during the 60 sec probe test (Fig. 4).
Figure 3. Mean Absolute heading error (/- SEM)
on the probe test conducted 1 week following drug
injections and the completion of place training
in the water maze.
Figure 4. Mean percent quadrant time (/- SEM)
on the probe test conducted 1 week following drug
injections and the completion of place training
in the water maze.
Accordingly, dividing the 60 sec probe test into
consecutive 20 sec time bins revealed that the
vardenafil group spent significantly more time in
the counter area (4x the platform diameter)
surrounding the former goal location during the
first 20 sec of the probe test (Fig. 5).
Figure 5. Mean percent of time (/- SEM) in the
goal area across successive 20 sec time bins on
the probe test conducted 1 week following drug
injections and the completion of place training
in the water maze.

• Conclusion
• The data suggests that vardenafil improves
  retention performance in aged rats.
  
• These findings provide pre-clinical evidence that
  PDE-5 inhibitors may attenuate age related memory
  decline.

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