A drug used to improve blood flow to the brain also could help
improve learning and memory and reduce the risk of Alzheimer's
disease, according to a new study released today by investigators
at the Translational Genomics Research Institute (TGen) and Arizona
State University.
Fasudil has been used for more than 10 years to help protect the
brain in stroke patients by dilating blood vessels when blood flow
is curtailed.
Now, a team of Arizona psychologists, geneticists and
neuroscientists report in today's edition of the journal Behavioral
Neuroscience that hydroxyfasudil, the active form of the parent
drug Fasudil, improved spatial learning and working memory in
middle-aged rats when negotiating a complicated maze.
The findings suggest that hydroxyfasudil may influence similar
cognitive processes in humans involving the hippocampus, a part of
the brain that has been shown to deteriorate in patients with
age-related disorders.
"If Fasudil proves to be safe and effective in enhancing learning
and memory, it could represent a viable new option for the
prophylactic treatment of disorders with a cognitive decline
component. This could include diseases like Alzheimer's as well as
general age-related impairment. In short, it may be a new
pharmaceutical weapon that could be used even before the occurrence
of symptoms," said Dr. Matthew Huentelman, an Investigator in
TGen's Neurogenomics Division.
Clinical trials are being explored in the areas of cognitive
impairment and dementia, said Huentelman, the scientific paper's
first author.
Although far from proving anything about human use of the drug, the
findings supports the scientific quest for a substance that could
treat progressive cognitive impairment, cushion the impact of
aging, or even enhance learning and memory throughout one's life
span.
"Fasudil shows great promise as a cognitive enhancer during aging,"
said Dr. Heather Bimonte-Nelson, an Assistant Professor in ASU's
Department of Psychology and the paper's lead author. "The effects
in our aging-animal model were robust, showing enhancements in both
learning and two measures of memory. The possibility that these
findings may translate to benefits to human brain health and
function is very exciting."
In the study, the researchers gave daily injections of
hydroxyfasudil to middle-aged (17-18 months old) male rats,
starting four days before behavioral testing and continuing
throughout testing. Injection made it easy to give the drug to
rats, but people take it in the form of a pill.
Rats were tested on a water radial-arm maze, which assessed how
well they remembered which of the radiating arms had a reward, a
sign of accurate spatial learning and working memory. Rats given a
high dose (0.3750 mg per kg of weight) of hydroxyfasudil
successfully remembered more items of information than those given
a low dose (0.1875 mg per kg). Both dosed groups performed
significantly better than control-group rats given saline solution.
On this same test, the high-dose group showed the best learning
(fewest total errors) and best working memory (measured two
different ways).
For every test of learning, the scores of the low-dose group fell
between the scores of the no-dose and high-dose groups, meaning
that learning and memory boosts depended on the size of the
dose.
Fasudil, is used to protect the brain by dilating blood vessels
when blood flow is curtailed. In the body, Fasudil breaks down into
the more potent hydroxyfasudil molecule, which the authors
hypothesize may alter memory by affecting the function of a gene
called KIBRA. The authors recently demonstrated that KIBRA might
play a role in memory in healthy young and late-middle-aged
humans.
Hydroxyfasudil inhibits the activity of Rho-kinase enzymes, which
have been shown to inhibit Rac, a vital protein that supports key
cellular functions. The authors speculated that blocking Rho-kinase
enables Rac, in turn, to activate more of an enzyme called protein
kinase C-zeta, which may in turn affect the KIBRA protein.
The authors received financial support from the Evelyn F. McKnight
Brain Research Foundation, the National Institute on Aging, the
National Institute of Neurological Disorders and Stroke, and the
state of Arizona. They maintain that they have no competing
financial interests. Four of the authors hold stock in Sygnis
Pharma AG, a German pharmaceutical company that owns the rights to
develop this drug class as a potential memory enhancer. They stated
that Sygnis was not directly involved in this study, did not fund
any part of it, and did not influence the decision to study these
drugs or the conclusion.
The findings appear in the February issue of Behavioral
Neuroscience, which is published by the Washington, D.C.-based
American Psychological Association.
Article: "Peripheral Delivery of a ROCK Inhibitor Improves Learning
and Working Memory," Matthew J. Huentelman, PhD, and Dietrich A.
Stephan, PhD, Translational Genomics Research Institute, Phoenix,
Arizona and Arizona Alzheimer's Consortium; Joshua Talboom, BS,
Arizona State University; Jason J. Corneveaux, BS, David M. Reiman,
undergraduate student, and Jill D. Gerber, BS, Translational
Genomics Research Institute, Phoenix, Arizona; Carol A. Barnes,
PhD, Arizona Alzheimer's Consortium and University of Arizona; Gene
E. Alexander, PhD, Arizona Alzheimer's Consortium and University of
Arizona; Eric M. Reiman, PhD, Arizona Alzheimer's Consortium and
University of Arizona; Heather A. Bimonte-Nelson, PhD, Arizona
Alzheimer's Consortium and Arizona State University, Tempe,
Arizona; Behavioral Neuroscience.
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About TGen
The Translational Genomics Research Institute (TGen) is a
non-profit organization dedicated to conducting groundbreaking
research with life changing results. Research at TGen is focused on
helping patients with diseases such as cancer, neurological
disorders and diabetes. TGen is on the cutting edge of
translational research where investigators are able to unravel the
genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen
believes it can make a substantial contribution to the efficiency
and effectiveness of the translational process. For more
information, visit: www.tgen.org.
Press Contact:
Steve Yozwiak
TGen Senior Science Writer
602-343-8704
[email protected]
Arizona State University Press Contact:
Skip Derra
(480) 965-4823
[email protected]
About the American Psychological Association
APA is the largest scientific and professional organization
representing psychology in the United States and is the world's
largest association of psychologists. APA's membership includes
more than 148,000 researchers, educators, clinicians, consultants
and students. Through its divisions in 54 subfields of psychology
and affiliations with 60 state, territorial and Canadian provincial
associations, APA works to advance psychology as a science, as a
profession and as a means of promoting human welfare.
Press Contact:
American Psychological Association
Public Affairs Office
(202) 336-5700
[email protected]