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Roughly one third of people age 60 and over suffer from memory and
recall woes. As the average age of the U.S. population climbs, the
number of people ravaged by Alzheimer's disease and other forms of
dementia continues to rise.
"Since the development of a basic understanding of the biochemical
pathways involved in memory formation, the holy grail of CNS research
in the pharmaceutical industry is the identification of a safe, orally
active drug that activates memory-associated pathways and enhances
memory," says lead author Pamela Maher, Ph.D., a researcher in the
Cellular Neurobiology Laboratory at the Salk Institute.
Maher hit upon the beneficial effects of fisetin when she screened a
collection of flavonoids, substances with anti-oxidant activities
found in many plants, for their neuroprotective abilities in tissue
culture models of neurodegenerative disease.
Maher found that some of those compounds, including fisetin, induced
differentiation or maturation of neural cells. Maher explains, "That
suggested to us that these compounds might be particularly beneficial,
since they might not only protect neural cells from dying but might be
able to promote new connections between nerve cells."
Interestingly the signaling pathway activated by fisetin in neural
differentiation also played a role in memory formation, a process
neuroscientists call "long-term potentiation" or LTP. LTP allows
memories to be stored in the brain by strengthening connections
between neurons. "We wanted to find out whether we could detect any
effects of fisetin on long-term potentiation and the formation of
memories in animals," Maher recalls.
Since the hippocampus plays an important role in establishing new
memories, Maher, and co-authors Tatsuhiro Akaishi and Kazuho Abe, both
at Musashino University in Tokyo, Japan, extended the study and found
that fisetin activates the same signaling pathway in rat hippocampal
tissues and also induces LTP.
Next, they tested fisetin's effects in a so-called object
discrimination test in mice. The mice get to explore two objects for a
certain amount of time. The next day, one of the objects is replaced
with a novel one. If the mice remember the object from the day before,
they spend less time exploring the old one and instead turn their
attention to the novel object. Indeed, mice administered a single dose
of fisetin could better recall familiar objects. In fact, fisetin
worked almost as well as rolipram, a substance known to enhance memory.
Memory loss caused by neurodegenerative disease occurs due to loss of
neurons, a situation very different from that of healthy mice. Thus
the ultimate goal is to stop neuronal loss. Nevertheless,
memory-enhancing drugs can improve Alzheimer's disease symptoms.
The observations that fisetin protects and promotes survival of
cultured neurons and boosts memory in healthy mice make it a promising
candidate for further studies. Notes Maher, "This is the first time
that the function of a defined natural product has been characterized
at the molecular level in the central nervous system and also shown to
enhance both LTP in vitro and long-term memory in vivo."
"The good news is that fisetin is readily available in strawberries
but the bad news is that because of its natural product status there
may be little financial interest in getting it into human clinical
trials for diseases associated with memory loss such as Alzheimer's,
where the treatment options are currently very limited," says Maher.
Besides strawberries, fisetin is found in tomatoes, onions, oranges,
apples, peaches, grapes, kiwifruit and persimmons. Gingko biloba
leaves, while rich in other flavonoids, do not contain fisetin.
While eating strawberries sounds like an enjoyable alternative to
popping a pill, Maher cautions that it would take about 10 pounds a
day to achieve a beneficial effect, which might prove too much even
for the most avid strawberry lovers.
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