Cornell Medical College Advances
by Herman Rosen, M.D.
Methods of Treating and Screening From Alzheimer’s to Cancer
A new mechanism for cell survival and cell death – a paradigm
describing the regulation of the growth factors called neurotrophins–has
been discovered by scientists in the Division of Hematology–Oncology
at Weill Cornell Medical College. Their findings, recently published
in Science, have implications for new treatments and methods
of screening for conditions ranging from Alzheimer’s disease to
Neurotrophins are peptide growth factors that act upon different
cells, though the Weill Cornell scientists focused on neurons
and cells from blood vessels. Most growth factors, Dr. Barbara
L. Hempstead, Professor of Medicine, explains, exhibit a single
action on a class of cells. Some growth factors cause cells to
proliferate; others cause them to die. However, studies have demonstrated
that the neurotrophins can have complex, and even opposing, pro-survival
or pro-death actions on a cell. What Dr. Hempstead and colleagues
found was that the same class of growth factors, at different
stages of their synthesis, can have opposite effects. That is,
the initial forms of neurotrophins–or proneurotrophins – bind
to a receptor called p75, leading to apoptosis, or cell death.
Meanwhile, the mature (cleaved) neurotrophins interact with trk
(pronounced “track”) receptors, leading to cell survival, and,
when blood vessels are injured, to responses to that injury.
Recent studies in Canada suggest that some proneurotrophins are
“upregulated” in neurodegenerative diseases like Alzheimer’s.
Therefore, Dr. Hempstead’s work suggests a potential mechanism
by which diseases such as Alzheimer’s may progress, as well as
potential strategies by which a person’s risk for those diseases
might be measured, or by which the disease might even be treated.
The goal would be to find specific drugs that would lower the
levels of proneurotrophins and raise the levels of cleaved neurotrophins
in the nervous system.
The neurotrophins (molecules that were initially identified nearly
50 years ago by the scientist Rita Levi-Montelcini) can also play
a critical role in the response of blood vessels to injury. Thus,
Dr. Hempstead’s findings have important implications in atherosclerosis,
as well as for the important field of blood vessel formation,
To combat atherosclerosis, strategies using neurotrophins could
be employed to promote blood vessel growth in regions where the
blood supply has been compromised by disease.
The findings also extend to cancer. To fight cancer, a strategy
may be to promote the binding of proneurotrophins and p75 receptors
in the appropriate tissues–to promote the dying off of cancerous
cells. The investigators modified natural proneurotrophin to produce
a novel, cleavage-resistant proneurotrophin, suggesting a potential
strategy for the creation of a new kind of anti-tumor drug.
Receptor May Lead to New Therapies for Heart Attacks
When a heart attack strikes, the nerve endings in the heart release
excessive amounts of the neurotransmitter noradrenaline, leading
to arrhythmias, or disturbances of the heartbeat, with sometimes
fatal consequences. In an article in Proceedings of the National
Academy of Sciences, two scientists at Weill Cornell Medical
College – Drs. Roberto Levi and Randi Silver – report on studies
showing how the activation of a histamine receptor, the H3-receptor,
limits this release of noradrenaline via two independent systems,
based on the intracellular concentrations of calcium and sodium.
The research suggests a novel, potential therapeutic approach
to heart attack, or to myocardial ischemia in general.
Histamine is a chemical found in many tissues in the body, and
the H3–receptor is the third important receptor to have been discovered
for it. The H1-receptor produces allergies, and blocking this
receptor is how antihistamines work. The H2-receptor is involved
in the secretion of stomach acid and its discovery has led to
remedies for duodenal ulcer. The H3-receptor may prove to be as
important as the first two if Drs. Levi and Silver’s research
leads to practical results.
The authors observed the results of exposing neuroblastoma cells
to an H3-receptor agonist (a chemical that activates the receptor)
and to an H3-receptor antagonist (a chemical that blocks the receptor).
The receptor proved to be necessary for the limiting of both noradrenaline
release and calcium intake to the cells. The activated receptor
inhibits the entry of sodium and calcium into cells.
Thus, to limit the release of noradrenaline and the consequent
risk of arrhythmia in the event of ischemia, the research suggests
a potential strategy of stimulating the H3-receptor.
Dr. Levi adds that it is important to put the relationship between
arrhythmia and histamine in perspective. Severe arrhythmias can
result from the release of large amounts of histamine which stimulates
the heart’s H2-receptors when there is a massive allergic reaction.
In most myocardial ischemia, only a small amount of histamine
is released in the heart, and its effect on the H3-receptors is
favorable, tending to reduce the release of noradrenaline. The
H3-receptor needs only a little histamine to be stimulated, whereas
the H2-receptor needs much more, and the H1-receptor still more.
Herman Rosen is Clinical Professor of Medicine at Weill Medical
College of Cornell University.
Education Update, Inc., P.O. Box 20005, New York, NY 10001. Tel:
(212) 481-5519. Fax: (212) 481-3919. Email: email@example.com.
All material is copyrighted and may not be printed without express consent of
the publisher. © 2001.