Weill Cornell Medical College Advances
Edited by Herman Rosen, M.D.

New 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 atherosclerosis.

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, or angiogenesis.

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.

Histamine 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. #

Dr. Herman Rosen is Clinical Professor of Medicine at Weill Medical College of Cornell University.

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